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 technical field of pharmaceuticals, and particularly relates to novel substituted nitrogen-containing bicyclic compounds and pharmaceutical compositions comprising these compounds, as well as their methods of use and applications. In particular, the novel substituted nitrogen-containing bicyclic compounds described in the present invention can be used to inhibit PARP1 and for the prevention, treatment or alleviation of diseases mediated by PARP1, especially cancer. Background Art

[0002] Cancer refers to a malignant tumor originating from epithelial tissue and is the most common type of malignant tumor. Generally, the term "cancer" as commonly used by people refers to all malignant tumors in general. Cancer is a group of diseases characterized by abnormal cell differentiation and proliferation. In the advanced stage, it spreads to other regions of the body, including bones and vital organs. Cancer has biological characteristics such as abnormal cell differentiation and proliferation, uncontrolled growth, metastasis and invasiveness. Its occurrence is a complex process involving multiple factors and multiple steps, which can be divided into three processes: carcinogenesis, tumor promotion, and progression. The etiology of malignant tumors has not been fully understood, but it is closely related to infections, smoking, occupational exposure, environmental pollution, genetic factors, and unreasonable diet.

[0003] Cancer is one of the major diseases that endanger human health and undermine family and social harmony. It is a major global health problem and remains a leading cause of death. Since 2010, cancer has ranked second among the factors causing human death, second only to cardiovascular and cerebrovascular diseases. The global cancer incidence situation is becoming increasingly severe, with both the incidence and mortality rates continuing to rise. According to the speculation of relevant institutions, with the growth and aging of the population, as well as the development of society and the formation of bad living habits, in the next 20 years, the number of newly diagnosed cancer cases globally may reach as high as 22 million per year, and the number of deaths caused by cancer during the same period may also soar to 13 million per year. Approximately 60% of the newly diagnosed cancer cases globally occur in developing countries, and the annual mortality rate also accounts for 70% of the global total.

[0004] Although significant progress has been made in the feasibility of various treatment options for cancer, the currently available chemotherapy is still unsatisfactory, and the prognosis for most patients diagnosed with cancer remains bleak. Therefore, the research and development of new anti-tumor drugs (or anti-cancer drugs) is of great significance.

[0005] Poly(ADP)-ribose polymerase (PARP) is a type of nuclear enzyme that catalyzes ADP ribosylation and widely exists in eukaryotic cells. There are at least 18 subtypes, all of which contain the highly conserved PARP catalytic sequence. According to the degree of modification of ADP ribosylation it catalyzes, it can be divided into three categories: The first category catalyzes the formation of long-chain and branched poly(ADP-ribose) chains (PAR), including PARP1, PARP2, Tank1, and Tank2; the second category catalyzes the formation of mono(ADP-ribosyl)transferases (MAR), including PARP3, 4, 6-8, 10-12, 14-16; the third category does not have enzymatic catalytic ability, including PARP9 and PARP13. Although these subtypes all have similar catalytic domains, only PARP1 and PARP2 subtypes contain DNA-binding domains, which can bind to damaged DNA and repair the damaged DNA through the base excision repair (BER) pathway. Among them, PARP1 was the first to be discovered, has the highest content in cells, accounting for 85% - 90% of the total PARP activity in cells. It mainly participates in DNA damage repair, is the most important PARP enzyme, and is also the most deeply studied and widely used subtype, which is involved in the treatment of diseases such as cancer, stroke, inflammation, diabetes, myocardial ischemia, and neurodegenerative diseases.

[0006] PARP1 is composed of 1014 amino acid residues with a relative molecular mass of 116 kDa. Its primary structure is highly conserved in eukaryotes (for example, the amino acid sequences of humans and mice have 92% homology), including three domains: the C-terminal catalytic domain, the middle auto-regulatory domain (AD), and the N-terminal domain (DBD). Among them, the C-terminal catalytic domain includes two active catalytic sites: the supply domain and the acceptor domain; the middle auto-regulatory domain includes two closely linked nuclear localization signal sequences and has Caspase-3 cleavage function; the N-terminal domain includes three zinc finger motifs.

[0007] PARP1 and PARP2 have very similar structures and are important protein modification enzymes involved in DNA damage repair, and are highly expressed in a variety of tumors. Among them, the PARP1 subtype plays an important role in the DNA damage repair pathway and undertakes 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 the growth of tumors. In recent years, several PARP1 inhibitor drugs have been approved for marketing, and several PARP1 inhibitor drugs have entered the clinical research stage. Thus, PARP1 inhibitors have become one of the hotspots in the research and development of anti-tumor drugs.

[0008] The mechanism of action of PARP1 inhibitors in tumors is complex and diverse, mainly including the synthetic lethality theory, the theory of participating in DNA damage repair in tumor cells, and the theory of participating in the regulation of nuclear factor-κB (NF-κB) and heat shock protein 70 (HSP70) in tumor cells. Although the mechanism of action of PARP1 inhibitors has not been fully clarified, the tumor-suppressing effect they exert has brought new hope for the treatment of tumors.

[0009] Since many chemotherapeutic drugs exert their anti-tumor effects by damaging the DNA structure of tumor cells, and tumor cells can repair the damaged DNA with the help of PARP1, counteracting chemotherapeutic drugs and thus developing drug resistance. Therefore, PARP1 inhibitors can be used as sensitizers and combined with other chemotherapeutic drugs to overcome drug resistance and improve the curative effect. At the same time, studies have also found that using PARP1 inhibitors alone on tumor cells with BRCA1 / 2 (breast cancer 1 / 2) deletion or mutation can also produce good anti-tumor effects.

[0010] Compared with other clinical PARP1 / 2 inhibitors, PARP inhibitors with increased selectivity for PARP1 have the advantages of improved efficacy and reduced toxicity. And strong selective inhibition of PARP1 will lead to the capture of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) by collapsing the replication forks in the S phase. PARP1-DNA capture 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 with selectivity for PARP1.

[0012] Through continuous and unremitting research efforts, the inventors have obtained a class of unexpected new highly selective PARP1 inhibitors. The substituted nitrogen-containing bicyclic compounds described in the present invention have strong PARP1 inhibitory activity and can therefore be used to treat diseases mediated by PARP1, especially cancer. Summary of the Invention

[0013] The present invention provides a novel class of substituted nitrogen-containing bicyclic compounds as highly selective PARP1 inhibitors, which can be used to inhibit PARP1 and thus can be used to treat diseases mediated by PARP1, especially for the treatment of cancer. And through experiments, it is found that the substituted nitrogen-containing bicyclic compounds of the present invention have stable properties, good safety, and good pharmacodynamic and pharmacokinetic properties, such as good brain / plasma ratio, good bioavailability or good metabolic stability, etc. Therefore, it has good prospects for clinical application.

[0014] The present invention also provides a method for preparing such compounds, a pharmaceutical composition containing such compounds, and the use of such compounds and the pharmaceutical composition containing such compounds in the preparation of drugs.

[0015] On the one hand, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

[0016]

[0017] wherein: X is CR x or N;

[0018] is a 3- to 12-membered heterocyclic group;

[0019] R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-C(=O)NH 2 、-C(=O)NHCH 3 、

[0020] -C(=O)N(CH 3 ) 2 、-C(=O)-(C 1 -C 6 alkyl), -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl or 3- to 8-membered heterocyclic group;

[0021] Each R 2a and R 2b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl), -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6 -C 10 aryl or 5- to 10-membered heteroaryl;

[0022] R 2 is -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2, -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6

[0023] alkyl), -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 8 cycloalkyl-L-, 3-8 membered heterocyclic-L-, C 6 -C 10 aryl-L- or 5-10 membered heteroaryl-L-; wherein, said R 2 is unsubstituted or substituted by 1, 2, 3, 4 or 5 R w ;

[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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic, C 6 -C10 an aryl or a 5- to 10-membered heteroaryl;

[0027] each R a and R b are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1 -C 6 hydroxyalkyl;

[0028] each R 3 , R 3a and R 3b are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl), -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C6 Alkylamino or C 1 -C 6 Hydroxyalkyl;

[0029] R 4 is H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Halogenated alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 Aryl or 5-10 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, -OH, -NH 2 、-NO 2 、-CN、C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, C 1 -C 6 Alkoxy and C 1 -C 6 Groups of halogenated alkoxy;

[0030] Each R x and R z are independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(=O)NH 2 、C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, C 1 -C6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 hydroxyalkyl;

[0031] Each R w is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl), -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -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] In another embodiment, is

[0035]

[0036] Among them, * represents connecting -CH on the left 2 -, and ** represents connecting the pyridyl group on the right.

[0037] In one embodiment, R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 hydroxyalkyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclic group;

[0038] Each R 3 , R 3a and R 3b independently is H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkoxy), C 1 -C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino or C 1 -C 4 hydroxyalkyl;

[0039] each R x and R z is independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH, -COOH, -C(=O)NH 2 、C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 hydroxyalkyl.

[0040] In another embodiment, R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH, -SH, -COOH, -C(=O)NH 2 、-C(=O)NHCH 3 、-C(=O)N(CH 3 ) 2 、-C(=O)-CH 3 、-C(=O)-OCH 3 、methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CF 3 、-CH2 CF 2 CHF 2 , methoxy, ethoxy, n - propyloxy, isopropyloxy, - OCHF 2 , - OCF 3 , - OCHFCH 2 F, - OCF 2 CHF 2 , - OCH 2 CF 3 , - OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2 - hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl or morpholinyl;

[0041] Each R 3 , R 3a and R 3b is independently H, D, F, Cl, Br, I, - CN, - NO 2 , - NH 2 , - OH, - SH, - COOH, - C(=O)NH 2 , - C(=O)NHCH 3 , - C(=O)N(CH 3 ) 2 , - C(=O)-CH 3 , - C(=O)-OCH 3 , methyl, ethyl, n - propyl, isopropyl, allyl, propenyl, propargyl, propynyl, - CHF 2 , - CF 3 , - CHFCH 2 F, - CF 2 CHF 2 , - CH 2 CF 3 , - CH 2 CF 2 CHF 2 , methoxy, ethoxy, n - propyloxy, isopropyloxy, - OCHF 2 , - OCF 3 , - OCHFCH 2 F, - OCF 2 CHF 2 , - OCH 2 CF 3 , - OCH 2 CF 2 CHF 2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl;

[0042] Each R x and R z are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -COOH, -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , hydroxymethyl or 2-hydroxyethyl.

[0043] In one embodiment, R 4 is H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic group, C 6 -C 10 aryl or 5-6 membered heteroaryl, wherein the C 1 -C 4Alkyl, C 3 -C 6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 6 -C 10 Aryl and 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy and C 1 -C 4 Haloalkoxy groups.

[0044] In another embodiment, R 4 is H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, 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, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, -OH, -NH 2 , -NO 2 , -CN, methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 and -OCH 2 CF 2 CHF 2 .

[0045] In one embodiment, each R 2a and R 2b are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4(alkyl), -C(=O)-(C 1 -C 4 (alkoxy), C 1 -C 4 (alkyl), C 2 -C 4 (alkenyl), C 2 -C 4 (alkynyl), C 1 -C 4 (haloalkyl), C 1 -C 4 (alkoxy), C 1 -C 4 (haloalkoxy), C 1 -C 4 (alkylthio), C 1 -C 4 (alkylamino), C 1 -C 4 (hydroxyalkyl), C 1 -C 4 (cyanoalkyl), C 3 -C 6 (cycloalkyl), 3- to 6-membered heterocyclic group, C 6 -C 10 (aryl) or 5- to 6-membered heteroaryl.

[0046] In one embodiment, each R n and R n1 is independently H, D, C 1 -C 4 (alkyl), C 1 -C 4 (haloalkyl), C 3 -C 6 (cycloalkyl), 3- to 6-membered heterocyclic group, C 6 -C 10 (aryl) or 5- to 6-membered heteroaryl;

[0047] Each R a and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、C 1 -C 4 (alkyl), C 2 -C 4 (alkenyl), C 2 -C 4 (alkynyl), C 1 -C 4 (haloalkyl), C 1 -C 4 (alkoxy), C 1 -C 4 (haloalkoxy), C1 -C 4 alkylthio, C 1 -C 4 alkylamino or C 1 -C 4 hydroxyalkyl.

[0048] In one embodiment, R 2 is -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2- C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 3 -C 6 cycloalkyl-L-, 3-6 membered heterocyclic-L-, C 6 -C 10 aryl-L- or 5-6 membered heteroaryl-L-; wherein, said R 2 is unsubstituted or substituted by 1, 2, 3, 4 or 5 R w ;

[0049] Each R w is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2, -C(=O)-(C 1 -C 4 -alkyl), -C(=O)-(C 1 -C 4 -alkoxy), C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, 3-6 membered heterocyclic group, C 6 -C 10 -aryl or 5-6 membered heteroaryl;

[0050] Each L has the meaning as described in the present invention.

[0051] In one embodiment, each R 2a and R 2b are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 2 -alkyl), -C(=O)-(C 1 -C 2 -alkoxy), methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2, methoxy, ethoxy, n - propyloxy, isopropyloxy, - OCHF 2 , - OCF 3 , - OCHFCH 2 F, - OCF 2 CHF 2 , - OCH 2 CF 3 , - OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2 - hydroxyethyl, cyanomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indanyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0052] In one embodiment, each R n and R n1 is independently H, D, methyl, ethyl, n - propyl, isopropyl, n - butyl, tert - butyl, - CHF 2 , - CF 3 , - CHFCH 2 F, - CF 2 CHF 2 , - CH 2 CF 3 , - CH 2 CF 2 CHF 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

[0053] Each R a and R b is independently H, D, F, Cl, Br, I, - CN, - NO 2 , - NH 2 , - OH, - SH, methyl, ethyl, n - propyl, isopropyl, allyl, propenyl, propargyl, propynyl, - CHF 2 , - CF 3 , - CHFCH 2 F, - CF 2 CHF 2 , - CH 2 CF 3 , - CH 2 CF2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl.

[0054] In one embodiment, R 2 is -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-OCH 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L-, cyclopentyl-L-, cyclohexyl-L-, oxiranyl-L-, aziridinyl-L-, oxetanyl-L-, azetidinyl-L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolyl-L-, furyl-L-, thienyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-; wherein the R 2Unsubstituted or substituted by 1, 2, 3, 4 or 5 R w substituents;

[0055] Each R w is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 3 alkyl), -C(=O)-(C 1 -C 3 alkoxy), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; each L has the definition as described in the present invention.

[0056] 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, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II) or formula (III),

[0057]

[0058] Among them, each R 1 , R 2 , R 2a , R 2b , R 3 , R z , R 4 and n have the meanings as described in the present invention.

[0059] In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having one of the following structures, but not limited to:

[0060]

[0061]

[0062] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound represented by formula (I), (II) or (III) disclosed in the present invention.

[0063] In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0064] In yet 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 a disease mediated by PARP1.

[0065] 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.

[0066] In yet another embodiment, 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, urogenital tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and / or monocytic leukemia.

[0067] In another aspect, the present invention relates to the use of the compounds represented by formula (I), (II) or (III) disclosed in the present invention or their pharmaceutical compositions in the preparation of a drug for inhibiting PARP1.

[0068] On the other hand, the present invention relates to a method for preparing, separating and purifying the compounds represented by formula (I), (II) or (III).

[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 corresponding technical feature in other embodiments as long as they do not conflict.

[0070] The foregoing only outlines certain aspects of the present invention but is not limited to these aspects. The content of these aspects and other aspects will be described more specifically and completely below. All references in this specification are hereby incorporated by reference in their entirety. When there is a difference between the disclosure of this specification and the cited literature, 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 will now be described in detail, and examples thereof are illustrated by the accompanying structural formulas and chemical formulas. The present invention is intended to cover all alternative, modified and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is in no way limited to the methods and materials described in the present invention. In the case where one or more of the incorporated documents, patents and similar materials are different from or conflict with the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0074] It should be further recognized that certain features of the present invention are described in multiple separate embodiments for clarity, but can also be provided in combination in a single embodiment. Conversely, various features of the present invention are described in a single embodiment for brevity, but can also be provided separately or in any suitable sub-combination.

[0075] Unless otherwise indicated, the following definitions apply to the use of the present invention. For the purposes of the present invention, chemical elements are in accordance with the CAS version of the Periodic Table of the Elements and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be referred to the descriptions 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 there is an obvious conflict in the context, the articles "a", "an" and "the" used in the present invention are intended to include "at least one" or "one or more". Therefore, these articles used in the present invention refer to articles of one or more (i.e., at least one) objects. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the implementation of the said embodiment.

[0077] The term "stereoisomer" refers to compounds having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0078] The term "chiral molecule" is a molecule that has the property of not being superimposable on its mirror image; while an "achiral molecule" refers to a molecule that can be superimposed on its mirror image.

[0079] The term "enantiomer" refers to two non-superimposable but mirror-image isomers of a compound.

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

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

[0082] The stereochemical definitions and rules used in this invention generally follow S.P. 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. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one or more chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify 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 a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

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

[0084] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one of the possible isomers or a mixture thereof, such as a racemate and a mixture of diastereomers (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 substituents on the cycloalkyl may have cis or trans configurations.

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

[0086] The racemate of any resulting end product or intermediate can be resolved into its optical enantiomers by known methods familiar to those skilled in the art, e.g., by separating the diastereomeric salts obtained therefrom. The racemic product can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the 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 nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0087] The terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that can interconvert with each other via a low energy barrier. If tautomerization 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 that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0088] “Pharmaceutically acceptable” means those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of a patient without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended uses.

[0089] The term "optionally substituted with..." can be used interchangeably with the term "unsubstituted or substituted with...", that is, the structure is unsubstituted or substituted with one or more substituents described in the present invention. The substituents described in the present invention include, but are not limited to, D, F, Cl, Br, I, N 3 , -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -CONH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-alkyl, -C(=O)-alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxyalkyl, cyanoalkyl, aminoalkyl, (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclic)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene, cycloalkyl, heterocyclic, aryl, heteroaryl, etc.

[0090] Generally, the term "substituted" means that one or more hydrogen atoms in the given structure or group are replaced by specific substituents. Unless otherwise indicated, a substituent can be substituted at each reasonable substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more specific substituents selected, the substituents can be the same or different and can be substituted at each reasonable position in the structural formula.

[0091] In addition, it should be noted that unless otherwise explicitly indicated, in the present invention, the description methods "each... independently is", "... each independently is" and "... independently is" can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0092] The term "subject" used in the present invention refers to an animal. Typically, the animal is a mammal. The subject also refers to, for example, a primate (such as a human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

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

[0095] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group types or ranges. In particular, it is pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1 -C 6 alkyl" specifically refers to methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl independently disclosed.

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

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

[0098] The terms "halogen" and "halo" are used interchangeably in the present invention and 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 oxidized form of N, S and P; the form of primary, secondary, tertiary amines and quaternary ammonium salts; or the form in which the hydrogen on the nitrogen atom in the heterocycle 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, where R' is a substituent described in the present invention).

[0100] The term "alkyl" or "alkyl group" used in the present invention represents a saturated straight-chain or branched-chain monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group can optionally be substituted by one or more substituents described in the present invention. In one embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1-4 carbon atoms; and in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3), isopropyl (i-Pr, -CH(CH 3 )) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 )) 2 ), sec-butyl (s-Bu, -CH(CH 3 ))CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 )) 3 ), and so on.

[0101] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1-12 carbon atoms. In one embodiment, the alkylene radical contains 1-6 carbon atoms; in another embodiment, the alkylene radical contains 1-4 carbon atoms; in yet another embodiment, the alkylene radical contains 1-3 carbon atoms; still in one embodiment, the alkylene radical contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 ))CH 2 -), and so on. The alkylene radical is optionally substituted by one or more substituents described in the present invention.

[0102] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical containing 2-12 carbon atoms, having at least one unsaturated site, i.e., having a carbon-carbon sp 2 double bond, wherein the alkenyl radical can be optionally substituted by one or more substituents described in the present invention, including the "cis" and "trans" configurations, or the "E" and "Z" configurations. In one embodiment, the alkenyl radical contains 2-8 carbon atoms; in another embodiment, the alkenyl radical contains 2-6 carbon atoms; in yet another embodiment, the alkenyl radical contains 2-4 carbon atoms. Examples of alkenyl radicals include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (i.e., propenyl, -CH=CH-CH 3 ), and so on.

[0103] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing 2 to 12 carbon atoms, having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in the present invention. 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 (-CH 2 C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH 3 ), and the like.

[0104] The term "alkoxy" means that an alkyl group is linked to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in the present invention.

[0105] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), and the like.

[0106] The term "alkylthio" means that an alkyl group is connected to the rest of the molecule through a sulfur atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may optionally be substituted by one or more substituents described in the present invention.

[0107] Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH 3 ), ethylthio (EtS, -SCH 2 CH 3 ), 1-propylthio (n-PrS, n-propylthio, -SCH 2 CH 2 CH 3 ), 2-propylthio (i-PrS, i-propylthio, -SCH(CH 3 ) 2 ), 1-butylthio (n-BuS, n-butylthio, -SCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH 2 CH(CH 3 ) 2 ), 2-butylthio (s-BuS, s-butylthio, -SCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC(CH 3 ) 3 ), and so on.

[0108] The term "alkylamino" or "alkylamino group" includes "N-alkylamino" and "N,N-dialkylamino", where the amino group is independently substituted by one or two alkyl groups, and the alkyl group has the meaning as described in the present invention. Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), and so on. The alkylamino group is optionally substituted by one or more substituents described in the present invention.

[0109] The term "hydroxyalkyl" means that an alkyl group is substituted by one or more hydroxyl groups, where the alkyl group has the meaning as described in the present invention; 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" means that an alkyl group is substituted by one or more cyano groups, where the alkyl group has the meaning as described in the present invention; 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" means that an alkyl group is substituted by one or more amino groups, where the alkyl group has the meaning as described in the present invention; 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 that an alkyl group is substituted by one or more halogen atoms, where the alkyl group has the meaning as described in the present invention, and such examples include, but are not limited to, -CHF 2 、-CF 3 、-CHFCH 2 F、-CF 2 CHF 2 、-CH 2 CF 3 、-CHFCH 3 、-CH 2 CH 2 F、-CF 2 CH 3 、-CH 2 CF 2 CHF 2 and the like. In one embodiment, C 1 -C 6 haloalkyl contains fluorine-substituted C 1 -C 6 alkyl; in another embodiment, C 1 -C 4 haloalkyl contains fluorine-substituted C 1 -C 4 alkyl; in yet another embodiment, C 1 -C 2 haloalkyl contains fluorine-substituted C 1 -C 2 alkyl.

[0113] The term "haloalkoxy" means that the alkoxy group is substituted by one or more halogen atoms, where the alkoxy group has the meaning as described in the present invention. Such examples include, but are not limited to, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCH 2 CH 2 F, -OCF 2 CH 3 , -OCH 2 CF 2 CHF 2 and so on. In one embodiment, the C 1 -C 6 haloalkoxy contains a fluorine-substituted C 1 -C 6 alkoxy; in another embodiment, the C 1 -C 4 haloalkoxy contains a fluorine-substituted C 1 -C 4 alkoxy; in yet another embodiment, the C 1 -C 2 haloalkoxy contains a fluorine-substituted C 1 -C 2 alkoxy.

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

[0115] The terms “(alkoxy)-alkylene”, “(alkylamino)-alkylene”, “(cycloalkyl)-alkylene”, “(heterocyclic)-alkylene”, “(aryl)-alkylene”, “(heteroaryl)-alkylene” mean that the alkoxy, alkylamino, cycloalkyl, heterocyclic, aryl or heteroaryl groups are each independently linked to the remainder of the molecule through an alkylene group, wherein the alkoxy, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl and alkylene groups each have the meanings described in the present invention. For example, examples of (cycloalkyl)-alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, etc. For another example, examples of (aryl)-alkylene include, but are not limited to, phenylmethylene, phenylethylene, phenylpropyl, etc. The (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclic)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene are each independently optionally substituted by one or more substituents described in the present invention.

[0116] The term “carbocyclic group” or “carbocycle” means a monocyclic, bicyclic or tricyclic system, which is non-aromatic, saturated or partially unsaturated, and has a valence of one or more and contains 3-12 carbon atoms. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. In one embodiment, the carbocyclic group contains 3-10 carbon atoms, such as C 3- C 10 carbocyclic group; in another embodiment, the carbocyclic group contains 3-8 carbon atoms, such as C 3- C 8 carbocyclic group; in yet another embodiment, the carbocyclic group contains 3-6 carbon atoms, such as C 3- C 6 carbocyclic group. In another embodiment, the monocyclic carbocyclic group contains 4-8 carbon atoms, such as C 4- C 8 monocyclic carbocyclic group; in yet another embodiment, the monocyclic carbocyclic group contains 4-6 carbon atoms, such as C 4- C 6 monocyclic carbocyclic group. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The carbocyclic groups are 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 system containing 3 to 12 carbon atoms. The bicyclic or tricyclic system may include fused rings, bridged rings and spiro rings. In one embodiment, the cycloalkyl contains 3 to 10 carbon atoms, such as C 3- C 10 cycloalkyl; in another embodiment, the cycloalkyl contains 3 to 8 carbon atoms, such as C 3- C 8 cycloalkyl; in yet another embodiment, the cycloalkyl contains 3 to 6 carbon atoms, such as C 3- C 6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Among them, as described in the present invention, C 3- C 8 cycloalkyl includes C 3- C 6 cycloalkyl; the C 3- C 6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group is optionally substituted by one or more substituents described in the present invention.

[0118] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and both refer to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing 3 to 12 ring atoms, wherein one or more atoms on the ring are independently replaced by heteroatoms having the meaning as described in the present invention. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group composed of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 ); in yet another embodiment, the heterocyclic group is a monocyclic heterocyclic group composed of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 ); in another embodiment, the heterocyclic group is a bicyclic heterocyclic group composed of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 . The heterocyclic group is optionally substituted by one or more substituents described in the present invention.

[0119] The ring atoms of the heterocyclic group can be carbon groups or heteroatoms. 2 The - group is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to an S-oxide, and the nitrogen atom of the ring is optionally oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to, oxirane, 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 yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. -CH 2 Examples of -groups substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone, 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 carbon 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, wherein each ring system contains a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through 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 described in the present invention.

[0121] ​​​The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic 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, and each ring system contains a ring composed of 5 - 7 atoms. The heteroaryl group is generally, 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", "aromatic heterocycle", or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, the heteroaryl composed of 5 - 10 atoms 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, 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 - thiadiazolyl, 1,3,4 - thiadiazolyl, 1,2,5 - thiadiazolyl, pyrazinyl, 1,3,5 - triazinyl; also include the following bicyclics, but are by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2 - indolyl), purinyl, quinolinyl (such as 2 - quinolinyl, 3 - quinolinyl, 4 - quinolinyl), isoquinolinyl (such as 1 - isoquinolinyl, 3 - isoquinolinyl or 4 - isoquinolinyl), imidazo[1,2 - a]pyridyl, pyrazolo[1,5 - a]pyridyl, pyrazolo[1,5 - a]pyrimidinyl, imidazo[1,2 - b]pyridazinyl, [1,2,4]triazolo[4,3 - b]pyridazinyl, [1,2,4]triazolo[1,5 - a]pyrimidinyl, [1,2,4]triazolo[1,5 - a]pyridyl, and so on.

[0123] The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacting with other functional groups. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" is a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl, and benzyl. A "carboxy protecting group" is a substituent of a carboxy group used to block or protect the functionality of the carboxy group, and common carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and so on. General descriptions of protecting groups can be found in the literature: 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 represents a compound that is converted in vivo to a compound represented by formula (I), (II), or (III). Such conversion is affected by the hydrolysis of the prodrug in the blood or its enzymatic conversion to the parent structure in the blood or tissues. The prodrug compounds of the present invention can be esters, and in the existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in the present invention containing a hydroxy group can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylating the hydroxy groups on the parent compound.

[0125] "Metabolite" refers to the product obtained by the metabolic action of a specific compound or its salt in vivo. The metabolites of a compound can be identified by techniques well-known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compounds, including the metabolites produced by bringing the compounds of the present invention into sufficient contact with a mammal for a period of time.

[0126] "Pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in books and literature such as ion exchange method to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. The salts obtained by appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4Salts. The present invention also contemplates quaternary ammonium salts formed from compounds of any group containing N. Water-soluble, 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 with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -C 8 Sulfonates and aromatic sulfonates. Although other salts can be used, for example, in the separation or purification of products, non-toxic physiologically acceptable salts are preferred.

[0127] These salts can be formed by conventional means, for example, by reacting the free base form of the product with an equivalent of one or more appropriate acids in a solvent or medium in which the salt is insoluble, or in a solvent (such as a solvent from which water is removed in vacuo), or by lyophilization, or by exchanging the anion of an existing salt for another anion on a suitable ion exchange resin.

[0128] The "solvate" of the present invention refers to an association formed by one or more solvent molecules with the compounds 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 in which the solvent molecule is water.

[0129] When the solvent is water, the term "hydrate" can be used. In one embodiment, a molecule of a compound of the present invention can combine with one water molecule, such as a monohydrate; in another embodiment, a molecule of a compound of the present invention can combine with more than one water molecule, such as a dihydrate; in yet another embodiment, a molecule of a compound of the present invention can combine 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 compound in the non-hydrated form.

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

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

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

[0133] In the structures disclosed in the present invention, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of the structure are contemplated within the present invention and are included in the present invention as the disclosed compounds. When the stereochemistry is specified by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of the structure are thereby defined and specified.

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

[0135] The compounds represented by formula (I), (II), or (III) can exist in the form of salts. In one embodiment, the salts refer to pharmaceutically acceptable salts. 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 mammalian subject being treated therewith. In another embodiment, the salts are not necessarily pharmaceutically acceptable salts and can be intermediates for the preparation and / or purification of the compounds represented by formula (I), (II), or (III) and / or for the separation of the enantiomers of the compounds represented by formula (I), (II), or (III).

[0136] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, in appropriate cases, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Lists of additional 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 in the present invention is also intended to represent both the non-isotope-enriched form and the isotope-enriched form of these compounds. The isotope-enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight 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] On the other hand, the present invention relates to intermediates for the preparation of the compounds of formula (I), (II) or (III).

[0139] On the other hand, the present invention provides a pharmaceutical composition, which comprises the 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 the form of a liquid, solid, semi-solid, gel or spray.

[0140] Pharmaceutical Compositions, Formulations and Administration of the Compounds of the Invention

[0141] 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 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 prophylactic ingredients.

[0142] The dosage form of the compound used in the method of the present invention can be determined by the specific compound selected, the type of pharmacokinetic distribution required by the route of administration, and the condition of the patient.

[0143] Preparations suitable for oral, sublingual, intranasal or parenteral administration are prepared by known methods in the pharmaceutical art and contain at least one active compound. See, for example, REMINGTON′S PHARMACEUTICAL SCIENCES (16th ed. 1980).

[0144] Generally, the preparations of the present invention comprise an active ingredient (compound represented by formula (I), (II) or (III)) and are usually admixed with, diluted by or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as an excipient, carrier or medium for the active ingredient. Thus, the preparations can be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions and sterile packaged powders.

[0145] In the preparation of the preparations, it may be necessary to grind the active compound to provide a suitable particle size before mixing with other components. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, its particle size is adjusted by grinding to provide a uniform particle size distribution in the preparation, for example, about 40 mesh. In one embodiment of the present invention, the particle size is about 0.1 - 100 μm.

[0146] Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel H.C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0147] As used herein, “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition upon mixing to avoid interactions that would significantly reduce the efficacy of the disclosed compounds of the present invention upon administration to a patient and / or that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, e.g., having a sufficiently high purity.

[0148] Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients can be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients can be selected that aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected that aid in the production of a stable dosage form. Certain pharmaceutically acceptable excipients can be selected that aid in the delivery or transport of the compounds of the present invention from one organ or part of the body to another organ or part of the body upon administration to a patient. Certain pharmaceutically acceptable excipients can be selected that enhance patient compliance.

[0149] Examples of some suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, 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, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives (such as methyl paraben and propyl paraben), stabilizers, surfactants, and buffering agents. One skilled in the art will recognize that certain pharmaceutically acceptable excipients can provide more than one function and provide alternative functions, depending on how much of the excipient is present in the formulation and what other excipients are present in the formulation. Known methods in the art can be employed to formulate the compounds of the present invention so as to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0150] One skilled in the art has the knowledge and skills in the art to enable them to select the appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to one skilled in the art that describe pharmaceutically acceptable excipients and are used to select 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).

[0151] For the preparation of pharmaceutical compositions with the compounds described in the present invention, pharmaceutically acceptable carriers can be either solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, 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 the following: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th th ed., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

[0152] Disclosures of various carriers for formulating pharmaceutically acceptable compositions and well-known techniques for their preparation are found 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, the contents of each of which are incorporated herein by reference. The use of carriers, except for any conventional carrier that is incompatible with the compounds of the present invention, such as by producing any undesired biological effects or interacting in a harmful manner with any other component in a pharmaceutically acceptable composition, is within the scope of the present invention.

[0153] The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. Descriptions of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0154] Accordingly, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising the compound disclosed in the present invention can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

[0155] 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.

[0156] It should also be recognized that certain compounds of the present invention may exist in free form for treatment, 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, can directly or indirectly provide the compounds of the present invention or their metabolites or residues.

[0157] In one embodiment, the compounds disclosed in the present invention can be formulated into oral dosage forms. In another embodiment, the compounds disclosed in the present invention can be formulated into inhalation dosage forms. In another embodiment, the compounds disclosed in the present invention can be formulated into nasal dosage forms. In yet another embodiment, the compounds disclosed in the present invention can be formulated into transdermal dosage forms. In yet another embodiment, the compounds disclosed in the present invention can be formulated into topical dosage forms.

[0158] The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, powdered tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredients from contacting 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 can help mask unpleasant tastes or odors and prevent 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, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets prepared by more than one compression cycle, including multilayer tablets, and compression-coated or dry-coated tablets.

[0159] Tablet dosage forms can be prepared from the active ingredient in the form of powder, crystals or granules, alone or in combination with one or more carriers or excipients described in the present invention, said carriers and excipients including binders, disintegrants, controlled-release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweetening agents are particularly useful in forming chewable tablets and lozenges.

[0160] The pharmaceutical compositions provided by the present invention can be provided in soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as dry-fill capsules (DFC), consist of two sections, one of which is 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 the addition of glycerol, sorbitol or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those described in the present invention, including methyl paraben and propyl paraben, as well as sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semi-solid 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 can also be coated as known to those skilled in the art to improve or maintain the dissolution of the active ingredient.

[0161] The pharmaceutical compositions provided by the present invention can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is completely dispersed in the form of small spheres in another liquid, which can be water-in-oil or oil-in-water type. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifying agents and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as bis(lower alkyl) acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars such as sucrose and can also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water for accurate and convenient administration.

[0162] The pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for inhaled administration to a patient, such as a dry powder formulation, an aerosol, a suspension, or a solution composition. In one embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhaled administration to a patient using a dry powder formulation. In yet another embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhaled administration to a patient through a nebulizer. The dry powder composition delivered to the lungs by inhalation generally comprises the compound disclosed in the present invention in a fine powder form and one or more pharmaceutically acceptable excipients in a fine powder form. Pharmaceutically acceptable excipients particularly suitable for use as dry powder formulations are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. The fine powder can be prepared by, for example, micronization and grinding. Generally, the size-reduced (e.g., micronized) compound can be defined by a D 50 value (e.g., measured by laser diffraction) of from about 1 to 10 microns.

[0163] The pharmaceutical composition suitable for transdermal administration can be prepared into a discontinuous patch intended to maintain close contact with the epidermis of the patient 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).

[0164] The pharmaceutical composition suitable for topical administration can be formulated into an ointment, a cream, a suspension, a lotion, a powder, a solution, a paste, a gel, a spray, an aerosol, or an oil. For example, ointments, creams, and gels can be formulated with a water or oil base, and suitable thickeners and / or gelling agents and / or solvents. Such bases can include water, and / or oil such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. The thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, polycarbophil, and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0165] The compounds of the present invention can also be conjugated with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, poly(hydroxypropylmethacrylamide)-phenol, poly(hydroxyethylasparagine)-phenol, or poly(oxyethylene-polylysine) substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be conjugated with a class of biodegradable polymers used in the controlled release of drugs, such as polylactic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0166] The pharmaceutical composition provided by the present 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, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0167] The pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nano-systems and solid forms suitable for making solutions or suspensions in a liquid before injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, ibid.).

[0168] The pharmaceutical composition 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, solubilizing enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, polyvalent chelating or chelating agents, antifreeze agents, cryoprotectants, thickening agents, pH regulators and inert gases.

[0169] The pharmaceutical composition provided by the present invention can be administered by rectal suppository. By mixing the drug with a suitable non-irritating excipient (such as cocoa butter, glycerides 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 will show relatively large variations, and each drug has its unique therapeutic characteristics. Therefore, the precise mode of administration, dosage form and treatment regimen for each individual should be determined by a practicing physician.

[0170] The pharmaceutical composition provided by the present invention can be formulated into immediate or modified release dosage forms, including delayed, sustained-release - pulsed - controlled, targeted and programmed release forms.

[0171] Although the compounds of the present invention can be administered directly without any formulation, the compounds of the present invention are usually taken in the form of pharmaceutical preparations containing pharmaceutically acceptable excipients and at least one active ingredient. These preparations can be administered by various routes, including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration. Many of the compounds used in the methods of the present invention are effective as injection and oral compositions.

[0172] For transdermal drug delivery, a transdermal delivery device ("patch") is required. Such transdermal patches can be used to continuously or intermittently infuse controlled amounts of the compounds of the present invention. The structure and application of transdermal patches for delivering drugs are well known in the art. See, for example, US 5,023,252. Such patches can be made to release drugs continuously, pulsatilely, or on demand.

[0173] Compounds of formula (I), (II), or (III) or pharmaceutically acceptable salts thereof are generally administered via the oral route in pharmaceutical dosage forms that include 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 dosage form in which administration occurs depends on the disease to be treated and the patient, and the pharmaceutical composition can be administered in different doses.

[0174] The pharmaceutical dosage forms of the compounds of formula (I), (II), or (III) described above can be prepared for oral administration, specifically in the form of tablets or capsules, and particularly relate to techniques aimed at providing drug release targeted to the colon (Patel, M.M. Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8(10), 1247 - 1258).

[0175] The pharmaceutical dosage forms of the compounds of formula (I), (II), or (III) described above can be conveniently administered in unit dosage forms and can be prepared by any method well known in the pharmaceutical art, for example, as described in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA. (1985). The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutically acceptable excipients as described above.

[0176] A pharmaceutical preparation suitable for oral administration may comprise one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with fillers, binders, lubricants and / or surfactants such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as emulsifiers, suspending agents and / or preservatives. The liquid composition may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. Such two-piece hard shell capsules may be prepared, for example, by filling a compound of formula (I), (II) or (III) into a hydroxypropyl methylcellulose (HPMC) or gelatin shell.

[0177] Dry shell preparations typically contain 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, flavorants, preservatives and opacifiers may also be present. Liquid fill materials include solid drugs that have been dissolved, solubilized or dispersed (using a suspending agent such as polyethylene glycol 4000, hydrogenated castor oil or beeswax) or liquid drugs in a combination of one or more vehicles such as glycols, polyols, vegetable oils, mineral oils, triglycerides and surface active agents.

[0178] As used herein, the term "therapeutically effective amount" refers to the total amount of each active component sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of a disease upon administration or upon reaching equilibrium in the body. 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 particular drug used, the mode of administration, the clearance rate of the particular drug, the duration of treatment, combination therapy, age, weight, sex, diet and the health of the patient, etc. Descriptions of other factors to be considered regarding "therapeutically effective amount" in the art 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.

[0179] Oral formulations are preferred, particularly tablets or capsules, which may be formulated by methods known to those skilled in the art to provide a dose of the active compound in the range of 0.1 mg to 1000 mg.

[0180] In the treatment of humans, a suitable daily dose of a compound of 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 the compound actually administered will be determined by the attending physician according to the relevant circumstances, including the disease being treated, the route of administration selected, the one or more compounds actually to be taken, the age, weight and response of the specific patient, and the severity of the patient's symptoms. Therefore, the above dose range should not limit the scope of the present invention in any way. In some cases, dose levels below the lower limit of the above dose range may be more appropriate, while in other cases, higher doses that do not produce any side effects may be employed, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

[0181] The term "administering" means providing an individual with a therapeutically effective amount of a drug, and the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, etc. The pharmaceutical dosage forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

[0182] The preferred route of administration will vary with the clinical characteristics, and the dosage variation must depend on the condition of the patient being treated. The doctor will determine the appropriate dosage according to the individual patient. The therapeutically effective amount per unit dose depends on the body weight, physiological function and the selected dosing regimen. The amount of the compound per unit dose refers to the weight of the compound at each administration, excluding the weight of the carrier (the drug contains a carrier).

[0183] The pharmaceutical composition provided by the present invention can be formulated for single-dose or multi-dose administration. The single-dose preparation is packaged in ampoules, vials or syringes. The multi-dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral preparations must be sterile, as known and practiced in the art.

[0184] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the expected therapeutic effect, or with substances that supplement the expected effect.

[0185] In one embodiment, the treatment method of the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Each embodiment of the present invention includes treating the diseases mentioned in the present invention by administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof.

[0186] In one embodiment, the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention can be administered by any suitable route of administration, including systemic administration and local 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. Local administration includes administration to the skin as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention can be administered orally. In another embodiment, the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention can be administered by inhalation. In still another embodiment, the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention can be administered intranasally.

[0187] In one embodiment, the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention can be administered as a single dose, or according to a dosing regimen, at different time intervals over a specified period of time. For example, it can be administered once, twice, three times, or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. The suitable dosing regimen of the compound of the present invention or the pharmaceutical composition comprising a 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 person skilled in the art. In addition, the suitable dosing regimen of the compound of the present invention or the pharmaceutical composition comprising a compound of the present invention, including the duration of implementing the regimen, depends on factors within the knowledge and experience of a person skilled in the art, such as 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 concurrent therapies, and the desired therapeutic effect. Such a person skilled in the art should also understand that adjustment of the appropriate dosing regimen may be required for the response of an individual patient to the dosing regimen or when an individual patient requires changes over time.

[0188] 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 and other therapeutic agents can be administered separately via the same or different administration routes, or administered in the form of the same pharmaceutical composition. This is selected by those skilled in the art according to the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such combination products use the compounds of the present invention (within the dosage ranges described herein) and other pharmaceutically active agents (within their dosage ranges).

[0189] Accordingly, in one aspect, the present invention includes combination therapies that include 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 of the aforementioned additional therapeutic agents.

[0190] 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 can ultimately release the compound of the present invention in the body when administered to a patient. When administering the compound of the present invention in the form of a prodrug, those skilled in the art can implement one or more of the following methods: (a) changing the onset time of the compound in the body; (b) changing the duration of action of the compound in the body; (c) changing the delivery or distribution of the compound in the body; (d) changing the solubility of the compound in the body; and (e) overcoming side effects or other difficulties faced by the compound. Typical functional derivatives for preparing prodrugs include variants of the compound that are cleaved chemically or enzymatically in the body. These variants for preparing phosphates, amides, esters, thioesters, carbonates, and carbamates are well known to those skilled in the art.

[0191] Uses of the Compounds and Pharmaceutical Compositions of the Invention

[0192] The compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicaments for inhibiting PARP1 and / or PARP2, and can also be used to prepare medicaments for preventing, treating, or alleviating PARP-mediated diseases, particularly cancer.

[0193] Specifically, the amount of the compound in the compound or pharmaceutical composition of the present invention can effectively, detectably, and selectively inhibit PARP1 and / or PARP2.

[0194] The compounds of the present invention can be applied to, but are not 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. The 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.

[0195] The compounds of the present invention can be applied to, but are not limited to, administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient to prevent, treat or alleviate cancer. The cancer further includes, but is 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, urogenital tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and / or monocytic leukemia.

[0196] The compounds of the present invention can be applied to, but are not limited to, administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient to prevent, treat or alleviate neurodegenerative diseases. 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 injury.

[0197] The compounds of the present invention can be applied to, but are not limited to, administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient to prevent, treat or alleviate cardiovascular diseases. The cardiovascular diseases further include, but are not limited to, angina pectoris, myocardial infarction, cardiogenic shock, arteriosclerosis, coronary artery disease, cardiovascular tissue injury and hyperlipidemia.

[0198] In addition to being beneficial for human treatment, the compounds and pharmaceutical compositions of the present invention can also be applied to veterinary treatment of mammals in pets, exotic animals and farm animals. Some other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0199] General Synthetic Procedures

[0200] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, but only provides methods for practicing the present invention.

[0201] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definitions of the substituents are as shown in formula (I), (II) or (III). The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0202] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0203] In the examples described below, all temperatures are 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 Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0204] Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform are obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried over anhydrous sodium sulfate before use.

[0205] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvent (unless otherwise indicated), reaction bottles are plugged with appropriate rubber stoppers, and substrates are injected via syringes. Glassware is dried.

[0206] The chromatographic column uses a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0207] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 H NMR spectrum with CDC1 3 、DMSO-d 6 、CD 3 OD or Acetone-d 6is the solvent (in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When there are multiple peaks, the following abbreviations will be 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), tt (triplet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0208] The determination conditions for low-resolution mass spectrometry (MS) data are as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate is 0.6 mL / min. Mobile phase: 5% - 95% (CH 3 CN) in (H 2 O) containing 0.1% formic acid), using electrospray ionization (ESI), and detected by UV at 210 nm / 254 nm.

[0209] For pure compounds, Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) is used and detected by UV at 210 nm / 254 nm.

[0210] The following abbreviations are used throughout the present invention:

[0211]

[0212] The following synthetic schemes describe the steps for preparing the compounds disclosed in the present invention. Unless otherwise specified, each R 1 、R 2 、R 3 and R 4 has the definitions described in the present invention.

[0213] Synthetic Scheme 1

[0214]

[0215] M represents a leaving group, such as -I, -Br, -Cl, -OH, -OMs, -OTs, etc.

[0216] The compound shown in formula (8) can be prepared by Synthesis Scheme 1: The compound shown in formula (1) and the compound shown in formula (2) undergo a coupling reaction to obtain the compound shown in formula ( 3 ); The compound shown in formula ( 3 ) is oxidized by an oxidant to obtain the compound shown in formula ( 4 ); The ester group of the compound shown in formula (4) is reduced to obtain the compound shown in formula ( 5 ); The hydroxyl group of the compound shown in formula ( 5 ) undergoes a bromination reaction to obtain the compound shown in formula (6); The compound shown in formula ( 6 ) and the compound shown in formula ( 7 ) undergo a substitution reaction to obtain the compound shown in formula ( 8 ).

[0217] Synthesis Scheme 2

[0218]

[0219] M represents a leaving group, such as -I, -Br, -Cl, -OH, -OMs, -OTs, etc.

[0220] The compound shown in formula (8) can be prepared by Synthesis Scheme 2: The compound shown in formula ( 1a ) and the compound shown in formula (2) undergo a coupling reaction to obtain the compound shown in formula ( 3a ); The compound shown in formula ( 3a ) is oxidized by an oxidant to obtain the compound shown in formula ( 4a ); The ester group of the compound shown in formula (4a) is reduced to obtain the compound shown in formula ( 5 ); The hydroxyl group of the compound shown in formula ( 5 ) undergoes a bromination reaction to obtain the compound shown in formula (6); The compound shown in formula ( 6 ) and the compound shown in formula ( 7 ) undergo a substitution reaction to obtain the compound shown in formula ( 8 ).

[0221] Synthesis Scheme 3

[0222]

[0223] R 2n has the definition as R in the present invention 2 described, such as C 1 -C6 Alkyl and the like.

[0224] The compound represented by formula ( 8b ) can be prepared by Synthesis Scheme III: The compound represented by formula ( 1b ) and the compound represented by formula ( 2b ) undergo a substitution reaction to obtain the compound represented by formula ( 3b ); The compound represented by formula ( 3b ) and the compound represented by formula ( 4b ) undergo a coupling reaction to obtain the compound represented by formula ( 5b ); The hydroxyl group of the compound represented by formula ( 5b ) undergoes a bromination reaction to obtain the compound represented by formula (6b); The compound represented by formula ( 6b )

[0225] and the compound represented by formula ( 7 ) undergo a substitution reaction to obtain the compound represented by formula ( 8b ).

[0226] Synthesis Scheme IV

[0227]

[0228] The compound represented by formula ( 8c ) can be prepared by Synthesis Scheme IV: The compound represented by formula ( 1c ) and the compound represented by formula ( 7c ) undergo a substitution reaction to obtain the compound represented by formula ( 9c ); The compound represented by formula ( 9c ) and the compound represented by formula ( 10 ) undergo a coupling reaction to obtain the compound represented by formula ( 8c ).

[0229] The compound represented by formula ( 8d ) can be prepared by Synthesis Scheme IV: The compound represented by formula ( 1c ) and the compound represented by formula ( 7 ) undergo a substitution reaction to obtain the compound represented by formula ( 9 ); The compound represented by formula ( 9 ) and the compound represented by formula ( 10 ) undergo a coupling reaction to obtain the compound represented by formula ( 8d ).

[0230] The compounds, pharmaceutical compositions and their applications provided by the present invention will be further described below in conjunction with examples.

[0231] Intermediate 1: 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolylamide hydrochloride

[0232]

[0233] It was prepared according to the synthesis method of intermediate 23 in Example 7 of patent application WO2021013735. Example

[0234] 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

[0235]

[0236] Step 1) Synthesis of Ethyl 8-Cyclopropyl-2-Methyl-3-Oxo-1,2,3,4-Tetrahydroquinoxaline-6-Carboxylate

[0237] Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.80 g, 2.55 mmol) and potassium cyclopropyltrifluoroborate (0.75 g, 5.1 mmol) were successively added to a flask, 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. After stirring evenly, Pd(dppf)Cl 2 (0.19 g, 0.26 mmol) was added. The reaction system was purged with nitrogen and heated to 105 °C for 12 h. After cooling to room temperature, water (15 mL) was added to quench the reaction. The mixture was extracted with EtOAc (15 mL × 3). The organic phases were combined, 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 obtain a pale yellow oily product (0.655 g, 93.46%).

[0238] MS(ESI,pos.ion)m / z:275.20[M+H] + .

[0239] Step 2) Synthesis of Ethyl 8-Cyclopropyl-2-Methyl-3-Oxo-3,4-Dihydroquinoxaline-6-Carboxylate

[0240] Ethyl 8-cyclopropyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.45 g, 1.64 mmol) was added to a flask, stirred and dissolved in DCM (9 mL). After cooling, DDQ (0.41 g, 1.80 mmol) was added under an ice bath. The reaction mixture was then transferred to room temperature and stirred overnight. The solvent was removed by concentration under reduced pressure. Saturated aqueous sodium bicarbonate solution (18 mL) was added to quench the reaction, and a solid precipitated. The mixture was stirred for 30 min, and the filter cake was collected by filtration, washed with saturated aqueous sodium bicarbonate solution, and dried in vacuo to obtain an off-white solid (0.345 g, 77.24%).

[0241] MS(ESI,pos.ion)m / z:273.20[M+H] + .

[0242] Step 3) Synthesis of 5-Cyclopropyl-7-(Hydroxymethyl)-3-Methylquinoxalin-2(1H)-One

[0243] Ethyl 8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.341 g, 1.25 mmol), THF (12.5 mL) were successively added to a 100 mL flask, cooled, and LAH (0.098 g, 2.5 mmol) was added portionwise under an ice bath. Stir until no more heat is released, then transfer to room temperature and continue the reaction for 4 h. Cool, quench with water (2.5 mL) under an ice bath, then adjust the pH to 3 - 4 by dropping dilute hydrochloric acid (1 M). Extract with THF (10 mL), wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (DCM / MeOH (v / v) = 9 / 1) to obtain an off-white solid (0.18 g, 62.42%).

[0244] MS(ESI,pos.ion)m / z:231.2[M+H] + .

[0245] Step 4) Synthesis of 7-(Bromomethyl)-5-Cyclopropyl-3-Methylquinoxalin-2(1H)-One

[0246] 5-Cyclopropyl-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.179 g, 0.78 mmol) and DCM (10 mL) were added to a flask, cooled, and phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise under an ice bath. Stir until no more heat is released, then transfer to room temperature and continue the reaction for 4 h. Concentrate under reduced pressure to remove the solvent, wash the residue with MTBE (10 mL × 2) to obtain a yellow solid (0.22 g, 99%), and directly proceed to the next step of the reaction.

[0247] Step 5) Synthesis of 5-(4-((8-Cyclopropyl-2-Methyl-3-Oxo-3,4-Dihydroquinoxalin-6-Yl)Methyl)Piperazin-1- Yl)-6-Fluoro-N-Methylnicotinamide

[0248] 7-(Bromomethyl)-5-cyclopropyl-3-methylquinoxalin-2(1H)-one (0.22 g, 0.75 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamine hydrochloride (0.29 g, 0.83 mmol) and potassium iodide (0.025 g, 0.15 mmol) were added to a flask, stirred and dissolved in ACN (5 mL), cooled, and DIPEA (0.91 mL, 5.25 mmol) was slowly added dropwise under an ice bath. Heat to 80 °C and react for 2 h. Cool to room temperature, continue stirring, and a solid precipitates. Filter to collect the filter cake, wash the filter cake with MTBE (5 mL × 3) and water (5 mL × 3), and dry in vacuo to obtain a white solid (0.184 g, 54.42%).

[0249] MS(ESI,pos.ion)m / z:451.3[M+H] + ;

[0250] 1 H NMR(400MHz,DMSO-d 6 )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).

[0251] 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)picolylamide

[0252]

[0253] Step 1) Synthesis of Ethyl 4-((1-Methoxy-1-Oxopropan-2-Yl)Amino)-3-Nitrobenzoate

[0254] Ethyl 4-fluoro-3-nitrobenzoate (3.0 g, 14.07 mmol) and DL-alanine methyl ester hydrochloride (2.36 g, 16.88 mmol) were added to a flask, stirred and dissolved in acetonitrile (30 mL). After cooling, potassium carbonate (4.67 g, 33.77 mmol) was added under an ice bath, and the mixture was heated to 70 °C and reacted overnight. After cooling to room temperature, the reaction was quenched by adding water (60 mL) with stirring. A solid precipitated out, and the filter cake was collected by filtration and dried in vacuo to obtain a bright yellow solid (3.86 g, 92.57%).

[0255] MS(ESI,pos.ion)m / z:297.20[M+H] + .

[0256] Step 2) Synthesis of Ethyl 2-Methyl-3-Oxo-1,2,3,4-Tetrahydroquinoxaline-6-Carboxylate

[0257] 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) to a flask, and heat to 70 °C for reaction for 1 h. Cool to room temperature, quench with 15 mL of water, extract with EtOAc (20 mL × 2), combine the organic phases, wash with water (10 mL) and saturated brine (10 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid (1.58 g, 99.92%).

[0258] MS(ESI,pos.ion)m / z:235.20[M+H] + .

[0259] Step 3) Synthesis of Ethyl 8-Bromo-2-Methyl-3-Oxo-1,2,3,4-Tetrahydroquinoxaline-6-Carboxylate

[0260] Add ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.46 g, 6.23 mmol) to a flask, dissolve it in 1,4-dioxane (30 mL), cool, add NBS (1.13 g, 6.35 mmol) under an ice bath, and gradually warm to room temperature and stir overnight. Quench with saturated sodium thiosulfate, extract with EtOAc (40 mL × 2), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 2 / 1) to obtain an off-white solid (1.56 g, 79.93%).

[0261] 1 H NMR(599MHz,DMSO-d 6 )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);

[0262] MS(ESI,pos.ion)m / z:313.20[M+H] + .

[0263] Step 4) Synthesis of Ethyl 2-Methyl-3-Oxo-8-Phenyl-1,2,3,4-Tetrahydroquinoxaline-6-Carboxylate

[0264] Add 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), and Pd(dppf)Cl 2(0.070 g, 0.096 mmol), sodium carbonate (0.41 g, 3.84 mmol), were stirred and dissolved in 1,4 - dioxane (12 mL) and water (3 mL), and heated to 105 °C for reaction overnight. Cooled to room temperature, quenched with water (25 mL), extracted with EtOAc (20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 2) to obtain a brown solid (0.54 g, 90.81%).

[0265] MS(ESI, pos.ion) m / z: 311.20 [M + H] + .

[0266] Step 5) Synthesis of Ethyl 2-Methyl-3-Oxo-8-Phenyl-3,4-Dihydroquinoxaline-6-Carboxylate

[0267] Ethyl 2 - methyl - 3 - oxo - 8 - phenyl - 1,2,3,4 - tetrahydroquinoxaline - 6 - carboxylate (0.54 g, 1.74 mmol) was successively added to a flask, stirred and dissolved in DCM (19 mL), cooled, and DDQ (0.43 g, 1.91 mmol) was added under an ice bath, then transferred to room temperature for reaction for 8 h. Quenched with saturated aqueous sodium bicarbonate solution (38 mL), stirred for 2 h, extracted with DCM (25 mL×3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an orange - yellow solid (0.517 g, 96.37%).

[0268] MS(ESI, pos.ion) m / z: 309.20 [M + H] + .

[0269] Step 6) Synthesis of 7-(Hydroxymethyl)-3-Methyl-5-Phenylquinoxalin-2(1H)-One

[0270] Ethyl 2 - methyl - 3 - oxo - 8 - phenyl - 3,4 - dihydroquinoxaline - 6 - carboxylate (0.51 g, 1.64 mmol) was successively added to a flask, stirred and dissolved in THF (16.4 mL), cooled, and LAH (0.196 g, 5.01 mmol) was added in portions under an ice bath, stirred until no more heat was released, then transferred to room temperature and continued to react for 4 h. Cooled, quenched with water (5 mL) under an ice bath, and then the pH was adjusted to 3 - 4 by dropping dilute hydrochloric acid (1 M), extracted with THF (25 mL×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain a white solid (0.28 g, 63.57%).

[0271] MS(ESI, pos.ion) m / z: 267.40 [M + H] +.

[0272] Step 7) Synthesis of 7-(Bromomethyl)-3-Methyl-5-Phenylquinoxalin-2(1H)-One

[0273] Add 7-(hydroxymethyl)-3-methyl-5-phenylquinoxalin-2(1H)-one (0.15 g, 0.56 mmol), DCM (10 mL) to a flask, cool it, and dropwise add phosphorus tribromide (0.08 mL, 0.85 mmol) under an ice bath. Stir until no heat is released, then transfer it to room temperature and continue the reaction for 4 h. Concentrate under reduced pressure to remove the solvent. Wash the residue with MTBE (10 mL × 2) to obtain 0.185 g of a yellow solid, which is directly used for the next step.

[0274] Step 8) Synthesis of 6-Fluoro-N-Methyl-5-(4-((2-Methyl-3-Oxo-8-Phenyl-3,4-Dihydroquinoxalin-6-Yl)Meth yl)Piperazin-1-Yl)Nicotinamide

[0275] Add 7-(bromomethyl)-3-methyl-5-phenylquinoxalin-2(1H)-one (0.185 g, 0.56 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamine hydrochloride (0.21 g, 0.62 mmol) and potassium iodide (0.019 g, 0.11 mmol) to a flask, stir and dissolve in ACN (4 mL), cool it, and dropwise add DIPEA (0.68 mL, 3.92 mmol) under an ice bath. Heat to 80 °C and react for 2 h. Cool to room temperature, and a solid precipitates out with continued stirring. Filter to collect the filter cake. Wash the filter cake successively with MTBE (4 mL × 3) and water (4 mL × 3), and dry it under vacuum to obtain a white solid (0.177 g, 64.73%).

[0276] MS(ESI,pos.ion)m / z:487.20[M+H] + ;

[0277] 1 H NMR(400MHz,DMSO-d 6 )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).

[0278] 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

[0279]

[0280]

[0281] Step 1) Synthesis of Methyl (4-Bromo-2-Fluoro-6-Nitrophenyl)Aminopropionate

[0282] 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 the reaction was carried out 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), and dried over anhydrous Na 2 SO 4 dried, filtered, and concentrated under reduced pressure to obtain a yellow liquid (13 g, 96%).

[0283] MS (ESI, pos. ion) m / z: 321.1 [M+H] + .

[0284] Step 2) Synthesis of 7-Bromo-5-Fluoro-3-Methyl-3,4-Dihydroquinoxalin-2(1H)-One

[0285] (4-Bromo-2-fluoro-6-nitrophenyl)alanine methyl ester (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 the reaction was carried out at 60 °C for 16 h. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, water (100 mL) was added and stirred for 1 h, and then filtered. The solid was dried at 50 °C for 12 h to obtain a pale yellow solid (10.49 g, 90%).

[0286] MS (ESI, pos. ion) m / z: 259.0 [M+H] + .

[0287] Step 3) Synthesis of 7-Bromo-5-Fluoro-3-Methylquinoxalin-2(1H)-One

[0288] 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 the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, saturated NaHCO 3 solution (400 mL) was added and stirred, and the solid was filtered and dried in vacuo at 50 °C for 12 h to obtain a pale yellow solid (9.0 g, 95%).

[0289] MS (ESI, positive ion) m / z: 257.0 [M+H] + .

[0290] Step 4) Synthesis of 7-Bromo-5-Isopropoxy-3-Methylquinoxalin-2(1H)-One

[0291] At 0 °C, 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). After addition, the reaction was carried out at room temperature for 15 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / EtOAc (v / v) = 4 / 1) to obtain a pale yellow solid (400 mg, 69%).

[0292] MS (ESI, positive ion) m / z: 297.1 [M+H] + .

[0293] Step 5) Synthesis of 7-(HydroxyMethyl)-5-Isopropoxy-3-Methylquinoxalin-2(1H)-One

[0294] 7-Bromo-5-isopropoxy-3-methylquinoxalin-2(1H)-one (1.20 g, 4.04 mmol), (tributylstannyl)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 protection, the reaction was carried out at 80 °C for 14 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a pale yellow solid (910 mg, 90%).

[0295] MS (ESI, positive ion) m / z: 249.2 [M+H] + .

[0296] Step 6) Synthesis of 7-(Bromomethyl)-5-Isopropoxy-3-Methylquinoxalin-2(1H)-One

[0297] CBr 4 (602 mg, 1.81 mmol) was added to a solution of 7-(hydroxymethyl)-5-isopropoxy-3-methylquinoxalin-2(1H)-one (300 mg, 1.21 mmol) and PPh 3 (476 mg, 1.81 mmol) in DCM (8 mL). The reaction was carried out at room temperature for 18 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain a yellow solid (300 mg, 80%).

[0298] MS (ESI, pos. ion) m / z: 311.1 [M+H] + .

[0299] Step 7) Synthesis of 6-Fluoro-5-(4-((8-Isopropoxy-2-Methyl-3-Oxo-3,4-Dihydroquinoxalin-6-Yl)Methyl) Piperazin-1-Yl)-N-Methylnicotinamide

[0300] 7-(Bromomethyl)-5-isopropoxy-3-methylquinoxalin-2(1H)-one (300 mg, 0.96 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamide (297 mg, 1.25 mmol), and DIPEA (496 mg, 3.84 mmol) were successively added to MeCN (8 mL), and the reaction was carried out at 70 °C for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), and dried over anhydrous Na 2 SO 4 2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a pale yellow solid (130 mg, 29%).

[0301] MS (ESI, pos. ion) m / z: 469.3 [M+H] + ;

[0302] 1 1H NMR (400 MHz, DMSO-d 6 6) δ (ppm) 12.15 (s, 1H), 8.39 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.62–7.51 (m, 1H), 6.81 (s, 2H), 4.79–4.73 (m, 1H), 3.57 (s, 2H), 3.23–3.10 (m, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.61–2.53 (m, 4H), 2.37 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H).

[0303] 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)picolylamide

[0304]

[0305] Step 1) Synthesis of 7-bromo-3-methyl-5-phenoxyquinoxalin-2(1H)-one

[0306] 7-Bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (1.0 g, 3.89 mmol), phenol (730 mg, 7.78 mmol), K 2 CO 3 (1.61 g, 11.67 mmol) were added to a solution of DMF (12 mL). After addition, the mixture was reacted under microwave at 120 °C for 18 h. The reaction solution was diluted with water (50 mL), and a solid precipitated. The solid was filtered, dissolved in MeOH (5 mL) and DCM (50 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / EtOAc (v / v) = 4 / 1) to obtain a pale yellow solid (300 mg, 23%).

[0307] MS (ESI, pos. ion) m / z: 331.1 [M+H] + .

[0308] Step 2) Synthesis of 7-(Hydroxymethyl)-3-Methyl-5-Phenoxyquinoxalin-2(1H)-One

[0309] 7-Bromo-3-methyl-5-phenoxyquinoxalin-2(1H)-one (300 g, 0.91 mmol), (tributylstannyl)methanol (321 mg, 1.00 mmol), Xphos-Pd-G2 (71 mg, 0.09 mmol) were added to 1,4-dioxane (16 mL). Under nitrogen protection, the mixture was reacted at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a pale yellow solid (200 mg, 78%).

[0310] MS (ESI, pos. ion) m / z: 283.2 [M+H] + .

[0311] Step 3) Synthesis of 7-(Bromomethyl)-3-Methyl-5-Phenoxyquinoxalin-2(1H)-One

[0312] CBr 4 (114 mg, 0.35 mmol) was added to a solution of 7-(hydroxymethyl)-3-methyl-5-phenoxyquinoxalin-2(1H)-one (65 mg, 0.23 mmol) and PPh 3 (90 mg, 0.35 mmol) in DCM (6 mL). The mixture was reacted at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a yellow solid (75 mg, 94%).

[0313] MS (ESI, pos. ion) m / z: 345.1 [M+H] + .

[0314] Step 4) Synthesis of 6-Fluoro-N-Methyl-5-(4-((2-Methyl-3-Oxo-8-Phenoxy-3,4-Dihydroquinoxalin-6-Yl)Synthesis of ((1-Methylpiperazin-1-yl)pyridinecarboxamide)

[0315] 7-(Bromomethyl)-3-methyl-5-phenoxyquinoxalin-2(1H)-one (50 mg, 0.14 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamide (43 mg, 0.18 mmol), and DIPEA (72 mg, 0.56 mmol) were successively added to MeCN (4 mL), and the reaction was carried out 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), and anhydrous Na 2 SO 4 was dried, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a pale yellow solid (25 mg, 34%).

[0316] MS (ESI, pos. ion) m / z: 503.3 [M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 12.37 (s, 1H), 8.40 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 10.5, 8.2 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.15 (dd, J = 15.8, 8.4 Hz, 1H), 7.09–7.01 (m, 3H), 6.75 (s, 1H), 3.55 (s, 2H), 3.17–3.09 (m, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.59–2.53 (m, 4H), 2.36 (s, 3H).

[0318] 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)picolylamide

[0319]

[0320]

[0321] Step 1) Synthesis of Ethyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate

[0322] Ethyl 4-fluoro-3-nitrobenzoate (6.42 g, 30.13 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (12.49 g, 90.36 mmol) and DL-alanine methyl ester hydrochloride (4.63 g, 33.13 mmol) were added, the temperature was raised to 100 °C and the reaction was carried out for 3 hours. The reaction was stopped, and 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, concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=4 / 1) to obtain a yellow solid (1.6 g, 17.9%).

[0323] MS(ESI,pos.ion)m / z:297.4[M+H] + 。

[0324] Step 2) Synthesis of Ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0325] Ethyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate (1.5 g, 5.06 mmol), acetic acid (10 mL), and iron powder (1.41 g, 25.30 mmol) were added to a reaction flask, the temperature was raised to 80 °C, and the reaction was carried out for 5 hours. The reaction was stopped, and the reaction mixture 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 pale yellow solid (1.10 g, 92.7%).

[0326] MS(ESI,pos.ion)m / z:235.2[M+H] + 。

[0327] Step 3) Synthesis of Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0328] 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), N-bromosuccinimide (0.42 g, 2.37 mmol) was added under stirring at room temperature, and the reaction was carried out for 16 hours. Water (150 mL) was added, and 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%).

[0329] MS(ESI,pos.ion)m / z:313.3[M+H] + 。

[0330] Step 4) Synthesis of Ethyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0331] Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.1 g, 0.32 mmol) was dissolved in dichloromethane (4 mL). Activated manganese dioxide (0.2 g, 1.96 mmol, 85%) was added under stirring at room temperature. The mixture was stirred and reacted at room temperature for 2.5 h, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a pale yellow solid (0.078 g, 78.5%).

[0332] MS(ESI,pos.ion)m / z:311.2[M+H] + 。

[0333] Step 5) Synthesis of Ethyl 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxylate

[0334] Ethyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.084 g, 0.27 mmol), aniline (0.038 g, 0.41 mmol), dichloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.021 g, 0.027 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.026 g, 0.054 mmol), sodium tert-butoxide (0.052 g, 0.54 mmol), and toluene (5 mL) were added to a reaction flask. The nitrogen was displaced, and the mixture was heated to 100 °C under nitrogen protection and reacted for 18 h. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and 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%).

[0335] MS(ESI,pos.ion)m / z:324.2[M+H] + 。

[0336] Step 6) Synthesis of 7-(Hydroxymethyl)-3-methyl-5-(phenylamino)quinoxalin-2(1H)-one

[0337] Ethyl 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxylate (0.16 g, 0.49 mmol) was dissolved in tetrahydrofuran (5 mL). At 0 °C, lithium aluminum hydride (0.07 g, 1.85 mmol) was added. After the addition, the mixture was kept warm and reacted for 22 h, then heated to 65 °C and reacted for another 4.5 h. The reaction was stopped, cooled to room temperature, and water (0.5 mL) was added dropwise to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid (0.05 g, 35.92%).

[0338] MS(ESI,pos.ion)m / z:282.2[M+H] + 。

[0339] Step 7) Synthesis of 2-Methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carbaldehyde

[0340] Dissolve 7-(hydroxymethyl)-3-methyl-5-(phenylamino)quinoxalin-2(1H)-one (0.04 g, 0.14 mmol) in a mixed solution of tetrahydrofuran (2 mL) and dichloromethane (2 mL). Add Dess-Martin reagent (0.12 g, 0.28 mmol) at 0 °C, then warm to room temperature and react for 16 hours. Quench the reaction and filter. Wash the filter cake with dichloromethane (10 mL). Concentrate the filtrate to obtain a yellow oil (0.038 g, 95.6%).

[0341] MS(ESI,pos.ion)m / z:280.2[M+H] + 。

[0342] Step 8) Synthesis of 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxalin-6- yl)methyl)piperazin-1-yl)pyridinecarboxamide

[0343] Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (0.05 g, 0.21 mmol) in a mixed solution of dichloromethane (2 mL) and methanol (2 mL). Add 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). React at room temperature for 20 hours. Concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 15 / 1) to obtain a yellow solid (0.014 g, 20.5%).

[0344] MS(ESI,pos.ion)m / z:502.3[M+H] + ;

[0345] HRMS:calcd.for C 27 H 28 FN 7 O 2 [M+H] + :502.2361,found:502.2368;

[0346] 1 H NMR(400MHz,DMSO-d 6)δ(ppm) 12.19 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.21 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.68–7.51 (m, 1H), 7.34 (d, J = 4.2 Hz, 4H), 7.05 (s, 1H), 7.03–6.92 (m, 1H), 6.65 (s, 1H), 3.51 (s, 2H), 3.19–3.12 (m, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.59–2.52 (m, 4H), 2.44 (s, 3H).

[0347] 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

[0348]

[0349]

[0350] Step 1) Synthesis of 7-Bromo-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0351] 7-Bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (0.8 g, 3.11 mmol, referring to Step 3 of Example 3), 4-fluorophenol (1.05 g, 9.33 mmol), and K 2 CO 3 (1.29 g, 9.33 mmol) were added to a DMSO (12 mL) solution. After addition, the mixture was subjected to microwave reaction at 130 °C for 16 h. The reaction solution was diluted with water (60 mL), and a solid precipitated. The solid was filtered, 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 pale yellow solid (0.6 g, 55%).

[0352] MS (ESI, pos. ion) m / z: 349.2 [M+H] + .

[0353] Step 2) Synthesis of 5-(4-Fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0354] 7-Bromo-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one (600 mg, 1.72 mmol), (tributylstannyl)methanol (607 mg, 1.89 mmol), and Xphos-Pd-G2 (135 mg, 0.17 mmol) were added to 1,4-dioxane (16 mL). The reaction system was purged with nitrogen and then reacted at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a pale yellow solid (350 mg, 68%).

[0355] MS(ESI,pos.ion)m / z:301.2[M+H] + 。

[0356] Step 3) Synthesis of 7-(Bromomethyl)-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0357] At 0 °C, CBr 4 (776 mg, 2.34 mmol) was added to a solution of 5-(4-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (350 mg, 1.17 mmol) and PPh 3 (613 mg, 2.34 mmol) in dichloromethane (20 mL). After 1 h, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a yellow solid (300 mg, 71%).

[0358] MS(ESI,pos.ion)m / z:363.1[M+H] + 。

[0359] Step 4) Synthesis of 6-Fluoro-5-(4-((8-(4-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)meth yl)piperazin-1-yl)-N-methylpyridinecarboxamide

[0360] 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 successively added to acetonitrile (8 mL). The reaction mixture was heated at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na 2 SO 4 4, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a pale yellow solid (260 mg, 60%).

[0361] MS(ESI,pos.ion)m / z:521.3[M+H] + ;

[0362] HRMS:calcd.for C 27 H 26 F 2 N 6 O 3 [M+H] + :521.2034,found:521.2111;

[0363] 1 H NMR(400MHz,DMSO-d 6 )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).

[0364] 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

[0365]

[0366] Step 1) Synthesis of Methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0367] Methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate(0.31g,1.04mmol,refer to Step 3 of Example 8)was added to a 100mL reaction flask,stirred and dissolved in dichloromethane(12mL),cooled,and 2,3-dichloro-5,6-dicyanobenzoquinone(0.26g,1.14mmol)was added in portions under an ice bath.The mixture was stirred evenly and transferred to room temperature for reaction for 4h.The solvent was removed by concentration under reduced pressure,cooled,and quenched with saturated aqueous sodium bicarbonate solution(24mL).A solid precipitated out.The mixture was stirred for 30min,and the filter cake was collected by filtration.The filter cake was washed with saturated aqueous sodium bicarbonate solution and dried in vacuo to obtain a brownish-red solid(0.18g,58.46%).

[0368] MS(ESI,pos.ion)m / z:297.10,299.05[M+H] + 。

[0369] Step 2) Synthesis of 5-Bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0370] Methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.18 g, 0.61 mmol) was added to a 50 mL reaction flask, stirred and dissolved in tetrahydrofuran (9 mL). After cooling, lithium aluminum hydride (0.070 g, 1.79 mmol) was added under an ice bath, and the reaction was continued at 0 °C for 2 h. The reaction was quenched by adding water (1.79 mL) under an ice bath, and the pH was adjusted to 3 - 4 by dropwise addition of 1 M dilute hydrochloric acid. The mixture was extracted with tetrahydrofuran (10 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) = 95 / 5) to obtain a brick-red solid (0.112 g, 68.70%).

[0371] MS(ESI,pos.ion)m / z:269.20,271.15[M+H] + 。

[0372] Step 3) Synthesis of 5-Bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one

[0373] 5-Bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.11 g, 0.41 mmol) and dichloromethane (10 mL) were added to a 100 mL reaction flask. After cooling, phosphorus tribromide (0.060 mL, 0.64 mmol) was added dropwise under an ice bath. The mixture was stirred until no more heat was released, and then transferred to room temperature and reacted overnight. The solvent was removed by concentration under reduced pressure to obtain a yellow solid product (0.135 g, 99.5%), which was directly used for the next step of the reaction.

[0374] Step 4) Synthesis of 5-(4-((8-Bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)- 6-fluoro-N-methylpyridinecarboxamide

[0375] 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) were added to a 100 mL reaction flask, stirred and dissolved in acetonitrile (2.5 mL). After cooling, N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) was slowly added dropwise under an ice bath. The mixture was stirred evenly and heated to 80 °C for 2 h. After cooling to room temperature, a solid precipitated out. The filter cake was collected by filtration, washed with methyl tert-butyl ether (2.5 mL × 2) and water (2.5 mL × 2), and dried in vacuo to obtain an off-white solid (145 mg, 72.87%).

[0376] MS(ESI,pos.ion)m / z:489.15,490.10[M+H] + 。

[0377] Step 5) Synthesis of 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinox alin-6-yl)methyl)piperazin-1-yl)pyridinecarboxamide

[0378] In 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), tributyl(prop-2-yn-1-yl)stannane (0.12 g, 0.36 mmol) were successively added, and stirred and dissolved in 1,4-dioxane (8 mL). Then Xphos-Pd-G2 (0.024 g, 0.031 mmol) was added. After purging with nitrogen, the mixture was heated to 90 °C and reacted overnight. It was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to obtain a white solid (0.030 g, 32.73%).

[0379] MS(ESI,pos.ion)m / z:449.40[M+H] + ;

[0380] HRMS:calcd.for C 24 H 25 FN 6 O 2 [M+H] + :449.2096,found:449.2128;

[0381] 1 H NMR(400MHz,DMSO-d 6 )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).

[0382] 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

[0383]

[0384] Step 1) Synthesis of Methyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate

[0385] At room temperature, DL-alanine methyl ester hydrochloride (9.81 g, 70.31 mmol) and K 2 CO 3 (17.35 g, 125.55 mmol) were added to a solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.22 mmol) in acetonitrile (100 mL), and then the mixture was heated to 70 °C and reacted for 12 h. After the reaction solution was cooled, it was filtered through diatomaceous earth, and the filtrate was 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 obtain a yellow solid product (14 g, 98.78%).

[0386] MS(ESI, pos.ion) m / z: 283.1 [M+H] + .

[0387] Step 2) Synthesis of Methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0388] At room temperature, iron powder (13.85 g, 248 mmol) was added to a solution of methyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate (14 g, 49.60 mmol) in acetic acid (200 mL), and the mixture was heated to 80 °C and stirred for 5 h. After the reaction solution was cooled, water (500 mL) was added, and the mixture was filtered. The solid was dried to obtain a yellow solid product (8.5 g, 77.82%).

[0389] MS(ESI, pos.ion) m / z: 221.3 [M+H] + .

[0390] Step 3) Synthesis of Methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0391] At room temperature, NBS (4.00 g, 22.47 mmol) was added to a solution of methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (4.5 g, 20.43 mmol) in 1,4-dioxane (50 mL), and then the mixture was stirred at room temperature for 8 h. 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, filtered, and the filtrate was 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 obtain a yellow solid product (4.5 g, 73.62%).

[0392] MS(ESI, pos.ion) m / z: 299.1, 301.1 [M+H]+ .

[0393] Step 4) Synthesis of Methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0394] At room temperature, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)fluorobenzene (0.37 g, 2.61 mmol), Pd(dppf)Cl 2 (0.074 g, 0.10 mmol) and sodium carbonate (0.43 g, 4.02 mmol) were added 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). After displacing N 2 , the mixture was heated to 105 °C and reacted for 12 h. The reaction solution was cooled to room temperature, quenched with water (25 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and 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 product (0.4 g, 63.44%).

[0395] MS(ESI,pos.ion)m / z:315.2[M+H] + .

[0396] Step 5) Synthesis of Methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0397] Under an ice bath, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.32 g, 1.40 mmol) was added to a solution of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.40 g, 1.27 mmol) in dichloromethane (12 mL), and then slowly warmed to room temperature and stirred for 3 h. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (38 mL), stirred for 2 h, extracted with dichloromethane (25 mL × 3), the organic phases were combined, then washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an orange-yellow solid product (0.21 g, 52.84%).

[0398] MS(ESI,pos.ion)m / z:313.1[M+H] + .

[0399] Step 6) Synthesis of 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0400] Under an ice bath, lithium aluminum hydride (0.080 g, 2.04 mmol) was added portionwise to a solution of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.21 g, 0.67 mmol) in tetrahydrofuran (16.4 mL). The mixture was stirred until no more heat was evolved, then transferred to room temperature and reacted for an additional 4 h. After cooling, the reaction was quenched by adding water (5 mL) under an ice bath, and the pH was adjusted to 3 - 4 by dropwise addition of 1 M dilute hydrochloric acid. The mixture was extracted with tetrahydrofuran (25 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to remove the solvent, and 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%).

[0401] MS(ESI,pos.ion)m / z:285.2[M+H] + 。

[0402] Step 7) Synthesis of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0403] Under an ice bath, 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.16 g, 0.56 mmol), dichloromethane (10 mL) were taken, and then phosphorus tribromide (0.056 mL, 0.59 mmol) was added dropwise. The mixture was stirred for 5 min and then transferred to room temperature and reacted for an additional 2 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was washed with methyl tert-butyl ether (10 mL × 2) and dried to obtain a crude yellow solid (0.13 g, 96.77%), which was directly used for the next step of the reaction.

[0404] MS(ESI,pos.ion)m / z:347.1,349.1[M+H] + 。

[0405] Step 8) Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)meth yl)piperazin-1-yl)-N-methylpicolinamide

[0406] At room temperature, 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) were added to a solution of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxalin-2(1H)-one (0.19 g, 0.55 mmol) in acetonitrile (20 mL). Then the mixture was heated to 70 °C and stirred 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 a yellow solid product (0.029 g, 10.50%).

[0407] MS(ESI,pos.ion)m / z:505.4[M+H] + ;

[0408] HRMS:calcd.for C 27 H 26 F 2 N 6 O 2 [M+H] + :505.2085,found:505.2186;

[0409] 1 H NMR(400MHz,DMSO-d 6 )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).

[0410] 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

[0411]

[0412] Step 1:Synthesis of methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0413] At room temperature,(3-fluorophenyl)boronic acid(0.45 g,7.43 mmol),Pd(dppf)Cl 2 (0.18 g,0.25 mmol),and sodium carbonate(1.06 g,10.02 mmol)were added to a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate(1.5 g,5.01 mmol)in 1,4-dioxane(20 mL)and water(5 mL).Then the nitrogen was displaced,and the mixture was heated to 105 °C and reacted for 10 h.The reaction solution was diluted with dichloromethane,filtered through diatomaceous earth,and the organic phase was concentrated under reduced pressure.The residue was separated and purified by silica gel column chromatography(eluent:dichloromethane / ethyl acetate(v / v)=90 / 10)to obtain a yellow solid product(0.65 g,41.24%).

[0414] MS(ESI,pos.ion)m / z:315.1,316.2[M+H] + 。

[0415] Step 2) Methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0416] At 0 °C, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.56 g, 2.48 mmol) was added to a solution of methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.65 g, 2.07 mmol) in dichloromethane (50 mL). The reaction was monitored by TLC at room temperature for 5 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), and the mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 9 / 1) to give a white solid product (0.55 g, 85.16%).

[0417] MS(ESI,pos.ion)m / z:313.15[M+H] + 。

[0418] Step 3) Synthesis of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0419] At 0 °C, N 2 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) was slowly added lithium aluminum hydride (0.2 g, 5.28 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min and then at room temperature for 3 h. After the reaction was complete, water (0.2 mL), aqueous NaOH solution (0.2 mL, 15%), and water (0.6 mL) were added sequentially at 0 °C, and the mixture was stirred for 10 min. The mixture was filtered through diatomaceous earth, and the filter cake was added with water and dissolved in dilute hydrochloric acid (14 mL, 1 M). The solution was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to give a gray solid product (0.3 g, 59.92%).

[0420] MS(ESI,pos.ion)m / z:285.2[M+H] + 。

[0421] Step 4) Synthesis of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0422] Under an ice bath, phosphorus tribromide (0.15 mL, 1.59 mmol) was added dropwise to a solution of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.3 g, 1.06 mmol) in dichloromethane (8 mL). The mixture was stirred for 5 - 10 min and then allowed to react at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 98 / 2) to obtain a white solid powder (0.27 g, 73.70%).

[0423] MS(ESI,pos.ion)m / z:347.15,349.15[M+H] + 。

[0424] Step 5) Synthesis of 6-fluoro-5-(4-((8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)meth yl)piperazin-1-yl)-N-methylpicolinamide

[0425] At room temperature, potassium iodide (6.5 mg, 0.0039 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.2 g, 0.86 mmol), and N,N-diisopropylethylamine (1.03 mL, 6.24 mmol) were added to a solution of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxalin-2(1H)-one (0.27 g, 0.78 mmol) in acetonitrile (15 mL). The mixture was stirred for 5 - 10 min and then allowed to react at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to obtain a white solid powder (0.15 g, 38.23%).

[0426] MS(ESI,pos.ion)m / z:505.25[M+H] + ;

[0427] HRMS:calcd.for C 27 H 26 F 2 N 6 O 2 [M+H] + :505.2158,found:505.2191;

[0428] 1 H NMR(400MHz,DMSO-d 6)δ(ppm) 12.34 (s, 1H), 8.40–8.32 (m, 1H), 7.87–7.80 (m, 1H), 7.60–7.46 (m, 2H), 7.44–7.38 (m, 2H), 7.33–7.26 (m, 2H), 7.26–7.19 (m, 1H), 3.66 (s, 2H), 3.22–3.14 (m, 4H), 2.76 (d, J=4.8 Hz, 3H), 2.64–2.56 (m, 4H), 2.34 (s, 3H).

[0429] 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

[0430]

[0431] Step 1) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0432] In a 100 mL reaction flask, methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.60 g, 2.01 mmol), 4-fluorophenylboronic acid (0.37 g, 2.61 mmol), Pd(dppf)Cl 2 (0.074 g, 0.10 mmol), and sodium carbonate (0.43 g, 4.02 mmol) were successively added, stirred and dissolved in 1,4-dioxane (12 mL) and water (3 mL). After purging with nitrogen, the mixture was heated to 105 °C and reacted overnight. It was cooled to room temperature, the insoluble matter was filtered off, the organic phase was collected, water was added for liquid separation, and it 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 obtain a white solid (0.383 g, 60.75%).

[0433] MS(ESI, pos.ion) m / z: 315.15 [M+H] + .

[0434] Step 2) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0435] Methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.38 g, 1.22 mmol) was added to a 100 mL reaction flask, stirred and dissolved in dichloromethane (12 mL). After cooling, 2,3-dichloro-5,6-dicyanobenzoquinone (0.30 g, 1.33 mmol) was added under an ice bath. The reaction mixture was then transferred to room temperature and reacted for 6 h. The solvent was removed by concentration under reduced pressure. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (24 mL), and the mixture was stirred for 30 min. A solid precipitated out. The solid was collected by filtration, washed with saturated aqueous sodium bicarbonate solution, and dried in vacuo to obtain a brownish-yellow solid (0.30 g, 79.46%).

[0436] MS(ESI,pos.ion)m / z:313.20[M+H] + 。

[0437] Step 3) Synthesis of 5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0438] Methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.30 g, 0.96 mmol) was added to a 100 mL reaction flask, stirred and dissolved in tetrahydrofuran (11 mL). After cooling, lithium aluminum hydride (0.106 g, 2.71 mmol) was added under an ice bath. The reaction mixture was gradually warmed to room temperature and reacted overnight. After cooling, the reaction was quenched by adding water (2.7 mL) under an ice bath, and then 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3 - 4. The mixture was extracted with tetrahydrofuran (10 mL×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) = 95 / 5) to obtain an off-white solid (0.186 g, 68.11%).

[0439] MS(ESI,pos.ion)m / z:285.20[M+H] + 。

[0440] Step 4) Synthesis of 7-(bromomethyl)-8-fluoro-5-(4-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0441] 8-Fluoro-5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.186 g, 0.65 mmol) and dichloromethane (8.5 mL) were added to a 100 mL reaction flask. After cooling, phosphorus tribromide (0.079 mL, 0.85 mmol) was added dropwise under an ice bath. The mixture was stirred until no more heat was evolved, and then transferred to room temperature and reacted for 4 h. The solvent was removed by concentration under reduced pressure to obtain a crude yellow solid, which was directly used in the next step of the reaction.

[0442] Step 5) Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)meth yl)piperazin-1-yl)-N-methylpicolinamide

[0443] In a 100 mL reaction flask, 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) were added. The mixture was stirred and dissolved in acetonitrile (4 mL). After cooling, N,N-diisopropylethylamine (0.77 mL, 4.41 mmol) was added dropwise under an ice bath. The reaction mixture was heated to 80 °C and reacted for 2 h. After cooling to room temperature, a solid precipitated. The solid was filtered and the filter cake was collected. The filter cake was washed with methyl tert-butyl ether (4 mL × 3) and water (4 mL × 3), and then dried under vacuum to obtain a white solid (0.19 g, 59.43%).

[0444] MS(ESI,pos.ion)m / z:505.30[M+H] + ;

[0445] HRMS:calcd.for C 27 H 26 F 2 N 6 O 2 [M+H] + :505.2158,found:505.2160;

[0446] 1 H NMR(400MHz,DMSO-d 6 )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).

[0447] 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

[0448]

[0449] Step 1) Synthesis of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0450] At room temperature, 3-pyridylboronic acid pinacol ester (0.89 g, 4.34 mmol), Pd(PPh 3 ) 4 (0.19 g, 0.17 mmol) and K 2 CO 3 (0.92 g, 6.68 mmol) were added 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). Then, nitrogen was displaced, and the mixture was heated to 110 °C and reacted for 8 h. The reaction solution was diluted with dichloromethane, filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to obtain a light red solid product (0.55 g, 55.33%).

[0451] MS(ESI,pos.ion)m / z:298.25[M+H] + 。

[0452] Step 2) Synthesis of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-3,4-dihydroquinoxaline-6-carboxylate

[0453] At 0 °C, 2,3-dichloro-5,6-dicyanobenzoquinone (0.63 g, 2.78 mmol) was added 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). The reaction was monitored by TLC at room temperature and reacted for 5 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 9 / 1) to obtain a white solid product (0.44 g, 80.55%).

[0454] MS(ESI,pos.ion)m / z:296.15[M+H] + 。

[0455] Step 3) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one

[0456] At 0 °C, N 2Under ice bath, lithium aluminum hydride (0.17 g, 4.47 mmol) was slowly added 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). The mixture was stirred at 0 °C for 5 min and then at room temperature for 3 h. After the reaction was complete, water (0.2 mL), 15% aqueous NaOH solution (0.2 mL), and water (0.6 mL) were added at 0 °C, and the mixture was stirred for 10 min. It was filtered through diatomaceous earth and washed with dichloromethane (50 mL) and tetrahydrofuran (50 mL). Dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to give a gray solid product (0.19 g, 47.71%).

[0457] MS(ESI,neg.ion)m / z:266.15[M-H] - 。

[0458] Step 4) Synthesis of 7-(bromomethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one

[0459] Under ice bath, phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise 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). The mixture was stirred for 5 - 10 min and then at room temperature for 3.5 h. Concentrated in vacuo directly for the next reaction step.

[0460] Step 5) 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

[0461] At room temperature, potassium iodide (4.8 mg, 0.029 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.17 g, 0.70 mmol), and N,N-diisopropylethylamine (0.96 mL, 5.8 mmol) were added to a solution of 7-(bromomethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one (0.19 g, 0.58 mmol) in acetonitrile (10 mL). The mixture was stirred for 5 - 10 min and then at room temperature for 5 h. Concentrated 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%).

[0462] MS(ESI,pos.ion)m / z:488.20[M+H] + ;

[0463] HRMS:calcd.for C 26 H26 FN 7 O 2 [M+H] + :488.5469,found:488.2227;

[0464] 1 H NMR(400MHz,DMSO-d 6 )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).

[0465] 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

[0466]

[0467]

[0468] Step 1) Synthesis of methyl 5-bromo-6-fluoropicolinate

[0469] Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol), AgF 2 (4.73 g, 32.41 mmol), and acetonitrile (30 mL) were successively added to a sealed tube, and the reaction was carried out at room temperature for 48 h. After filtration, the filter cake was rinsed with EA (20 mL), and concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a white solid (0.57 g, 26%).

[0470] MS(ESI,pos.ion)m / z:234.0,236.0[M+H] + 。

[0471] Step 2) Synthesis of tert-butyl 6-methyl 2-fluoro-5',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate Step 3) Synthesis of tert-butyl 2-fluoro-6-(methylcarbamoyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxy

[0472] 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 H 2 O (2 mL) were successively added to 1,4-dioxane (20 mL). Under nitrogen protection, the temperature was raised to 85 °C and the reaction was carried out for 16 h. The reaction solution was concentrated under reduced pressure, water (50 mL) and EA (80 mL) were added, and extraction and liquid separation were carried out. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a pale yellow solid (0.48 g, 66.8%).

[0473] MS (ESI, pos. ion) m / z: 337.4 [M+H] + 。

[0474] late ​

[0475] Methyl 5-(1-(tert-butoxycarbonyl)-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 methanol solution of methylamine (10 mL, 2 M). The reaction was carried out in a sealed tube at 50 °C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a colorless liquid (0.38 g, 70.6%).

[0476] MS (ESI, pos. ion) m / z: 336.2 [M+H] + 。

[0477] Step 4) Synthesis of 2-Fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0478] 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 an ethyl acetate solution of HCl (1 mL, 4 M) was added dropwise. The reaction was carried out at room temperature for 5 h. The reaction solution was concentrated under reduced pressure to obtain a brown oily product (0.21 g, 85.5%).

[0479] MS (ESI, pos. ion) m / z: 236.3 [M+H] + 。

[0480] Step 5) Synthesis 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

[0481] At room temperature, 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.53 g, 2.22 mmol), N,N-diisopropylethylamine (3.06 g, 23.68 mmol) and potassium iodide (0.012 g, 0.074 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.49 g, 1.48 mmol, reference Example 7 step 3)) in acetonitrile (20 mL), and then the temperature was raised to 80 °C and the reaction was carried out for 3 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid product (0.32 g, 44.58%).

[0482] MS(ESI,pos.ion)m / z:486.30,488.3[M+H] + 。

[0483] Step 6) 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

[0484] At room temperature, tributyl(propargyl)stannane (0.18 g, 0.56 mmol) and Xphos-Pd-G2 (0.037 g, 0.046 mmol) were added to a solution of 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.15 g, 0.31 mmol) in 1,4-dioxane (20 mL), and the atmosphere was replaced with N 2 and then heated to 90 °C and stirred for 12 h. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid product (0.075 g, 54.58%).

[0485] MS(ESI,pos.ion)m / z:446.5[M+H] + ;

[0486] HRMS:calcd.for C 25 H 24 FN 5 O 2 [M+H] + :446.1914,found:446.2001;

[0487] 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 12.31 (s, 1H), 8.67–8.61 (m, 1H), 8.09 (t, J = 8.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.26 (s, 1H), 3.64 (s, 2H), 3.31–3.25 (m, 2H), 3.16–3.12 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.70–2.66 (m, 2H), 2.42 (s, 3H), 2.14 (s, 3H).

[0488] 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

[0489]

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

[0491] 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. After addition, the reaction was carried out at 50 °C for 8 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 3 / 1) to obtain a yellow solid (50 mg, 40%).

[0492] MS (ESI, pos. ion) m / z: 255.1 [M+H] + .

[0493] Step 2) Synthesis of 7-Bromo-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one

[0494] Aqueous 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, and then diethyl (bromodifluoromethyl)phosphonate (2.10 g, 7.85 mmol) was added. After addition, the reaction was carried out at room temperature for 16 h. The reaction solution was diluted with ethyl acetate (30 mL) and water (20 mL), and extracted and separated. The upper organic layer was separated, and anhydrous Na 2 SO 4It was dried, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a white solid (100 mg, 21%).

[0495] MS(ESI,pos.ion)m / z:305.0[M+H] + 。

[0496] Step 3) Synthesis of 5-(Difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0497] 7-Bromo-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (100 mg, 0.33 mmol), (tributylstannyl)methanol (127 mg, 0.40 mmol), and Xphos-Pd-G2 (26 mg, 0.03 mmol) were added to 1,4-dioxane (4 mL), and the reaction was carried out under nitrogen protection at 80 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a pale yellow solid (50 mg, 60%).

[0498] MS(ESI,pos.ion)m / z:257.1[M+H] + 。

[0499] Step 4) Synthesis of 7-(Bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one

[0500] At 0 °C, CBr 4 (133 mg, 0.40 mmol) was added to a solution of 5-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (50 mg, 0.20 mmol) and PPh 3 (105 mg, 0.40 mmol) in dichloromethane (3 mL). After completion of the addition, the reaction was carried out at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a white solid (40 mg, 64%).

[0501] MS(ESI,pos.ion)m / z:319.1[M+H] + 。

[0502] Step 5) Synthesis of 5-(4-((8-(Difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper azin-1-yl)-6-fluoro-N-methylpicolinamide

[0503] 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 successively added to acetonitrile (3 mL), and the reaction was carried out 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), and dried over anhydrous Na 2 SO 4 4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a pale yellow solid (40 mg, 67%).

[0504] MS (ESI, pos. ion) m / z: 477.4 [M+H] + ;

[0505] HRMS: calcd. for C 22 H 23 F 3 N 6 O 3 [M+H] + : 477.1784, found: 477.1880;

[0506] 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.57 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.34–7.28 (m, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.99 (t, J = 74.7 Hz, 1H), 3.65 (s, 2H), 3.29–3.19 (m, 4H), 3.00 (d, J = 4.9 Hz, 3H), 2.72–2.64 (m, 4H), 2.63 (s, 3H).

[0507] Example 14 5-(4-((8-(Difluoromethoxy)-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0508]

[0509] Step 1) Synthesis of methyl 4-chloro-3-(difluoromethoxy)-5-nitrobenzoate

[0510] At room temperature, sodium dichloroacetate (9.87 g, 64.77 mmol) was added to a solution of methyl 4-chloro-3-hydroxy-5-nitrobenzoate (5 g, 21.59 mmol) in N,N-dimethylformamide (10 mL), and then the mixture was heated to 100 °C and stirred for 0.5 h. After the reaction solution was cooled, water (100 mL) was added, and the mixture was extracted with EA (100 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (PE / EA (v / v) = 3 / 1) to obtain a white solid product (1.5 g, 24.67%).

[0511] MS(ESI,pos.ion)m / z:282.4[M+H] + .

[0512] Step 2) Synthesis of Methyl 3-(Difluoromethoxy)-4-((1-methoxy-1-oxobutan-2-yl)amino)-5-nitrobenzoate Step 3) Synthesis of Methyl 8-(Difluoromethoxy)-2-ethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0513] At room temperature, methyl 2-aminobutyrate hydrochloride (0.98 g, 6.40 mmol) was added to a solution of methyl 4-chloro-3-(difluoromethoxy)-5-nitrobenzoate (1.5 g, 5.33 mmol) in DMF (10 mL), and then the mixture was stirred at room temperature for 16 h. The reaction solution was added to water (100 mL), and the mixture was extracted with EA (60 mL × 2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (PE / EA (v / v) = 4 / 1) to obtain a yellow oily product (0.47 g, 24.36%).

[0514] MS(ESI,pos.ion)m / z:363.1[M+H] + ;

[0515] Step 4) Synthesis of Methyl 8-(Difluoromethoxy)-2-ethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Step 5) Synthesis of 5-(Difluoromethoxy)-3-ethyl-7-(hydroxymethyl)quinoxalin-2(1H)-one

[0516] At room temperature, iron powder (0.31 g, 5.58 mmol) was added to a solution of methyl 3-(difluoromethoxy)-4-((1-methoxy-1-oxobutan-2-yl)amino)-5-nitrobenzoate (0.45 g, 1.24 mmol) in acetic acid (5 mL), and then the temperature was raised to 80 °C and stirred for 3.5 h. After the reaction solution was cooled, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was added to water (100 mL) and extracted with DCM (100 mL×2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain a yellow oily product (0.36 g, 96.52%).

[0517] MS(ESI,pos.ion)m / z:301.2[M+H] + ;

[0518] Step 6) Synthesis of 7-(Bromomethyl)-5-(difluoromethoxy)-3-ethylquinoxalin-2(1H)-one

[0519] At room temperature, 2,3-dichloro-5,6-dicyanobenzoquinone (0.31 g, 1.35 mmol) was added to a solution of methyl 8-(difluoromethoxy)-2-ethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.37 g, 1.23 mmol) in DCM (5 mL), and then stirred for 3 h. Water (100 mL) was added to the reaction solution, and it was extracted with DCM (100 mL×2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain a yellow solid product (0.3 g, 81.08%).

[0520] MS(ESI,pos.ion)m / z:299.1[M+H] + ;

[0521] Step 7) Synthesis of 5-(4-((8-(Difluoromethoxy)-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper

[0522] At 0 °C, lithium aluminum hydride (0.042 g, 1.11 mmol) was added to a solution of methyl 8-(difluoromethoxy)-2-ethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.22 g, 0.74 mmol) in THF (5 mL). Then, the reaction mixture was stirred at 0 °C for 2.5 h. The reaction was quenched with dilute hydrochloric acid (2 M, 1 mL), and the mixture was extracted with EA (50 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain a yellow solid product (0.19 g, 95.32%).

[0523] MS(ESI,pos.ion)m / z:271.2[M+H] + ;

[0524] azin-1-yl)-6-fluoro-N-methylpicolinamide

[0525] At 0 °C, triphenylphosphine (0.46 g, 1.75 mmol) and carbon tetrabromide (0.46 g, 1.4 mmol) were added to a solution of 5-(difluoromethoxy)-3-ethyl-7-(hydroxymethyl)quinoxalin-2(1H)-one (0.19 g, 0.70 mmol) in DCM (5 mL). Then, the reaction mixture was slowly warmed to room temperature and stirred for 16 h. Water (40 mL × 2) was added to the reaction mixture, and the mixture was extracted with DCM (50 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 2 / 1) to obtain a white solid product (0.17 g, 72.58%).

[0526] MS(ESI,pos.ion)m / z:333.1[M+H] + ;

[0527] Step 1) Synthesis of tert-Butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate Step 2) Synthesis of 6-(Piperazin-1-yl)nicotinonitrile

[0528] At room temperature, 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamide (0.086 g, 0.36 mmol), DIPEA (0.093 g, 0.72 mmol), and KI (0.002 g, 0.012 mmol) were added to a solution of 7-(bromomethyl)-5-(difluoromethoxy)-3-ethylquinoxalin-2(1H)-one (0.080 g, 0.24 mmol) in ACN (20 mL). Subsequently, the reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v) = 20 / 1), a yellow solid product (0.08 g, 67.92%) was obtained.

[0529] MS (ESI, pos. ion) m / z: 491.3 [M+H] + ;

[0530] 1 H NMR (600 MHz, DMSO-d 6 ) δ (ppm) 12.42 (s, 1H), 8.42–8.37 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.60–7.54 (m, 1H), 7.37 (t, J = 74.5 Hz, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 3.61 (s, 2H), 3.18 (t, J = 4.8 Hz, 4H), 2.80 (q, J = 7.3 Hz, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.57 (t, J = 4.4 Hz, 4H), 1.21 (t, J = 7.1 Hz, 3H).

[0531] Example 15 5-(4-((8-(Difluoromethoxy)-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide

[0532]

[0533]

[0534] At room temperature, N,6-dimethyl-5-(piperazin-1-yl)pyridinecarboxamide (0.084 g, 0.36 mmol), DIPEA (0.093 g, 0.72 mmol) and KI (0.002 g, 0.012 mmol) were added to a solution of 7-(bromomethyl)-5-(difluoromethoxy)-3-ethylquinoxalin-2(1H)-one (0.080 g, 0.24 mmol) in ACN (20 mL). Subsequently, the reaction mixture was heated to 80 °C and reacted for 3 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v) = 20 / 1), a yellow solid product (0.09 g, 77.03%) was obtained.

[0535] MS (ESI, pos. ion) m / z: 487.3 [M+H] + ;

[0536] 1 H NMR (400 MHz, DMSO-d6 ) δ (ppm) 12.41 (s, 1H), 8.44–8.39 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.51–7.45 (m, 1H), 7.31 (d, J = 74.6 Hz, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 3.62 (s, 2H), 3.01–2.90 (m, 4H), 2.83–2.80 (m, 2H), 2.80–2.78 (m, 3H), 2.65–2.54 (m, 4H), 2.48 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H).

[0537] Example 16 6-(4-((8-(Difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile

[0538]

[0539] Step 3) Synthesis of 6-(4-((8-(Difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper

[0540] At room temperature, Ruphos-Pd-G3 (0.48 g, 0.57 mmol) was added to a solution of 6-bromopyridine-3-carbonitrile (1.5 g, 8.20 mmol), tert-butyl piperazine-1-carboxylate (1.53 g, 8.20 mmol), and cesium carbonate (5.34 g, 16.4 mmol) in 1,4-dioxane (30 mL), and then N was displaced 2 , and the mixture was heated to 110 °C and reacted overnight. It was filtered through diatomaceous earth, the filtrate was concentrated by rotary evaporation, and the residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 6:1) to obtain a yellow solid product (1.7 g, 71.93%).

[0541] MS (ESI, pos. ion) m / z: 189.10 [M + H - 100] + .

[0542] azin-1-yl)nicotinonitrile

[0543] At room temperature, 4 M hydrochloric acid dioxane solution (14.75 ml, 59.0 mmol, 4 M) was added to ethyl acetate (25 mL) of 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 5.90 mmol), and the reaction was carried out overnight. After the reaction was completed, the reaction solution was directly filtered to obtain a solid product, which was dried at room temperature to obtain a light yellow solid (0.65 g, 58.57%).

[0544] MS (ESI, pos. ion) m / z: 189.20 [M + H] + .

[0545] Step 2) Synthesis of tert-Butyl 4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate Step 3) Synthesis of 6-Chloro-N-methyl-5-(piperazin-1-yl)picolinamide

[0546] At room temperature, to a solution of 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (0.1 g, 0.31 mmol) in acetonitrile (3 mL) was added N,N-diisopropylethylamine (0.12 g, 0.93 mmol) and 6-(piperazin-1-yl)nicotinonitrile (0.088 g, 0.46 mmol), and then the temperature was raised to 80 °C. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in DCM (30 mL), washed with water (15 mL×3), the organic phase was dried, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 95 / 5) to obtain a crude product. The obtained product was recrystallized to obtain a white solid product (0.11 g, 82.32%).

[0547] MS(ESI,pos.ion)m / z:427.10[M+H] + ;

[0548] 1 H NMR(599MHz,DMSO-d 6 )δ12.42(s,1H),8.47(d,J=2.4Hz,1H),7.84(dd,J=9.1,2.4Hz,1H),7.36(t,J=74.5Hz,1H),7.15–7.05(m,2H),6.92(d,J=9.1Hz,1H),3.69–3.65(m,4H),3.59(s,2H),2.49–2.46(m,4H),2.41(s,3H).

[0549] Example 17 6-Chloro-5-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0550]

[0551] Step 1) Synthesis of tert-butyl 4-(2-chloro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0552] At room temperature, Ruphos PdG3 (0.83 g, 1.0 mmol) was added to a solution of methyl 5-bromo-6-chloropicolinate (5 g, 19.96 mmol), tert-butyl piperazinecarboxylate (4.09 g, 21.96 mmol) and Cs 2 CO 3 (13.01 g, 39.92 mmol) in 1,4-dioxane (100 mL), and N was displaced.2 It was then heated to 80 °C and stirred for reaction for 12 h. After the reaction solution was cooled, it was filtered with diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain a yellow solid product (0.2 g, 2.82%).

[0553] MS (ESI, pos. ion) m / z: 356.1 [M+H] + ;

[0554] Step 4) Synthesis of 6-Chloro-5-(4-((8-(Difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)meth

[0555] At room temperature, methylamine (0.48 g, 15.3 mmol) was added to a solution of tert-butyl 4-(2-chloro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (0.18 g, 0.51 mmol) in MeOH (15 mL), and then the mixture was stirred at room temperature for reaction for 12 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 3 / 2) to obtain a yellow oily product (0.15 g, 83.57%).

[0556] MS (ESI, pos. ion) m / z: 355.1 [M+H] + ;

[0557] yl)piperazin-1-yl)-N-methylpicolinamide

[0558] At room temperature, 1,4-dioxane solution of hydrochloric acid (4 M, 0.32 mL, 1.26 mmol) was added to a solution of tert-butyl 4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (0.15 g, 0.42 mmol) in EA (10 mL), and then the mixture was stirred at room temperature for reaction for 10 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v) = 10 / 1) to obtain a yellow solid product (0.10 g, 92.87%).

[0559] MS (ESI, pos. ion) m / z: 255.1 [M+H] + ;

[0560] ​ ​

[0561] To a solution of 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (0.1 g, 0.31 mmol) in ACN (10 mL) were added 6-chloro-N-methyl-5-(piperazin-1-yl)nicotinamide (0.087 g, 0.34 mmol), N,N-diisopropylethylamine (0.12 g, 0.93 mmol) and potassium iodide (0.0026 g, 0.015 mmol), and then the mixture was heated to 80 °C and stirred for 3 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v) = 20 / 1), to obtain a white solid product (0.12 g, 77.69%).

[0562] MS (ESI, pos.ion) m / z: 493.2 [M+H] + ;

[0563] 1 H NMR (600 MHz, DMSO-d 6 ) δ (ppm) 12.43 (s, 1H), 8.45–8.40 (m, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 74.5 Hz, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 3.63 (s, 2H), 3.15–3.08 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.63–2.56 (m, 4H), 2.41 (s, 3H).

[0564] Example 18 Synthesis of 3-chloro-4-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)benzonitrile

[0565]

[0566] Step 1) Synthesis of tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate

[0567] At room temperature, to a solution of 4-bromo-3-chlorobenzonitrile (5 g, 23.10 mmol), tert-butyl piperazine-1-carboxylate (4.30 g, 23.1 mmol), and cesium carbonate (15.05 g, 46.2 mmol) in 1,4-dioxane (60 mL) was added Ruphos-Pd-G3 (1.35 g, 1.62 mmol), and then N 2, heated to 110 °C and reacted for 10 h. After the reaction solution was cooled, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1) to obtain a yellow solid product (3.5 g, 47.09%).

[0568] MS (ESI, pos. ion) m / z: 266.13 [M + H - 56] + .

[0569] Step 2) Synthesis of 3-chloro-4-(piperazin-1-yl)benzonitrile

[0570] At room temperature, to a solution of tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1 g, 3.11 mmol) in ethyl acetate (20 mL), hydrochloric acid-dioxane solution (1.13 g, 31.10 mmol, 4 M) was added, and the reaction was carried out at room temperature for 10 h. The reaction was stopped, and the reaction solution was directly filtered to obtain a solid product, which was dried at room temperature to obtain a yellow solid product (0.3 g, 43.55%).

[0571] Step 3) Synthesis of 3-chloro-4-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)benzonitrile Step 3) Synthesis of 3-chloro-4-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)benzonitrile

[0572] At room temperature, to a solution of 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (0.08 g, 0.25 mmol) in acetonitrile (3 mL), N,N-diisopropylethylamine (0.097 g, 0.75 mmol) and 3-chloro-4-(piperazin-1-yl)benzonitrile (0.083 g, 0.38 mmol) were added, and then the temperature was raised to 80 °C and the reaction was carried out for 2 h. The reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane (30 mL), washed with water (15 mL × 3), the organic phase was dried, evaporated to dryness, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1) to obtain a white solid product (0.07 g, 60.71%).

[0573] MS (ESI, pos. ion) m / z: 460.13 [M + H] + ;

[0574] 1 H NMR (400 MHz, DMSO-d 6)δ 12.42 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.75 (t, J = 74.4, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.16–7.03 (m, 2H), 3.61 (s, 2H), 3.19–3.04 (m, 4H), 2.64–2.53 (m, 4H), 2.41 (s, 3H).

[0575] Example 19 5-(4-((7-(Difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylnicotinamide

[0576]

[0577] Step 1) Synthesis of methyl 2-(difluoromethoxy)-4-fluoro-5-nitrobenzoate

[0578] Methyl 4-fluoro-2-hydroxy-5-nitrobenzoate (3.0 g, 13.94 mmol), K 2 CO 3 (21.31 g, 16.73 mmol) were added to DMF (20 mL), and then sodium difluorochloroacetate (6.38 g, 41.82 mmol) was added. The reaction was carried out at 80 °C for 21 h. The reaction solution was diluted with EtOAc (100 mL), washed with water (50 mL × 3), and then washed with saturated NaCl solution (50 mL). It was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 8 / 1) to obtain a pale yellow liquid (1.5 g, 40.57%).

[0579] MS (ESI, pos. ion) m / z: 266.1 [M + H] + .

[0580] Step 2) Synthesis of methyl 2-(difluoromethoxy)-4-((1-methoxy-1-oxopropan-2-yl)amino)-5-nitrobenzoate Step 2) Synthesis of methyl 2-(difluoromethoxy)-4-((1-methoxy-1-oxopropan-2-yl)amino)-5-nitrobenzoate

[0581] Methyl 2-(difluoromethoxy)-4-fluoro-5-nitrobenzoate (1.0 g, 3.77 mmol), DL-alanine methyl ester hydrochloride (1.05 g, 7.54 mmol), and DIPEA (1.95 g, 15.08 mmol) were added to 1,4-dioxane (12 mL). The reaction was carried out at 100 °C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to obtain a yellow liquid (940 mg, 71.57%).

[0582] MS(ESI,pos.ion)m / z:349.2[M+H] + ;

[0583] Step 3) Synthesis of methyl 7-(difluoromethoxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Step 3) Synthesis of methyl 7-(difluoromethoxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0584] Methyl 2-(difluoromethoxy)-4-((1-methoxy-1-oxopropan-2-yl)amino)-5-nitrobenzoate (940 mg, 2.70 mmol), Fe (904 mg, 16.20 mmol), and NH 4 Cl (866 mg, 16.20 mmol) were added to a mixture of MeOH (16 mL) and water (6 mL), and the reaction was carried out at 70 °C for 15 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. EtOAc (80 mL) and water (40 mL) were added for extraction and liquid separation. The organic phase was washed with saturated NaCl solution (40 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / EtOAc (v / v) = 3 / 1) to obtain a pale yellow solid (510 mg, 66%).

[0585] MS(ESI,pos.ion)m / z:287.2[M+H] + ;

[0586] Step 4) Synthesis of methyl 7-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0587] Methyl 7-(difluoromethoxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (500 mg, 1.75 mmol) and DDQ (476 mg, 2.10 mmol) were added to DCM (16 mL), and the reaction was carried out at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated NaHCO 3 (60 mL) was added for alkalization, and the mixture was filtered to obtain a solid. The solid was dissolved in a mixture of MeOH and DCM (3 mL / 30 mL), concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / EtOAc (v / v) = 3 / 1) to obtain a white solid (285 mg, 57.4%).

[0588] MS(ESI,pos.ion)m / z:285.2[M+H] + ;

[0589] Step 5) Synthesis of 6-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0590] Methyl 7-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (280 mg, 0.98 mmol), LiAlH 4(74 mg, 1.96 mmol) was added to a solution of THF (10 mL), and the reaction was carried out at room temperature for 15 h. The reaction solution was quenched by adding MeOH (2 mL), concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain a white solid (60 mg, 24%).

[0591] MS (ESI, pos. ion) m / z: 257.2 [M+H] + ;

[0592] Step 6) Synthesis of 7-(bromomethyl)-6-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one

[0593] At 0 °C, CBr 4 (44 mg, 0.13 mmol) was added to a solution of 6-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (17 mg, 0.07 mmol) and PPh 3 (35 mg, 0.13 mmol) in DCM (4 mL) under nitrogen protection, and the reaction was carried out at 0 °C for 15 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain a white solid (5 mg, 24%).

[0594] MS (ESI, pos. ion) m / z: 319.1 [M+H] + ;

[0595] Step 7) Synthesis of 5-(4-((7-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylnicotinamide Step 7) Synthesis of 5-(4-((7-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylnicotinamide

[0596] 7-(Bromomethyl)-6-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (5 mg, 0.01 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)nicotinamide (8 mg, 0.03 mmol), and DIPEA (12 mg, 0.10 mmol) were successively added to ACN (2 mL), and the reaction was carried out at 70 °C for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a white solid (3 mg, 40%).

[0597] MS (ESI, pos. ion) m / z: 477.1 [M+H] + ;

[0598] 1 H NMR (600 MHz, CDCl 3)δ10.62(s,1H),8.00(d,J=7.9Hz,1H),7.61(s,1H),7.51(dd,J=10.3,5.2Hz,1H),7.36(s,1H),7.29(dd,J=9.7,8.5Hz,1H),6.61(t,J=73.9Hz,1H),3.71(s,2H),3.25–3.20(m,4H),3.00(d,J=5.1Hz,3H),2.73–2.69(m,4H),2.60(s,3H).

[0599] Biological test

[0600] Example A: Evaluation of the inhibitory effect of the compounds of the present invention on the enzyme activities of PARP1 and PARP2

[0601] Experimental purpose: To evaluate the inhibitory effect of the compounds of the present invention on the enzyme activities of PARP1 and PARP2 by ELISA method.

[0602] Brief experimental procedure:

[0603] 1. Prepare a histone-coated 384-well plate: Add 25 μL of histone solution to each well and incubate overnight at 4°C.

[0604] 2. Prepare PBST buffer, blocking buffer (add 5% BSA and 0.05% Tween-20 to PBS buffer solution) and detection buffer (20 mM HEPES pH 7.5 + 100 mM NaCl + 2 mM DTT + 0.002% Tween-20 + 0.1% BSA).

[0605] 3. Wash the histone-coated 384-well plate 3 times with PBST buffer, block it at room temperature for 1 h with 50 μl of blocking buffer, and wash the 384-well plate 3 times with PBST buffer.

[0606] 4. Prepare a 2000-fold stock solution of the test compound with DMSO, take 50 nl of the stock solution and add it to 19.95 μl of detection buffer and mix well, then transfer 5 μL of the serially diluted test compound to each well.

[0607] 5. Enzymatic reaction (PARP1): PARP1&DNA mix is pre-incubated at 25°C for 10 minutes, add 10 μL of PARP1&DNA mix to each well and incubate with the test compound at room temperature for 10 minutes, then add 10 μL of 2.5×NAD + Incubate at 25°C for 60 minutes, and wash the 384-well plate 3 times with PBST buffer.

[0608] Enzymatic reaction (PARP2): PARP2 was pre-incubated at 25 °C for 10 minutes. 10 μL of PARP2 was added to each well and incubated with the test compound at room temperature for 10 minutes. Then 10 μL of 2.5× Biotin-NAD was added to each well and incubated at 25 °C for 90 minutes. The 384-well plate was washed 3 times with PBST buffer. + 6. Detection (PARP1): 20 μL of anti-Poly / Mono-ADP Ribose Rabbit mAb (anti-Poly / Mono-ADP-ribose rabbit monoclonal antibody) was added and incubated at room temperature for 1.5 hours. The 384-well plate was washed 3 times with PBST buffer. 20 μL of diluted anti-rabbit IgG, HRP-linked Antibody (diluted 1:2000 with blocking buffer) was added and incubated at room temperature for 1 hour. Then the 384-well plate was washed 3 times with PBST buffer. 25 μL of Femto-ECL Substrate A and Femto-ECL Substrate B (1:1) mixture was added.

[0609] 6. Detection (PARP2): 25 μL of Stre-HRP was added and incubated at room temperature for 1 hour. The 384-well plate was washed 3 times with PBS buffer. 25 μL of Femto-ECL Substrate A and Femto-ECL Substrate B (1:1) mixture was added.

[0610] 7. The chemiluminescence intensity was detected using an Envision multimode microplate reader.

[0611] 8. Data processing

[0612] The inhibition rate was calculated using formula (1) in Excel.

[0613] Formula (1): inh% = (Max - Signal) / (Max - Min) * 100

[0614] The data was fitted using formula (2) in XL-Fit to obtain the IC

[0615] value. 50 Formula (2): Y = Bottom + (Top - Bottom) / (1 + (IC

[0616] / X) * HillSlope); where Y is the inhibition percentage and X is the compound concentration. 50 In this experiment, Olaparib and AZD5305 were used as positive control drugs to ensure the normal operation of the experimental system. The experimental results are shown in Table A.

[0617] In this experiment, Olaparib and AZD5305 were used as positive control drugs to ensure the normal operation of the experimental system. The experimental results are shown in Table A.

[0618] Table A: Results of the determination of the inhibitory effects of the compounds of the present invention on the enzymatic activities of PARP1 and PARP2

[0619]

[0620]

[0621] From the experimental results, it can be seen that most of the compounds of the present invention have strong inhibitory effects on the enzymatic activity of PARP1, and individual compounds have strong inhibitory effects on both PARP1 and PARP2.

[0622] Example B: Evaluation of the inhibitory effect of the compounds of the present invention on the proliferation of DLD-1 BRCA2(- / -) cells

[0623] Experimental purpose: To evaluate the inhibitory effect of the compounds of the present invention on the proliferation of DLD-1 BRCA2(- / -) cells using the CTG method.

[0624] Brief experimental procedure:

[0625] 1. Cell pretreatment: DLD-1 BRCA2(- / -) cells were cultured in growth medium 1640 + 10% FBS (fetal bovine serum) + 1% Penicillin-Streptomycin. Cells in the logarithmic growth phase were digested with trypsin-EDTA, centrifuged and resuspended, and then DLD-1 BRCA2(- / -) was plated at 1,000 cells / well in a sterile 96-well opaque plate, 75 μl per well. After plating, the cell culture plate was placed at 37 °C, 5% CO 2 and cultured overnight until adherent, followed by treatment with the test compound.

[0626] 2. Drug treatment of DLD-1 BRCA2(- / -) cells: The test compound was prepared into a 10 mM stock solution with DMSO, and the test compound was diluted with growth medium to a 4× working solution (the test compound started at 40 μM and was diluted 9-fold at 4 concentrations), and then 25 μl of the 4× working solution was added to each well, so that the final concentrations of the test compound were 10000, 2500, 625, 156, 39, 9.7, 2.4, 0.61, 0.152 nM in sequence. At the same time, blank control wells containing the same concentration of DMSO were set, and 3 replicates were set for each concentration. After adding the test compound, it was placed in 5% CO 2 and cultured in an incubator at 37 °C for 7 days.

[0627] 3. After the culture was completed, 100 μl of Reagent was added to each well, the fluorescence intensity was measured, and the curve was fitted with GraphPad software to calculate the IC 50 value of cell proliferation inhibition.

[0628] The experimental results show that the compound of the present invention has a strong inhibitory effect on the proliferation of DLD-1 BRCA2 (- / -) cells.

[0629] Example C: Evaluation of the stability of the compound of the present invention in human and rat liver microsomes

[0630] Experimental purpose: To evaluate the stability of the compound of the present invention in human and rat liver microsomes by LC-MS / MS method.

[0631] Brief experimental procedure: At 37 °C, the test compound and human or rat liver microsomes were incubated together in 0.1 M potassium phosphate buffer (pH = 7.4 ± 0.1). By measuring the concentration of the test compound at different incubation times, the half-life of the compound was calculated by plotting "relative compound content" against "incubation time" in GraphPad Prism 5.01, and the intrinsic clearance was calculated. The experimental system is shown in Table 1:

[0632] Table 1: Experimental system

[0633]

[0634]

[0635] The ratio of the sample peak area to the internal standard peak area was obtained by LC / MS / MS analysis. Regarding the compound content at the 0 min point as 100%, the relative content of the compound at each time point was calculated. The half-life of the compound was calculated by plotting "relative compound content" against "incubation time", and the intrinsic clearance was calculated.

[0636] The experimental results show that the compound of the present invention has a longer half-life and a lower clearance rate. Therefore, the compound of the present invention has higher stability in human liver microsomes.

[0637] Example D: Pharmacokinetic evaluation of intravenous injection or gavage of the compound of the present invention in rats, mice, dogs and monkeys The inventors evaluated the pharmacokinetics of the compound of the present invention in rats, mice, dogs and monkeys. Among them, the animal information is shown in detail in Table 2.

[0638] Table 2: Information table of test animals of the present invention

[0639] Germline Grade Gender Body weight Age Source SD rats SPF Male 180-350g 6 - 11 weeks Hunan Slack Jingda Experimental Animal Co., Ltd. BALB / c mice SPF Male 18-30g 6 - 8 weeks Hunan Slack Jingda Experimental Animal Co., Ltd. Beagle dogs Ordinary grade Male 7 - 12 kg 6 - 12 months Beijing Mas Biotech Co., Ltd. Cynomolgus monkeys Ordinary grade Male 2.5 - 6.0 kg 3 - 6 years old Guangzhou Huazhen Biotechnology Co., Ltd.

[0640] Experimental method

[0641] The compounds of the present invention were administered to the test animals in the form of 5% DMSO + 30% PEG400 + 65% normal saline, 10% DMSO + 10% Kolliphor HS15 + 80% Saline, 10% DMSO + 89% (25% SBE - B - CD)+(2% HCl), 20% PEG400 + 80% sterile water for injection or 10% DMA + 10% HS15 + 30% PEG400 + 50% sterile water for injection solution. The animals were fasted for 12 h before administration and allowed free access to water. For the intravenous injection group, the administration dose was 1 mg / kg. Blood samples (about 0.15 mL) were taken from the vein at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dogs) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (mice and rats) or 0.083, 0.25, 0.5, 1.0, 2.0, 6.0, 8.0 and 24 h (monkeys). EDTA - K 2 was added in advance into the blood collection tubes as anticoagulant. The blood samples were centrifuged at 12,000 rpm for 2 minutes, the plasma was collected and stored at -20 °C or -70 °C. For the intragastric administration group, the administration dose was 1 mg / kg (mice, dogs and monkeys) or 5 mg / kg (rats). Blood samples (about 0.15 mL) were taken from the vein at the following time points after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dogs) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (mice and rats) or 0.25, 0.5, 1.0, 2.0, 6.0, 8.0 and 24 h (monkeys). EDTA - K 2 was added in advance into the blood collection tubes as anticoagulant. The blood samples were centrifuged at 12,000 rpm for 2 minutes, the plasma was collected and stored at -20 °C or -70 °C.

[0642] The above - collected plasma samples were processed (after thawing the frozen plasma at room temperature, vortexed for 15 s to mix evenly, 10 - 20 μL of plasma was taken, 120 - 150 μL of acetonitrile solution containing internal standard was added, vortexed for 5 min to mix evenly, centrifuged at 4,000 rpm for 5 minutes, 100 μL of the supernatant was taken, and 120 - 150 μL of water (v / v = 1 / 1) was added and mixed evenly), and then the concentration of the compound in the plasma was analyzed by LC - MS / MS. The analysis results showed that the compounds of the present invention had good pharmacokinetic properties in rats, mice, dogs and monkeys. It was indicated that the compounds of the present invention had better drug - like properties and better clinical application prospects.

[0643] Example E: Evaluation of the inhibitory effect of the compounds of the present invention on the proliferation of MDA - MB - 436 cells

[0644] Experimental objective: To evaluate the inhibitory effect of the compound of the present invention on the proliferation of MDA-MB-436 cells.

[0645] Brief experimental procedure:

[0646] 1. Cell pretreatment: MDA-MB-436 cells were cultured in growth medium DMEM + 10% FBS + 1% double antibody + 1% ITS + 16 μg / ml glutathione. Cells in the logarithmic growth phase were digested with trypsin-EDTA, centrifuged and resuspended, and then seeded at 500 - 1000 cells / well on a sterile opaque 96-well plate, with 90 μl per well. After seeding, the cell culture plate was placed at 37°C and 5% CO 2 and cultured overnight until adherent, followed by drug treatment.

[0647] 2. Drug treatment of MDA-MB-436 cells: The test compound was prepared into a 10 mM stock solution with DMSO, and the drug was diluted with growth medium to a 10× working solution (starting from 100 μM for the compound, diluted 9 concentrations in a 4-fold dilution). Then, 10 μl of the 10× working solution was added to each well, so that the final concentrations of the drug were 10000, 2500, 625, 156, 39, 9.7, 2.4, 0.61, 0.152 nM in sequence. At the same time, blank control wells containing the same concentration of DMSO were set, with 3 replicates for each concentration. After adding the drug, it was placed in 5% CO 2 and cultured in an incubator at 37°C for 7 days.

[0648] 3. After the culture was completed, 100 μl of Reagent was added to each well to measure luminescence. The curve was fitted with GraphPad software to calculate the IC 50 value of cell proliferation inhibition.

[0649] The experimental results showed that the compound of the present invention had a strong inhibitory effect on the proliferation of MDA-MB-436 cells.

[0650] In the description of this specification, the descriptions with reference to the terms "one embodiment", "one implementation", "some embodiments", "examples", "specific examples", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment, implementation, or example are included in at least one embodiment, implementation, or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment, implementation, or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments, implementations, or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments, implementations, or examples described in this specification and the features of different embodiments, implementations, or examples.

[0651] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

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 and 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 claim 1, 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 claim 1, 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; R 2 is -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.

6. The compound according to claim 1 or 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; 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.

7. The compound according to claim 1, 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 claim 1 or 7, 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.

9. A compound according to any one of claims 1 to 8, 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 to 8.

10. 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:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10; and The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

12. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by PARP1; The diseases mediated by PARP1 are cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases and metabolic diseases; the cancers are 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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