RU2802283C2 - New inhibitor based on a quinoline derivative - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a new compound of general formula (I) and a pharmaceutically acceptable salt thereof, which have inhibitory activity against TAM, CSF1R and TRK family kinases. In this formula, W is selected from hydrogen; R is a group represented by the general formula (b): in formula (b) fragment is attached via a linking group to groups M¹ and M²; each of X¹ and X² is independently selected from CR^a and NR^b and X³ is C=O; each of X⁴ and X⁵ is independently selected from C; each of M¹ and M² is selected from hydrogen and C_1-6alkyl, or M¹ and M² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; Cy² is selected from 6-14 membered aryl which is optionally substituted with one or more R², each R² being selected from hydrogen, halogen and C_1-6alkyl; Cy³ is optionally substituted with one or more R³; Y², Y³, Y⁶ and Y⁷ are each independently selected from CH or N and at least one of Y², Y³, Y⁶ and Y⁷ is N, with each R³ selected from hydrogen; Cy⁴ selected from optionally substituted with one or more R⁴, Y⁴ and Y⁵ are independently selected from CH or N, and at least one of Y⁴ and Y⁵ is N, ring B is phenyl; each R⁴ is independently selected from hydrogen, -NR^bR^c and C_1-6alkoxy; L is -O, R^b and R^c are absent or in each case each is selected from hydrogen; n is an integer 0-4; in the groups represented by formula (b), is a double bond moiety which is optionally present in the cyclic structure. The invention also relates to a pharmaceutical composition containing a compound of general formula (I) and having the property of an inhibitor of TAM, CSF1R and TRK family kinases, the use of a compound of general formula (I) in the manufacture of drugs for the treatment of diseases associated with the activity of TAM, CSF1R and TRK, a process for the preparation of a compound of formula (I); and an intermediate for its preparation.

EFFECT: obtaining a new inhibitor based on a quinoline derivative.

16 cl, 8 tbl, 24 ex

Description

The field of technology to which the invention belongs

The present invention relates to the field of medicine, in particular to a compound represented by the general formula (I) (which is an inhibitor of TAM family kinases and CSF1R kinase), a pharmaceutically acceptable salt thereof, an ester, a stereoisomer and a tautomer, a pharmaceutical composition containing the same, a pharmaceutical composition and their application. The compound of the present invention can selectively inhibit TAM family tyrosine kinases and CSF1R kinase and can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands. In addition, the compound of the present invention can be used to treat and/or prevent related diseases caused by NTRK, more specifically, said compound can be used to treat and/or prevent relevant drug resistant diseases caused by NTRK mutations.

Prerequisites for the creation of the invention

The TAM family includes three representatives, i.e. Axl, Mer and Tyro-3. This family contains an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain consists of repeating units formed by the binding of two immunoglobulin-like domains to two type III fibronectins. The conserved amino acid sequence KW(I/L)A(I/L)ES in its intracellular kinase domain is a unique structural feature of the TAM family. This family shares one common ligand, which is growth blocking protein 6 (GAS6), and the ligand can bind to all TAM receptors with varying degrees of binding. In addition, the TAM family further includes related receptors such as vitamin K-dependent protein S (ProS), Tubby barrel protein, recombinant human barrel protein 1 (Tulp1), and galectin-3 (WU Yan jun, Chinese Journal of New Drugs 2016; Lu Ping, Journal of Chinese Practical Diagnosis and Therapy, 2016).

Among others, Axl (also called UFO, Ark, Tyro-7, JTK1), Mer (also called c-Mer, Mertk, Eyk, Nyk, Tyro-12), Tyro-3 (also called Sky, Byk, Rse, Dtk etc.), galectin-3, Gas6, ProS are aberrantly expressed in a wide range of solid tumors, such as lung cancer, gastric cancer, and liver cancer, as well as in varieties of hemoblastoses, such as AML, ALL, and CML, and to a large extent degrees are associated with poor prognosis in terms of disease, disease progression, tumor metastasis, tumor drug resistance, and the like. (Douglas K, Nature reviews, 2014). In particular, Axl as a tyrosine kinase has been shown to be one of the causes of resistance to EGFR inhibitors in NSCLC and is strongly associated with the metastasis of various solid tumors. Drugs developed on the basis of this target also confirm that inhibition of Axl can prevent the development of resistance to EGFR inhibitors and tumor metastasis (T. Jimbo, Annals of Oncology, 2017; Sacha J. Holland, American Association for Cancer Research, 2010). At the same time, Axl, Mer, Tmyo-3, and TAM ligands also play an important role in tumor immunization. Inhibition of members of the TAM family and their ligands can invert the immunosuppressive environment of the tumor and increase the ability of the immune system to destroy tumor cells by stimulating the polarization of macrophages into M1 macrophages with increased activation and function of effector T cells and increased antitumor activity of NK cells (Yemsratch T. Akalu, Immunological Reviews, 2017; Greg Lemke, Nature Reviews Immunology, 2008). Therefore, the development of such inhibitors can have strong inhibitory and therapeutic effects against various solid tumors and hemoblastoses induced by members of this family, such as lung cancer, liver cancer, breast cancer, brain glioma, melanoma, AML, ALL and CML.

In addition to the above tumor diseases, TAM family receptors and their ligands can regulate several physiological functions such as vascular smooth muscle homeostasis, platelet aggregation, thrombus stabilization, erythropoiesis, oligodendrocyte survival, osteoclast function, phagocytosis of apoptotic cells, inflammation, and innate immunity. Therefore, the TAM family inhibitor can also be used in the case of relevant diseases caused by disturbance of the signaling pathway mediated by members of the TAM family, such as adenomyosis, vascular disease/damage, psoriasis, visual defect/impairment (caused by macular degeneration, diabetes, preterm birth, and etc.), kidney disease, rheumatoid arthritis and osteoporosis.

The colony stimulating factor receptor 1 (CSF1R), also referred to as c-FMS, FMS, FIM2, MCSF and CD115, is a single chain transmembrane glycoprotein consisting of 972 amino acid residues. Like FLT-3, PDGFR and KIT, it belongs to the type III receptor tyrosine kinase (RTK) family. CSF1R is exclusively expressed on the surface of monocyte lines such as macrophages. CSF1R ligands currently reported include column stimulating factor 1 (CSF1, macrophage column stimulating factor, also referred to as M-CSF) and interleukin-34 (IL-34). CSF1 influences various cellular functions of monocytic cell lines by binding to CSF1R. IL-34 can stably bind to CSF1R, thereby promoting the survival, proliferation and differentiation of monocytic cell lines. They make up the CSF1/IL-34/CSF1R pathway.

In the CSF1/CSF1R pathways, CSF1 and CSF1R form a signaling axis that promotes the growth of macrophages in the body and regulates the normal development and homeostasis of tissues and organs, while an imbalance in the body's homeostasis can cause various diseases, such as inflammation, diseases of the immune system, and tumors. Although macrophages have the ability to destroy tumor cells, tumor-associated macrophages (TAMs) mainly exert immunosuppressive effects. In particular, myeloid-derived suppressor cells (MDSCs) can induce macrophages to selectively ignore the presence of tumor cells through high expression of CSF1R, further promoting tumor development and metastasis. Currently, increased expression of CSF1/CSF1R has been found in a number of cancers, such as breast cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, and Hodgkin's lymphoma (O' Brien J, Am J Pathol, 2010). Overexpression of CSF1/CSF1R is associated with malignant invasion and poor prognosis for tumors. High expression of CSF1R can be found in CSF1-induced fibroblasts and epithelial cells, and eventually tumors develop in nude mice, suggesting that the CSF1/CSF1R axis promotes tumor cell proliferation and survival and has a vital function in oncogenesis and tumor development. . In addition, in bone metastases, CSF1R has a function in osteolytic bone destruction (Ono, Mol. Cancer Ther, 2006). Therefore, inhibition of the CSF1/IL-34/CSF1R signaling pathway can attenuate the immunosuppressive effect of tumors and increase the activity of the immune system, thereby suppressing the development and metastasis of tumors. It has also been reported that CSF1R inhibitors can significantly shrink tumors, such as the volume of tumors such as glioblastoma, and reduce tumor invasiveness and proliferation (Pyonteck Stephanie M, Nature Medicine, 2013). Thus, inhibition of the CFS1R pathway has become one of the main therapeutic targets for cancer.

Both TAM inhibitors and CSF1R inhibitors can attenuate the immunosuppressive environment of tumors and increase the ability of the immune system to destroy tumor cells. However, based on the complexity of tumor pathogenesis, if they can simultaneously target these two targets, they may exert their dual immunotherapeutic effect on tumors. At present, clinically used CSF1R inhibitors are generally used in combination with PD-1 in therapy, and there are no inhibitors available on the market that simultaneously target TAM and CSF1R.

The NTRK gene contains NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of proteins from the tropomyosin-related kinase (TRK) family: TRKA, TRKB, and TRKC, respectively. Gene expression studies demonstrate that the NTRK gene is predominantly expressed in the nervous system and is also expressed during embryonic development and in adults. When activated through signal induction, TRK can autophosphorylate and activate downstream signaling pathways to mediate a number of physiological functions. TRK downstream signaling molecules include SHC, FRS2, PLCγ, MAPK, PI3K, and PKC. Most of these signaling molecules are closely related to the functions of energy exchange, cell survival and proliferation. If TRK does not perform its function, the physiological functions of the cells can get out of control, due to which the cells can even transform into cancer cells. Therefore, if a chromosomal variation occurs in relation to NTRK gene fusion, the TRK fusion protein will be in a constantly active state, thereby triggering a permanent cascade of downstream signaling pathways that control the spread and growth of TRK fusion tumors (Yekaterina V. Khotskaya, Pharmacology & Therapeutics, 2017 ).

NTRK gene fusion can occur anywhere in the body and is found in a number of solid tumors in adults and children, including breast secretory carcinoma analogue (MASC), colon cancer, lung cancer, pancreatic cancer, thyroid cancer, and sarcoma varieties. Fusion in NTRK occurs at a low frequency of less than 5% in common types of cancer such as colon cancer and lung cancer; however, it is found in some rare cancers, such as congenital kidney tumor, childhood sarcoma, salivary gland cancer, and secretory breast cancer, with a very high mutation rate, and the incidence of individual cancers exceeds 90% (Clinical Medication Journal, Vol. 15, No. 12, Dec, 2017). Therefore, the development of NTRK inhibitors is of great clinical importance.

Although the first generation of NTRK inhibitors that target NTRK gene fusion, such as larotrectinib and entrectinib, are currently available, TKI (tyrosine kinase inhibitor) therapy that targets NTRK still faces the problem of acquired drug resistance. It has now been found that in some patients treated with a TRK inhibitor, some TRKs caused mutations at kinase sites such as NTRK1-LMNA-G667C and NTRK1-LMNA-V573M, leading to secondary drug resistance in cancer cells. including colon cancer, MASC, etc. (Marangela Russo, American Association for Cancer R ^e search, 2015; A. Drilon, Annals of Oncology, 2016). These emerging mutations prevent the first-generation NTRK inhibitors, entrectinib and larotrectinib, from binding to the kinase, thereby rendering the drug ineffective. Therefore, acquired drug resistance to first-generation NTRK inhibitor therapy is an unsolved problem, and second-generation NTRK inhibitors are urgently needed to address some drug resistance problems.

The essence of the invention

The present invention provides a novel inhibitor compound and a pharmaceutically acceptable salt, ester, stereoisomer and tautomer thereof (hereinafter sometimes referred to as the compound of the present invention). The compound of the present invention has an inhibitory effect on TAM family kinases. In addition, the compound of the present invention can also target CSF1R kinase and have an inhibitory effect on CSF1R kinase. The compound of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family receptor kinases and/or their ligands. In addition, the compound of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands. The compound of the present invention, by inhibiting TAM family kinases and CSF1R kinase, inverts immunosuppression in the tumor microenvironment, suppresses tumor growth, migration and/or development of drug resistance, and exerts a tumor immunity effect and an antitumor effect. In addition, the compound of the present invention can be used for the treatment and/or prevention of relevant diseases caused by NTRK, in particular relevant drug resistance diseases caused by NTRK mutations.

While technical solutions in accordance with the present invention include the following.

The compound represented by the general formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

where W is selected from hydrogen or C _1-6 alkyl;

R represents a group represented by the following general formula (a), (b) or (c):

in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl;

each Q is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O -R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

q is an integer 0-4;

in formulas (a) and (b) fragment attached via a linking group to the groups M ¹ and M ² ;

in formula (c) fragment attached via a linking group to the groups M ¹ and M ² ;

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O, NR ^b or O, and at least one of X ¹ , X ² and X ³ is C=O;

each of X ⁴ and X ⁵ is independently selected from C or N;

each of M ¹ and M ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy- R', -O-R', -C(O)-R', -SO ₂ -R' or -NR ^b C(O)-R', or M ¹ and M ² together with the atoms to which they are attached , can form 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ² , each R ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 -membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

Cy ³ is selected from 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, cyano, hydroxy, halogen , carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , - NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R' , -SO ₂ -R', -NR ^b C(O)-R', 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-14-membered heterocyclyl, 6-14-membered aryl or 5-10 -membered heteroaryl; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is selected from 3-14 membered heterocyclyl or 5-14 membered heteroaryl, both of which are optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl, or two R ⁴ together with the atoms to which they are attached can form a 5-6 membered cyclic group;

L is selected from -NR ^b -, -O-, -S- or -(CR ^a R ^a ) _m -, m is an integer 1-3;

R ^a is absent or independently selected in each occurrence from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^e R ^f , -C(O) R ^g , -C(O)NR ^e R ^f , -OC(O )NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R ', -C _1-6 alkoxy- R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^e C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^b and R ^c are absent or in each case each is independently selected from hydrogen, hydroxy, -C(O)R ^g , -C(O)NR ^e R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^d is absent or in each case independently selected from hydrogen, -NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -NR ^e SO ₂ R ^f , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -NR ^e C(O )-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^e and R ^f are absent or in each case independently selected from hydrogen, hydroxy, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14- a membered aryl or a 5-10 membered heteroaryl;

R ^g is absent or independently selected in each case from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3- 14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

R' is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

n is an integer 0-4,

in the groups represented by formula (b) and formula (c), is a double bond moiety which is optionally present in the cyclic structure;

provided that in the groups represented by formula (a) and formula (c), the fragment does not correspond to a hydrogen atom;

with the proviso that, in the group represented by formula (b), if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cu ² substituent is not a halogen atom.

In another embodiment, the above compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where W is selected from hydrogen or C _1-6 alkyl;

R represents a group represented by the following formula (a), (b), (b-1), (b-2) or (c):

in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl;

each Q is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O -R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

q is an integer 0-4;

in formulas (a), (b), (b-1) and (b-2) fragment attached via a linking group to the groups M ¹ and M ² ;

in formula (c) fragment attached via a linking group to the groups M ¹ and M ² ;

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O, NR ^b or O, and at least one of X ¹ , X ² and X ³ is C=O;

each of M ¹ and M ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R ', -C _1-6 alkoxy- R', -O-R', -C(O)-R', -SO ₂ -R' or -NR ^b C(O)-R'; or M ¹ and M ² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ² , each R ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 valalkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 -membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

Cy ³ is selected from 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, cyano, hydroxy, halogen , carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , - NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R' , -SO ₂ -R', -NR ^b C(O)-R', 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-14-membered heterocyclyl, 6-14-membered aryl or 5-10 -membered heteroaryl; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is selected from 3-14 membered heterocyclyl or 5-14 membered heteroaryl, both of which are optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl, or two R ⁴ together with the atoms to which they are attached, they can form a 5-6-membered cyclic group;

L is selected from -NR ^b -, -O-, -S- or -(CR ^a R ^a ) _m -, m is an integer 1-3;

R ^a at each occurrence is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^e R ^f , -C(O)R ^g , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , -NR ^e SO ₂ R ^g , C _{1- 6} alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R' , -O-R', -C(O)-R', -SO ₂ -R', -NR ^e C(O)-R', 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3- 14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

R ^b and R ^c are each independently selected from hydrogen, hydroxy, -C(O)R ^g , -C(O)NR ^e R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 -membered aryl or 5-10-membered heteroaryl;

R ^d at each occurrence is independently selected from hydrogen, -NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -NR ^e C(O)- R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^e and R ^f are absent or in each case independently selected from hydrogen, hydroxy, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14- a membered aryl or a 5-10 membered heteroaryl;

R ^g is absent or independently selected in each case from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3- 14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

R' is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

n is an integer 0-4,

in the groups represented by formula (b), formula (b-1) and formula (b-2), is a double bond moiety which is optionally present in the cyclic structure;

provided that in the groups represented by formula (a) and formula (c), the fragment does not correspond to a hydrogen atom;

with the proviso that in the group represented by formula (b), if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cu ² substituent is not a halogen atom,

in the group represented by formula (b-1), if X ¹ and X ³ are C=O, R ² as a substituent of Cy ² is not a halogen atom.

In another preferred embodiment, the above compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where W is selected from hydrogen or C _1-6 alkyl;

R represents a group represented by the following formula (a), (b-1) or (b-2):

in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl;

each Q is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R, -O- R', -C(C-)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

q is an integer 0-4;

in the formula (a), (b-1) or (b-2) fragment attached via a linking group to the groups M ¹ and M ² ; each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O, NR ^b or O, and at least one of X ¹ , X ² and X ³ is C=O;

each of M ¹ and M ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC1-valkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R' , -O-R', -C(O)-R', -SO ₂ -R' or -NR ^b C(O)-R', or M ¹ and M ² together with the atoms to which they are attached, may form 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ² , each R ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 -membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

Cy ³ is selected from 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, cyano, hydroxy, halogen , carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , - NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10- membered heteroaryl; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, both of which are optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl, or two R ⁴ together with the atoms to which they are attached can form a 5-6 membered cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or independently selected in each occurrence from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^e R ^f , -C(O)R ^e , -C(O)NR ^e R ^f , -OC(O )NR ^e R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R ', -C _1-6 alkoxy- R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^e C(O)-R', 3-8 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^b and R ^c are absent or in each case each is independently selected from hydrogen, hydroxy, -C(O)R ^g , -C(O)NR ^e R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R', 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^d is absent or in each case independently selected from hydrogen, -NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -NR ^e C(O )-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^e and R ^f are absent or in each case independently selected from hydrogen, hydroxy, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R' , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

R ^g is absent or independently selected in each case from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C(O)- R', -SO ₂ -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R' is 3-8 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

n is an integer 0-4,

in the groups represented by formula (b-1) and formula (b-2), is a double bond moiety which is optionally present in the cyclic structure;

with the proviso that in the group represented by formula (b-1), if X ¹ and X ³ are C=O, R ² as the Cu ² substituent is not a halogen atom; provided that in the groups represented by formula (a), the fragment

does not correspond to a hydrogen atom.

In another preferred embodiment, the above compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, has the structure represented by general formula (II),

where W is selected from hydrogen or C _1-6 alkyl;

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

each of X ⁴ and X ⁵ is independently selected from C or N;

each of M ¹ and M ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy , or M ¹ and M ² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from 6-14 membered aryl or 5-10 membered heteroaryl, both of which are optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

Cy ³ is selected from 3-8 membered cycloalkyl or 5-10 membered heteroaryl, both of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is 9-10 membered heteroaryl optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, - C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R ', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or independently selected in each occurrence from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^e R ^f , -C(O)R ^g , -C(O)NR ^e R ^f , -OC(O )NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R ', -C _1-6 alkoxy- R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^e C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^b and R ^c are absent or in each case each is independently selected from hydrogen, hydroxy, -C(O)R ^g , -C(O)NR ^e R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^d is absent or in each case independently selected from hydrogen, -NR ^e R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -NR ^e C(O )-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

R ^e and R ^f are absent or in each case independently selected from hydrogen, hydroxy, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R' , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

R ^g is absent or independently selected in each case from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C(O)- R', -SO ₂ -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R' is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

n is an integer 0-3;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O and X ³ is CR ^a ,

represents a fragment with a double bond, which is not necessarily present in the cyclic structure;

with the proviso that if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cy ² substituent is not a halogen atom.

In another preferred embodiment, said compound represented by formula (I) or said compound represented by general formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof has the structure represented by general formula (II),

where W is selected from hydrogen or C _1-6 alkyl;

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

each of M ¹ and M ² is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy , or M ¹ and M ² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from 6-14 membered aryl or 5-10 membered heteroaryl, both of which are optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

Cy ³ is selected from 3-8 membered cycloalkyl or 5-10 membered heteroaryl, both of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R' , -NR ^b C(O)-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is 9-10 membered heteroaryl optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)OR ^d , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, - C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R ', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a at each occurrence is independently selected from hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR ^e R ^f , -C(O)R ^g , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , -NR ^e SO ₂ R ^g , C _{1- 6} alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -C _1-6 alkyl-R', -C _1-6 alkoxy-R' , -O-R', -C(O)-R', -SO ₂ -R', -NR ^e C(O)-R', 3-8-membered cycloalkyl, 3-8-membered cycloalkenyl, 3- 14-membered heterocyclyl, 6-14-membered aryl or 5-10-membered heteroaryl;

R ^b and R ^c are each independently selected from hydrogen, hydroxy, -C(O)R ^g , -C(O)NR ^e R ^f , -SO ₂ -NR ^e R ^f , -SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 -membered aryl or 5-10-membered heteroaryl;

R ^d at each occurrence is independently selected from hydrogen, -NR ^e R ^f , -NR ^e C(O)OR ^g , -NR ^e C(O)R ^g , -NR ^e SO ₂ R ^g , C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C _1-6 alkoxy-R', -O-R', -NR ^e C(O)- R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

R ^e and R ^f are absent or in each case independently selected from hydrogen, hydroxy, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, -C _1-6 alkyl-R', -C(O)-R', -SO ₂ -R' , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-10 membered heteroaryl;

R ^g is absent or independently selected in each case from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy, -C _1-6 alkyl-R', -C(O)- R', -SO ₂ -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl;

n is an integer 0-3;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O and X ³ is CR ^a

represents a fragment with a double bond, which is not necessarily present in the cyclic structure;

with the proviso that if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cy ² substituent is not a halogen atom.

In another preferred embodiment, the above compound represented by formula (I) or (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

X ⁴ is selected from C or N, X ⁵ is C;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from phenyl or 5-6 membered heteroaryl, both of which are optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C( O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy;

Cy ³ is selected from 5-6 membered heteroaryl or 3-6 membered cycloalkyl, both of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _{1 -6} alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy;

Cy ⁴ is 9-10 membered heteroaryl optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C (O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _{1 -6} alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form 5-6- a membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a ;

preferably Cy ³ is each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N.

In another preferred embodiment, the above compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided, wherein

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

X ⁴ is selected from C or N, X ⁵ is C;

Cy ² is selected from phenyl or 5-6 membered heteroaryl, both of which are optionally substituted with one or more R ² ;

Su ³ is optionally substituted with one or more R ³ ;

each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N;

Su ⁴ is optionally substituted with one or more R ⁴ , Y ⁴ and Y ⁵ are independently selected from CH or N, and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl or 5-6 membered heteroaryl;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

each R ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ³ is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _{1 -6} alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a .

In another preferred embodiment, the above compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, has the structure represented by general formula (III),

where each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

Cy ² is selected from phenyl or 5-6 membered heteroaryl;

Y ² and Y ³ are independently selected from CH or N, and at least one of Y ² and Y ³ is N;

Su ⁴ is Y ⁴ and Y ⁵ are independently selected from CH or N and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl or 5-6 membered heteroaryl;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

each R ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ³ is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _{1 -6} alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5;

represents a fragment with a double bond, which is not necessarily present in the cyclic structure;

with the proviso that if X ¹ and X ³ are C=O, R ² as the Cu ² substituent is not a halogen atom;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a .

In another preferred embodiment, the above compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, has the structure represented by general formula (IV),

where each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

Cy ² is selected from phenyl or 5-6 membered heteroaryl;

each of Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ⁶ and Y ⁷ is N;

Su ⁴ is Y ⁴ and Y ⁵ are independently selected from CH or N and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl or 5-6 membered heteroaryl;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

each R ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ³ is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _{1 -6} alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5;

represents a fragment with a double bond, which is not necessarily present in the cyclic structure;

with the proviso that if X ¹ and X ³ are C=O, R ² as the Cu ² substituent is not a halogen atom;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a .

In another preferred embodiment, the above compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where R is the following group,

each of X ¹ , X ² and X ³ is independently selected from CR ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

Cy ² is selected from phenyl or 5-6 membered heteroaryl, both of which are optionally substituted with one or more R ² ;

Su ³ is optionally substituted with one or more R ³ ;

each of Yz, Y ³ , Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N;

Su ⁴ is optionally substituted with one or more R ⁴ , Y ⁴ and Y ⁵ are independently selected from CH or N, and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl or 5-6 membered heteroaryl;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

each R ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ³ is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , _{C6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, C1-6alkoxy , or haloC1-6alkoxy ;}

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _{1 -6} alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5;

represents a fragment with a double bond, which is not necessarily present in the cyclic structure;

with the proviso that if X ¹ and X ³ are C=O, R ² as the Cu ² substituent is not a halogen atom;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a .

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where each of X ¹ and X ² is independently selected from CR ^a or NR ^b , X ³ represents C=O;

Cy ² is phenyl optionally substituted with one or more R ² ;

Su ³ is optionally substituted with one or more R ³ ;

Y ² and Y ³ are independently selected from CH or N, and at least one of Y ² and Y ³ is N, each of Y ⁶ and Y ⁷ is independently selected from CH or N;

Su ⁴ selected from all of which are optionally substituted with one or more R ⁴ ;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached may form 3 -6-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

each R ² is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ³ is independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _{1 -6} alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _{1 -6} alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b and R ^c are absent, or in each case each is independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-1;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-3;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O.

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where M ¹ and M ² are each independently selected from hydrogen, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C( O)R ^d or C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Cy ² is selected from phenyl or pyridinyl, both of which are optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy;

Cy ³ is selected from 5-6 membered nitrogen-containing heteroaryl optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl , haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy;

Su ⁴ is optionally substituted with one or more R ⁴ , Y ⁴ and Y ⁵ are independently selected from CH or N, and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl or 5-6 membered heteroaryl;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is -O-;

R ^b is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

R ^d is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-2;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is C=O, X ² is CR ^a , and X ³ is CR ^a ;

preferably X ¹ is CR ^a , X ² is C=O, and X ³ is CR ^a .

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where W is hydrogen;

each of X ¹ and X ² is independently selected from CR ^a or NR ^b , X ³ is C=O;

X ⁴ is selected from C or N;

each of M ¹ and M ² is independently selected from hydrogen, hydroxy, halogen, nitro, or C _1-4 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Su ² is both of which are optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Su ³ selected from all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Su ⁴ selected from all of which are optionally substituted with one or more R ⁴ ;

each R ⁴ is independently selected from hydrogen, hydroxy, halogen, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, haloC _1-4 alkoxy or 3-14 membered heterocyclyl, or two R ⁴ together with atoms , to which they are attached, can form a 5-6-membered oxygen-containing cyclic group;

L is -O-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl;

R ^b is absent or in each case independently selected from hydrogen or C _1-6 alkyl;

n is an integer 0-1;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O.

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

where W is hydrogen;

X ¹ and X ² are selected from CR ^a or NR ^b , X ³ is C=O;

X ⁴ is C;

each of M ¹ and M ² independently selected from hydrogen, hydroxy or C _1-4 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6-membered cycloalkyl; or fragment may correspond to a hydrogen atom;

Su ² is optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, fluorine, chlorine, or C _1-4 alkyl;

Su ³ selected from all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen, fluorine, chlorine, or C _1-4 alkyl;

Su ⁴ is optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy, or two R ⁴ together with the atoms to which they are attached may form 5-6- a membered oxygen-containing cyclic group;

L is -O-;

R ^a is absent or in each occurrence is independently selected from hydrogen, C _1-4 alkyl or haloC _1-6 alkyl;

R ^b is absent or in each case independently selected from hydrogen or C _1-4 alkyl;

n is an integer 0-1;

preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O;

preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O.

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

each of X ¹ and X ³ is independently selected from CR ^a , C=O, or NR ^b , and X ¹ and X ³ are not both C=O; X ² is CR ^a or NR ^b .

In another preferred embodiment, a compound represented by formula (I) or (II) or (III) or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof is provided,

Cy ³ is a 5-6 membered heteroaryl optionally substituted with one or more R ³ .

More specifically, the present invention provides the following technical solutions.

SOLUTION 1. The compound represented by the general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

where W is hydrogen or C _1-6 alkyl optionally substituted with a substituent;

R is a group represented by the following general formula (a'), (b') or (c'):

in formula (a'), ring A is a 6-10 membered aromatic ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms selected from NR ^b , O and S, or a 5-6 membered heterocyclic ring, containing 1-4 heteroatoms selected from NR ^b , O and S; preferably ring A is a benzene ring, naphthalene ring, furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, pyrazole ring, thiazole ring, imidazole ring, pyridine ring, pyridazine ring, pyrimidine ring, a pyrazine ring, a pyran ring, a thiopyran ring, a pyrrolidine ring, a pyrroline ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, or a tetrahydropyran ring;

each Q is independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R', optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3- 12-membered cycloalkenyl optionally substituted with a substituent, 3-14-membered heterocyclyl optionally substituted with a substituent, 6-14-membered aryl optionally substituted with a substituent, or 5-10-membered heteroaryl optionally substituted with a substituent;

in formula (a') fragment attached via a linking group to a fragment

in formula (a'), each of X ⁶ and X ⁷ is independently selected from CR ^a R ^a , C=O and NR ^b , and at least one of X ⁶ and X ⁷ is C=O;

in formula (b') fragment attached via a linking group to a fragment

in formula (c') fragment attached via a linking group to a fragment

each of X ¹ , X ² and X ³ is independently selected from CR ^a R ^a , C=O and NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

each of X ⁴ and X ⁵ is independently selected from CR ^a or N;

each of M ¹ and M ² is independently selected from H, C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted substituent, -C _1-6 alkyl-R' optionally substituted by a substituent, or -C _1-6 alkoxy-R' optionally substituted by a substituent, or M ¹ and M ² together with the atoms to which they are attached can form 3- 8-membered cycloalkyl optionally substituted with a substituent, or fragment may correspond to a hydrogen atom;

Cy ² is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ² , 3-12 membered cycloalkenyl optionally substituted with one or more R ² , 3-14 membered heterocyclyl optionally substituted with one or more R ² , 6 -14 membered aryl optionally substituted with one or more R ² , or 5-10 membered heteroaryl optionally substituted with one or more R ² , each R ² being independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro , -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _{2 -8} alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R' optionally substituted with a substituent, -O-R', -C(O)-R' , -SO ₂ -R', -NR ^b C(C-)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

Cy ³ is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ³ , 3-14 membered heterocyclyl optionally substituted with one or more R ³ , or 5-10 membered heteroaryl optionally substituted with one or more R ³ , each R ³ is independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O) NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _{1 -6} alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R ' optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ⁴ , 3-14 membered heterocyclyl optionally substituted with one or more R ⁴ , 5-14 membered heteroaryl optionally substituted with one or more R ⁴ , and 6-14 membered aryl optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl- R', optionally substituted with a substituent, -C _1-6 alkoxy-R', optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O) -R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5 -10-membered heteroaryl optionally substituted with a substituent, or two R ⁴ together with the atoms to which they are attached, can form a 5-14-membered cyclic group;

L is selected from -NR ^b -, -O-, -S- and -(CR ^a R ^a ) _m -, where m is an integer 1-3;

R ^a is absent or independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC (O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent , C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R' optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, optional substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

each of R ^b and R ^c is absent, or in each occurrence each is independently selected from H, hydroxy, C _1-6 alkyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C(O )-R', -SO ₂ -R', 3-12-membered cycloalkyl, optionally substituted by a substituent, 3-12-membered cycloalkenyl, optionally substituted by a substituent, 3-14-membered heterocyclyl, optionally substituted by a substituent, 6-14-membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

R ^d is absent or independently selected at each occurrence from hydroxy, halogen, amino, -amino(C _1-6 alkyl optionally substituted with a substituent) _1-2 , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, -C _1-6 alkyl-R', optionally substituted with a substituent, -C _1-6 alkoxy-R', optionally substituted with a substituent, -O-R', 3-12-membered cycloalkyl, optionally substituted with a substituent, 3- 12-membered cycloalkenyl optionally substituted with a substituent, 3-14-membered heterocyclyl optionally substituted with a substituent, 6-14-membered aryl optionally substituted with a substituent, or 5-10-membered heteroaryl optionally substituted with a substituent;

each R' is independently selected from 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent , or 5-10 membered heteroaryl optionally substituted with a substituent;

q is an integer 0-4;

n is an integer 0-4.

Each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonamido, haloC _1-6 alkyl, haloC _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylthio, 3- 12-membered cycloalkyl, 6-14-membered aryl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl and oxo;

in the groups represented by formula (a'), formula (b') and formula (c'), is a double bond moiety, which is optionally present in the cyclic structure;

provided that in the groups represented by formula (a') and formula (c'), the fragment

does not correspond to a hydrogen atom;

with the proviso that in the group represented by formula (b'), if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cu ² substituent is not a halogen atom.

SOLUTION 2. A compound according to SOLUTION 1, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein

each of M ¹ and M ² is independently selected from H, C _1-6 alkyl optionally substituted with a substituent, and C _2-8 alkenyl optionally substituted with a substituent, or M ¹ and M ² together with the atoms to which they are attached may form 3-8 membered cycloalkyl optionally substituted with a substituent, or fragment may correspond to a hydrogen atom; preferably, M ¹ and M ² are each independently C _1-6 alkyl optionally substituted with a substituent, or M ¹ and M ² together with the atoms to which they are attached may form a 3-8 membered cycloalkyl optionally substituted with a substituent, or fragment may correspond to a hydrogen atom; preferably each of M ¹ and M ² independently represents C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

in formula (a'), ring A is a 6-10 membered aromatic ring; preferably ring A is a benzene ring or a naphthalene ring;

each Q is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent;

Cy ² is selected from 6-14 membered aryl optionally substituted with one or more R ² , or 5-10 membered heteroaryl optionally substituted with one or more R ² , preferably Cy ² is selected from phenyl or naphthalenyl, both of which are optionally substituted with one or several R ² ;

each R ² is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)OR ^d , C _1-6 alkyl optionally substituted with a substituent, or C _1-6 alkoxy optionally substituted with a substituent; preferably each R ² _is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC 1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy; preferably each R ² is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Cy ³ is selected from 3-8 membered cycloalkyl optionally substituted with one or more R ³ or 5-10 membered heteroaryl optionally substituted with one or more R ³ if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-10 membered aromatic group optionally substituted with one or more R ³ ; preferably Cy ³ is selected from 3-6 membered cycloalkyl optionally substituted with one or more R ³ or 5-6 membered heteroaryl optionally substituted with one or more R ³ if X ¹ or X ² is NR ^b , Cy ³ also may be selected from phenyl or naphthalene, both of which are optionally substituted with one or more R ³ ; preferably Cy ³ is selected from pyrrolyl optionally substituted with one or more R ³ , pyridinyl optionally substituted with one or more R ³ , pyrimidinyl optionally substituted with one or more R ³ , pyridazinyl optionally substituted with one or more R ³ , or pyrazinyl optionally substituted one or more R ³ ;

each R ³ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl optionally substituted with a substituent and C _1-6 alkoxy optionally substituted with a substituent; preferably each R ³ _is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC 1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy; preferably each R ³ is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Cy ⁴ is selected from 5-10 membered heterocyclyl optionally substituted with one or more R ⁴ , 5-10 membered heteroaryl optionally substituted with one or more R ⁴ , and 6-10 membered aryl optionally substituted with one or more R ⁴ ; preferably Cy ⁴ is selected from 9-10 membered heteroaryl, optionally substituted with one or more R ⁴ , and phenyl or naphthalene, both of which are optionally substituted with one or more R ⁴ ;

each R ⁴ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl optionally substituted with a substituent and C _1-6 alkoxy optionally substituted with a substituent or two R ⁴ together with the atoms to which they are attached may form a 5-6 membered cyclic group; preferably each R ⁴ is _{independently} selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC 1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylC _1-6 alkoxy and C _1-6 alkoxyC _1-6 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6-membered oxygen-containing cyclic group; preferably R ⁴ is selected from H, hydroxy, mercapto, halogen, C _1-4 alkyl, haloC _1-4 alkyl, _{C 1-4} alkoxy, C _1-4 alkoxyC 1-4 alkyl, C _1-4 alkylC _1-4 alkoxy , C _1-4 alkoxyC _1-4 alkoxy and haloC _1-4 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b -, -O- or -S-;

R ^a is absent or independently selected from H, halogen, hydroxy, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O )R ^d , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent; preferably R ^a is absent or in each case independently selected from H, hydroxy, halogen, carboxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkyl, preferably R ^a is absent or in each case independently selected from H, C _1-6 alkyl and C _1-6 alkoxy;

each of R ^b and R ^c is absent or in each case each of them is independently selected from H or C _1-6 alkyl optionally substituted with a substituent; preferably each of R ^b and R ^c is absent or in each case each of them is independently selected from H, C _1-6 alkyl or haloC _1-6 alkyl; preferably, each of R ^b and R ^c is absent, or in each case each of them is independently selected from H or C _1-6 alkyl;

R ^d is absent or in each occurrence is independently selected from hydroxy, halo, amino, -amino(C _1-6 alkyl optionally substituted with a substituent) _1-2 , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy, optionally substituted with a substituent; preferably R ^d is absent or in each case independently selected from hydroxy, amino, -amino(C _1-6 alkyl) _1-2 , C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy; preferably R ^d is absent or independently selected from hydroxy, amino, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy and haloC _1-4 alkoxy;

R' is selected from 3-8 membered cycloalkyl optionally substituted with a substituent, 3-8 membered cycloalkenyl optionally substituted with a substituent, 3-10 membered heterocyclyl optionally substituted with a substituent, 6-10 membered aryl optionally substituted with a substituent, or 5 -6-membered heteroaryl optionally substituted with a substituent; preferably R' is selected from 3-6 membered cycloalkyl optionally substituted with a substituent, 4-7 membered heterocyclyl optionally substituted with a substituent, 6-10 membered aryl optionally substituted with a substituent, or 5-6 membered heteroaryl optionally substituted with a substituent; предпочтительно R' выбран из циклопропила, циклобутила, циклопентила, циклогексила, фенила, нафталенила, оксациклопропила, оксациклобутила, оксациклопентила, оксациклогексила, оксациклогептила, пирролила, фуранила, тиофенила, оксазолила, изоксазолила, пиразолила, тиазолила, пиридинила, пиримидинила и пиридазинила;

each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) 2 amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonamido, haloC _1-6 alkyl, haloC _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylthio, 3-8 -membered cycloalkyl, 6-10 membered aryl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl and oxo; preferably each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylC _1-4 alkoxy, C _1-4 alkoxyC _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylaminocarbonyl, (C _1-4 alkyl) ₂ aminocarbonyl , C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonamido, haloC _1-4 alkyl, haloC _1-4 alkoxy, C _1-4 alkylsulfonyl, C _1-4 alkylthio, cyclo propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthalenyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, oxacycloheptyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and oxo,

n is 0, 1, 2, 3 or 4,

q is 0, 1, 2, 3, or 4.

SOLUTION 3. A compound according to SOLUTION 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, wherein

X ¹ is NR ^b , X ² is CR ^a R ^a , X ³ is C=O; or

X ¹ is CR ^a R ^a , X ² is NR ^b , X ³ is C=O; or

X ¹ is C=O, X ² is CR ^a R ^a , X ³ is C=O; or

X ¹ is CR ^a R ^a , X ² is C=O, X ³ is C=O; or

X ¹ is CR ^a R ^a , X ² is CR ^a R ^a , X ³ is C=O; or

X ¹ is C=O, X ² is CR ^a R ^a , X ³ is CR ^a R ^a ; or

X ¹ is CR ^a R ^a , X ² is C=O, X ³ is CR ^a R ^a .

SOLUTION 4. A compound according to any of SOLUTION 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

Where

X ⁴ is N, X ⁵ is CR ^a ; or

X ⁴ is CR ^a , X ⁵ is CR ^a ; or

X ⁴ is N, X ⁵ is N; or

X ⁴ is CR ^a , X ⁵ is N.

SOLUTION 5. A compound according to any of SOLUTIONS 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein

X ⁶ is C=O, X ⁷ is CR ^a R ^a ; or

X ⁶ is CR ^a R ^a , X ⁷ is C=O; or

X ⁶ is C=O, X ⁷ is NR ^b ; or

X ⁶ is NR ^b , X ⁷ is C=O.

SOLUTION 6. A compound according to any of SOLUTIONS 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein

on the rings of formula (a'), formula (b') and formula (c') there is only one C=O group.

SOLUTION 7. A compound according to any of SOLUTIONS 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein

Su ³ is a group represented by , optionally substituted with one or more R ³ , where is a single bond or a double bond, each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CR ^a R ^a and NR ^b , and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is is NR ^b , preferably Cy ³ is a group represented by , optionally substituted with one or more R ³ , each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N;

each R ³ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl optionally substituted with a substituent and C _1-6 alkoxy optionally substituted with a substituent; preferably each R ³ _is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC 1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkoxy; preferably each R ³ is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Su ⁴ is a group represented by , optionally substituted with one or more R ⁴ , where is a single bond or a double bond, each of Y ⁴ and Y ⁵ is independently selected from CR ^a R ^a and NR ^b and at least one of Y ⁴ and Y ⁵ is NR ^b , ring B is a benzene ring, naphthalene ring or a 5-6 membered heteroaromatic ring, preferably Cy ⁴ is the group represented by , optionally substituted with one or more R ⁴ , each of Y ⁴ and Y ⁵ is independently selected from CH or N, and at least one of Y ⁴ and Y ⁵ is N, preferably ring B is a benzene ring or 5-6- a membered heteroaromatic ring containing 1-3 heteroatoms selected from NR ^b , O and S;

each R ⁴ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl optionally substituted with a substituent and C _1-6 alkoxy optionally substituted with a substituent or two R ⁴ together with the atoms to which they are attached may form a 5-6 membered cyclic group; preferably each R ⁴ is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, amino C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylC _1-6 alkoxy and C _1-6 alkoxyC _1-6 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered an oxygen-containing cyclic group; preferably R ⁴ is selected from H, hydroxy, mercapto, halogen, C _1-4 alkyl, haloC _1-4 alkyl, _{C 1-4} alkoxy, C _1-4 alkoxyC 1-4 alkyl, C _1-4 alkylC _1-4 alkoxy , C _1-4 alkoxyC _1-4 alkoxy and haloC _1-4 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group;

L is selected from -NR ^b - and -O-.

SOLUTION 8. A compound according to any of SOLUTIONS 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

where R represents a group represented by formula (b'), a six-membered ring in a group represented by formula (b') is represented by any of the following, where is a single bond or a double bond,

X ¹ and X ² are as defined in DECISIONS 1-7.

SOLUTION 9. A compound according to any of SOLUTIONS 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof,

where Cy ³ is selected from the following groups, optionally substituted with one or more R ³ :

, preferably Cy ³ is selected from the following groups, optionally substituted with one or more R ³ : end * is attached to N and end • is attached to L, each R ³ is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy; preferably each R ³ is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl;

Cy ⁴ is selected from the following groups, optionally substituted with one or more R ⁴ :

preferably Cy ⁴ is the following group, optionally substituted with one or more R ⁴ :

each R ⁴ is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, C _{1 -6} alkoxyC _1-6 alkyl, C _1-6 alkylC _1-6 alkoxy and C _1-6 alkoxyC _1-6 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group; preferably R ⁴ is selected from H, hydroxy, mercapto, halogen, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkylC _1-4 alkoxy , C _1-4 alkoxyC _1-4 alkoxy and haloC _1-4 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group.

SOLUTION 10. A compound according to any of SOLUTIONS 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, having the structure represented by the general formula (II),

where each of the variables is as defined in SOLUTIONS 1-9.

SOLUTION 11. A compound according to any of SOLUTIONS 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, having the structure represented by the general formula (III),

where each of M ¹ and M ² independently represents C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6-membered cycloalkyl; preferably M ¹ and M ² together with the atoms to which they are attached, can form cyclopropyl;

each of X ¹ , X ² and X ³ is independently selected from CR ^a R ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O; preferably, X ¹ and X ² are each independently selected from CR ^a R ^a and NR ^b , X ³ is C=O,

each of Y ² and Y ³ is independently selected from CH or N, and at least one of Y ² and Y ³ is N;

L is selected from -NR ^b - and -O-;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5,

other variables are as defined in SOLUTIONS 1-9.

SOLUTION 12. A compound according to any of SOLUTIONS 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, having the structure represented by the general formula (IV),

where each of M ¹ and M ² independently represents C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6-membered cycloalkyl; preferably M ¹ and M ² together with the atoms to which they are attached, can form cyclopropyl;

each of X ¹ , X ² and X ³ is independently selected from CR ^a R ^a , C=O or NR ^b and at least one of X ¹ , X ² and X ³ is C=O; preferably, X ¹ and X ² are each independently selected from CR ^a R ^a and NR ^b , X ³ is C=O,

each of Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y6 and Y7 is N,

L is selected from -NR ^b - and -O-;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5,

other variables are as defined in SOLUTIONS 1-9.

In one embodiment, the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, said compound being:

The present invention also provides a pharmaceutical composition which contains a compound of any of formula (I), formula (II), formula (III) and formula (IV) as above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof.

The present invention also provides a pharmaceutical composition which contains a compound of any of formula (I), formula (II), formula (III) and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, and which may optionally contain one or more pharmaceutically acceptable carriers.

The present invention also provides a pharmaceutically acceptable composition which contains a compound of any of formula (I), formula (II), formula (III) and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof. , which optionally contains one or more pharmaceutically acceptable carriers.

In one embodiment of the present invention, the above pharmaceutical composition or formulation may further comprise one or more additional therapeutically active agents.

In one embodiment, the present invention provides a pharmaceutical composition which comprises a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer, and which may optionally contain at least one additional therapeutically active agent.

In one embodiment of the present invention, the additional therapeutically active agent is at least one selected from antimetabolites, growth factor inhibitors, mitosis inhibitors, antitumor hormones, alkylating agents, platinum group metals, topoisomerase inhibitors, hormones, immunomodulators, tumor suppressor genes. , cancer vaccines, inhibitors of immune checkpoints or antibodies associated with tumor immunotherapy, small molecule drugs and cell therapies.

In one embodiment of the present invention, the pharmaceutical composition or formulation may be administered to a patient or subject in need of such prevention and/or treatment by any suitable means known in the art, e.g., orally, parenterally (including subcutaneously, intramuscularly, intravenously, intra-arterially , intradermal, intrathecal and epidural), transdermal, rectal, nasal, transpulmonary, topical (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

In one embodiment of the present invention, the pharmaceutical composition or composition can be prepared as standard solid preparations such as tablets, capsules, pills and granules; or may also be prepared as oral liquid preparations such as oral solutions, oral suspensions and syrups. Suitable excipients, binders, disintegrants, lubricants, and the like can be added to form oral preparations. For parenteral administration, the pharmaceutical composition may be in the form of injections, including a sterile powder for injection and a concentrated solution for injection. In the case of injection, conventional methods of preparation known in the pharmaceutical field may be used, and when formulating an injection, an additional agent may be omitted, or a suitable additional agent may be added according to the properties of the drug. For rectal administration, the pharmaceutical composition may be in the form of suppositories and the like. For transpulmonary administration, the pharmaceutical composition may be in the form of inhalation preparations or aerosols, and the like.

In one embodiment, the present invention provides for the use of a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, of the aforementioned pharmaceutical compositions or the above composition in the manufacture of drugs intended for the treatment and / or prevention of diseases mediated by abnormal expression of TAM family receptor kinases and / or their ligands, while diseases mediated by abnormal expression of TAM family receptor kinases and / or their ligands include at least one of the following diseases: tumor formation, tumor immunity, adenomyosis, vascular disease/damage, psoriasis, visual defect/impairment (caused by macular degeneration, diabetes, preterm birth, etc.), kidney disease, rheumatoid arthritis, osteoporosis and so on.

In one embodiment of the present invention, a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the above pharmaceutical composition, or the above formulation are useful for the treatment and/or prevention of diseases mediated by abnormal expression of TAM family receptor kinases and/or their ligands, wherein diseases mediated by abnormal expression of TAM family receptor kinases and/or their ligands include at least one of the following diseases : tumor formation, tumor immunity, adenomyosis, vascular disease/damage, psoriasis, visual defect/impairment (caused by macular degeneration, diabetes, preterm birth, etc.), kidney disease, rheumatoid arthritis, osteoporosis, etc.

In one embodiment, the present invention provides for the use of a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, of the aforementioned pharmaceutical compositions or the above composition in the manufacture of drugs intended for the treatment and / or prevention of diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and / or their ligands, while diseases mediated by abnormal expression of TAM / family kinases and CSF1R receptor kinases and /or their ligands include at least one of the following diseases: tumor formation, tumor immunity, adenomyosis, vascular disease/damage, psoriasis, visual defect/impairment (caused by macular degeneration, diabetes, premature birth, etc.), kidney disease, rheumatoid arthritis, osteoporosis, and the like.

In one embodiment, the present invention provides a compound of any of formula (I), formula (II), formula (III) and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, the above pharmaceutical composition or the above composition, which are applicable for the treatment and/or prevention of diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands, while diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands , include at least one of the following diseases: tumor formation, tumor immunity, adenomyosis, vascular disease/damage, psoriasis, defect/impairment of vision (caused by macular degeneration, diabetes, preterm birth, etc.), kidney disease, rheumatoid arthritis, osteoporosis, etc.

In one embodiment, the present invention provides for the use of a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, of the aforementioned pharmaceutical compositions or the above composition in the manufacture of drugs intended for the treatment and/or prevention of relevant diseases caused by NTRK, in particular relevant drug resistance diseases caused by NTRK mutations, while the relevant diseases caused by NTRK include, without limitation, non-small cell lung cancer , colorectal cancer, similar to secretory breast carcinoma, sarcoma, astrocytoma, glioblastoma, spitzoid melanoma, cholangiocarcinoma, papillary thyroid cancer, secretory breast cancer, breast cancer of unknown pathological type, etc.

In one embodiment, the present invention provides a compound of any of formula (I), formula (II), formula (III) and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, the above pharmaceutical composition or the above composition, which are applicable for the treatment and/or prevention of relevant diseases caused by NTRK, in particular, relevant drug resistance diseases caused by NTRK mutations, while the relevant diseases caused by NTRK include, without limitation, non-small cell lung cancer, colorectal cancer , analogue of secretory breast carcinoma, sarcoma, astrocytoma, glioblastoma, spitzoid melanoma, cholangiocarcinoma, papillary thyroid cancer, secretory breast cancer, breast cancer of unknown pathological type, etc.

In one embodiment of the present invention, a compound of any of formula (I), formula (II), formula (III), and formula (IV) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the above pharmaceutical composition, or the above composition are applicable for the treatment and/or prevention of relevant diseases caused by NTRK, in particular relevant drug resistance diseases caused by NTRK mutations.

In one embodiment of the present invention, the tumor includes sarcoma, lymphoma and cancer, in particular lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, cancer endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, cancer bone, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cavity cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colonic villous adenoma, melanoma cell tumor and sarcoma.

Effect of the present invention

The compound of the present invention has an inhibitory effect on TAM family kinases. In addition, the compound of the present invention can also target CSF1R kinase and have an inhibitory effect on CSF1R kinase. The compound of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family receptor kinases and/or their ligands. In addition, the compound of the present invention can be used to treat and/or prevent diseases mediated by abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands. The compound of the present invention, by simultaneously targeting and inhibiting TAM family kinases and CSF1R kinase, inverts immunosuppression in the tumor microenvironment, suppresses tumor growth, migration and/or development of drug resistance, and exerts a tumor immunity effect and an antitumor effect.

In addition, the compound of the present invention has very good activity against the NTRK mutant target, has good prospects for use in patients with acquired resistance who have been treated with first generation NTRK inhibitors, and can provide treatment and/or prevention of related diseases caused by NTRK, in particular relevant drug-resistant diseases caused by NTRK mutations.

In addition, the compound of the present invention is characterized by a long in vivo half-life, excellent in vivo metabolic stability, excellent drug-forming capacity, and therefore, the compound of the present invention can improve the therapeutic effect of a drug, reduce patient burden due to administration , and provide improvement in patient compliance with the treatment regimen.

Detailed description of embodiments

Embodiments of the present invention will be described in more detail below with reference to specific embodiments, but those skilled in the art will appreciate that the specific embodiments described below are used merely to illustrate the present invention and should not be construed as limiting the scope of the present invention. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that are included within the scope of the present invention as defined by the appended claims. Embodiments of the present invention may be combined in any manner unless otherwise indicated. Transformations, variations and modifications of the technical solutions thus obtained are also included in the scope of the present invention and do not go beyond the scope of the present invention.

In the context of the present description, unless expressly defined otherwise or the meaning is beyond the understanding of specialists in the field of technology, in the case of hydrocarbons or groups that are derivatives of hydrocarbons containing 3 or more carbon atoms (such as propyl, propoxy, butyl, butane, butene , butenyl, hexane, etc.), it should be understood that the term without modification using the prefix "n-" has the same meaning as the term modified using the prefix "n-". For example, the term propyl is generally understood to mean n-propyl, while butyl is generally understood to mean n-butyl, unless explicitly stated otherwise.

All publications, patent applications, patents and other literature referenced in this specification are incorporated herein by reference. Unless otherwise indicated, all technical and scientific terms used in the description have the meaning generally understood by those skilled in the art. In case of conflict, the definition from this description will take precedence.

In the context of the present description, unless expressly defined otherwise, any features or techniques not specifically discussed will be understood in the meanings known in the art, without any significant changes. Moreover, any embodiment described in the specification may be loosely linked to one or more other embodiments described in the specification, and the technical solution or idea formed from it is considered part of the original disclosure or original entry, but cannot be considered. as new content that is not disclosed or expected in the description, unless experts in the art consider that the combination is clearly not feasible.

In the present invention, the expression "group C _a-b " (where a and b are integers equal to or greater than one, while a<b) means that the "group" contains a-b carbon atoms, for example, C _{1- 4} alkyl is alkyl containing 1-4 carbon atoms, C _1-4 alkoxy is alkoxy containing 1-4 carbon atoms, C _3-10 cycloalkyl is cycloalkyl containing 3-10 carbon atoms, and C _1-4 alkoxyC _1-4 alkyl is a group formed by adding an alkoxy containing 1-4 carbon atoms to an alkyl containing 1-4 carbon atoms.

In the present invention, "-yl" and "group" mean a monovalent group, or a divalent group, or a group with a higher valence value, which comply with the valence rule as necessary, for example, "cycloalkyl (also called cycloalkyl group)" includes a monovalent group obtained by removing one hydrogen atom from the corresponding hydrocarbon, or a divalent group or a group with a higher valence value obtained by removing two or more hydrogen atoms from the same carbon atom or from two or more different carbon atoms of the corresponding hydrocarbon. If "cycloalkyl" is used as an end group, it is naturally a monovalent group, and if a cycloalkyl group is used as a linking group in the structure, it is a divalent group or a group with a higher valence value. In the present invention, a monovalent group, or a divalent group, or a group with a higher valence value usually means a monovalent group or a divalent group, but the group may have a higher valence value (for example, it may be trivalent, tetravalent, pentavalent, hexavalent, etc. ), if it is needed.

Those skilled in the art can unambiguously determine the valence value represented by the notation "-yl" and "group". As used herein, a group "obtained by removing one or more hydrogen atoms" refers to a monovalent group obtained by removing one hydrogen atom, a divalent group obtained by removing two hydrogen atoms, a trivalent group obtained by removing three hydrogen atoms, a tetravalent group obtained by removing four hydrogen atoms. The number of hydrogen atoms to be removed may be determined according to the valence of the group (eg, the group may be monovalent, divalent, trivalent, tetravalent, etc.).

As used herein, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom.

In accordance with the present invention, "halo" refers to such a state in which the hydrogen atom(s) at any carbon atom in the substitutable group is(are) replaced by one or more of the same or different halogen atoms. "Halogen atom" is as defined above.

As used herein, "C _1-6 alkyl" refers to a linear or branched alkyl derivatized by removing one or more hydrogen atoms from an alkane containing 1-6 carbon atoms, which includes linear C _1-6 alkyl and branched C _1-6 alkyl. As such, it is well known to those skilled in the art that when C _1-6 alkyl is branched (branched C _1-6 alkyl), it has at least three carbon atoms. As an example "C _1-6 alkyl" can be illustrated, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl , 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl , 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. Said "C _1-4 alkyl" refers to alkyls containing 1-4 carbon atoms in the above examples.

As stated in the present invention, "hydroxyC _1-6 alkyl, cyanoC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl "refer to groups formed by replacing one or more hydrogen atoms in C _1-6 alkyl, respectively and independently, with one or more of hydroxy, cyano, amino, C _1-6 alkylamino, halogen, and C _1-6 alkoxy groups.

Groups containing "C _1-6 alkyl", such as "C _1-6 alkylamino", "(C _1-6 alksfamino", "C _1-6 alkylaminocarbonyl", "C _1-6 alkylcarbonyl", "C _{1- 6} alkylcarbonyloxy", "C _1-6 alkylsulfonamido", "C _1-6 alkylsulfonyl" and "C _1-6 alkylthio", refer to groups formed by the addition of C _1-6 alkyl to corresponding groups such as respectively -NH- , -CO-O-, -NH-CO-, -CO-, -SO ₂ NH-, -SO ₂ - or -S- For example, groups formed by the addition of groups represented by the above "C _1-6 alkyl" to the corresponding groups such as respectively -NH-, -CO-O-, -NH-CO-, -CO-, -SO ₂ NH-, -SO ₂ - or -S-.

As used herein, "C _2-8 alkenyl" refers to a linear or branched alkenyl derivatized by removing one or more hydrogen atoms from an alkene containing at least one C-C double bond and 2-8 carbon atoms. , for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadien-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3 -penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, 1,4-hexadien-1 -ill. Preferably the "C _2-8 alkenyl" contains one C-C double bond.

As used herein, "C _2-8 alkynyl" refers to a linear or branched alkynyl derivatized by removing one or more hydrogen atoms from an alkyne containing at least one C-C triple bond and 2-8 carbon atoms, for example, ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-1- yl, 2-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl, and the like. Preferably the "C _2-8 alkynyl" contains one C-C triple bond.

As used herein, “C _1-6 alkoxy” refers to a group derived from “C _1-6 alkyl” as defined above by being attached to the parent group via an oxygen atom, i.e. to the group "C _1-6 alkyl-O-", for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, neopentyloxy and n-hexyloxy and the like can be illustrated. "C _1-4 alkoxy" refers to alkoxy containing 1-4 carbon atoms in the above examples, ie. to the group "C _1-4 alkyl-O-".

As indicated in the present invention, groups containing "C _1-6 alkoxy", such as "haloC _1-6 alkoxy", "C _1-6 alkoxyC _1-6 alkoxy" and "C _1-6 alkylC _1-6 alkoxy" refers to groups formed by replacing one or more hydrogen atoms in C _1-6 alkoxy respectively and independently with one or more corresponding groups such as halogen, C _1-6 alkoxy, C _1-6 alkyl groups.

As used herein, "polycyclic ring" refers to a polycyclic ring system formed from two or more ring structures and in the form of a fused ring, a bridged ring, and a spiro ring. Said fused ring refers to a polycyclic ring structure formed from two or more ring structures, with each two ring structures having two adjacent ring atoms in common (i.e. one bond is typically used). Said bridged ring refers to a polycyclic ring structure formed from two or more ring structures, with each two ring structures sharing two non-adjacent ring atoms. Said spiro ring refers to a polycyclic ring structure formed from two or more ring structures, with each two ring structures sharing one ring atom.

As used in the present invention, "cycloalkyl" or "cycloalkyl group" (hereinafter collectively referred to as "cycloalkyl" herein) refers to a monovalent group, or a divalent group, or a group with a higher valence value (if necessary) formed from a cycloalkane . Said cycloalkane includes a monocyclic cycloalkane or a polycyclic cycloalkane. For example, it is "3-12 membered cycloalkyl", that is, it may contain 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbon atoms. Unless otherwise indicated, an X-membered cycloalkyl includes all possible monocyclic and polycyclic rings (including fused ring, spiro ring, and bridged ring). Cycloalkyl can be a 3-12 membered monovalent or divalent or higher valency group (if necessary), a 3-10 membered monovalent or divalent or higher valence group (if necessary). ), 3-8 membered monovalent group or divalent group or higher valence group (if necessary), 3-6 membered monovalent group or divalent group or higher valency group (if necessary), 4-6 membered monovalent group or divalent group or higher valence group (if necessary) or 5-7 membered monovalent group or divalent group or higher valence group (if necessary).

In particular, the (monovalent or divalent or higher valence) monocyclic cycloalkyl may be 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 3-8 membered cycloalkyl, 3-6 membered cycloalkyl, 4 -6-membered cycloalkyl, 5-6-membered cycloalkyl, 5-7-membered cycloalkyl. Examples thereof include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentan-1,3-diyl, cyclohexane-1,4-diyl, cycloheptan-1,4-diyl, and the like.

(Monovalent or divalent or higher valency) polycyclic cycloalkyl includes fused cycloalkyl, bridged cycloalkyl, spirocycloalkyl.

The (monovalent or divalent or higher valence) fused cycloalkyl may be a 6-11 membered fused cycloalkyl or a 7-10 membered fused cycloalkyl. Illustrative examples thereof include, without limitation, a monovalent group, or a divalent group, or a group with a higher valence value derived from bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2 .2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

(Monovalent, or divalent, or higher valence) cycloalkyl containing a bridged ring may be a monovalent group formed by removing one hydrogen atom from a 6-12-membered bridged ring, or 7-11 -membered ring connected by a bridge, or optionally a divalent group or a group with a higher valence value, formed by removing two or more hydrogen atoms from the same carbon atom or different carbon atoms. An example of said bridged ring includes, without limitation

The (monovalent or divalent or higher valence) cycloalkyl containing spiro ring may be a monovalent group formed by removal of one hydrogen atom from a 7-12 membered spiro ring or a 7-11 membered spiro ring, or a divalent group if necessary or a higher valency group formed by removing two or more hydrogen atoms from the same carbon atom or different carbon atoms. An example of said spiro ring includes, without limitation

As used in the present invention, "cycloalkenyl" refers to a group derived from the above cycloalkyl but having at least one double bond. For example, it may be "3-12 membered cycloalkenyl", that is, it may contain 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms forming a ring. Unless otherwise indicated, X-membered cycloalkenyl includes all possible monocyclic and polycyclic rings (including fused ring, spiro ring and bridged ring). Cycloalkenyl can be 3-12 membered cycloalkenyl, 3-8 membered cycloalkenyl, 4-6 membered cycloalkenyl, 7-11 membered spiro ring cycloalkenyl, 7-11 membered condensed ring cycloalkenyl, 6-11 membered cycloalkenyl with a bridged ring, etc. An example of cycloalkenyl includes, without limitation, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl, and the like. .

As used herein, "heterocycle" includes a non-aromatic cyclic hydrocarbon containing, as a ring atom, at least one heteroatom in the ring (for example, 1-5, 1-4, 1-3, 1-2 or 1) selected from O, S and N. It may be a heterocycle containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. Optionally, at least one double bond may be present in the ring. The heterocycle of the present invention may be a monocyclic system and may be a polycyclic system (in the form of a fused ring, a spiro ring and a bridged ring). As an example of a heterocycle, a monocyclic heterocycle such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, 1,4-dioxane, oxathiolanoxathiolane, tetrahydrothiopyrant, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole and tetrahydroisothiazole can be illustrated; and a polycyclic heterocycle such as indoline, isoindoline, benzopyran, benzo-1,4-dioxane, tetrahydroquinoline, benzo[d]oxazol-2(3H)-one, tetrahydrobenzothiophene. In addition, a heterocycle obtained by replacing at least one carbon atom in the above 7-12 membered spiro ring, 7-11 membered spiro ring, 6-12 membered bridged ring, or 7-11 membered ring can be illustrated. , bridged by a heteroatom selected from O, S and N, preferably 1-4 heteroatoms. In addition, the following groups according to the present invention can be further illustrated: 6-12 member fused ring group, 7-10 member fused ring group, 6-10 member fused ring group, 6-12 -membered saturated condensed ring, 6-12-membered spiro-heterocycle, 7-11-membered spiro-heterocycle, 6-12-membered saturated spiro-heterocycle, 7-11-membered saturated spiro-heterocycle, 6-12-membered bridged heterocycle, 7-11 -membered bridged heterocycle, 6-12-membered saturated bridged heterocycle, and 7-8-membered saturated bridged heterocycle.

As used in the present invention, "heterocyclyl" or "heterocyclic group" (hereinafter collectively referred to as "heterocyclyl") refers to a monovalent group, or a divalent group, or a group with a higher valence value obtained by obtaining a derivative from the above "heterocycle". In addition, as referred to in the present invention, "heterocyclyl" can also be a non-aromatic monovalent or divalent cyclic group or a cyclic group with a higher valency value, obtained by derivatization by replacing at least one carbon atom in the ring of the above cycloalkyl or cycloalkenyl at at least one heteroatom selected from O, S and N, preferably 1-4 heteroatoms. In addition, heterocyclyl also includes such a state in which a carbon atom or a sulfur atom is oxidized or nitrated, for example, a carbon or sulfur atom is replaced by C(=O), S(=O), S(=O) ₂ or S(= O)(=N).

In particular, "heterocyclyl" may be a heterocyclic group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. It may be 3-14 membered heterocyclyl, 3-10 membered heterocyclyl, 4-10 membered heterocyclyl, 3-8 membered heterocyclyl, 4-8 membered heterocyclyl, 4-6 membered heterocyclyl, 3-12- membered heterocyclyl, 4-12-membered heterocyclyl, including monocyclic heterocyclyl or polycyclic heterocyclyl.

In addition, "heterocyclyl" refers to a monovalent or (optionally) divalent monocyclic heterocyclyl or higher valence monocyclic heterocyclyl, monovalent or (optionally) divalent bicyclic heterocyclic system or higher valence bicyclic heterocyclic system or monovalent or (when necessary) a divalent polycyclic heterocyclic system or a higher valency polycyclic heterocyclic system (also referred to as a polycyclic ring system), including a saturated or partially saturated heterocyclyl but excluding an aromatic ring. Unless otherwise indicated, all possible saturated or partially saturated monocyclic and polycyclic rings are included (including fused ring, spiro ring and bridged ring). For example, "3-14 membered heterocyclyl".

The monovalent or (if appropriate) divalent monocyclic heterocyclyl or higher valence monocyclic heterocyclyl may be 3-14 membered heterocyclyl, 3-12 membered heterocyclyl, 3-10 membered heterocyclyl, 4-10 membered heterocyclyl, 3- 8-membered heterocyclyl, 3-8-membered saturated heterocyclyl, 4-8-membered heterocyclyl, 3-6-membered heterocyclyl, 4-6-membered heterocyclyl, 4-7-membered heterocyclyl, 5-7-membered heterocyclyl, 5- 6-membered heterocyclyl, 5-6-membered oxygen-containing heterocyclyl, 3-8-membered nitrogen-containing heterocyclyl, 5-6-membered nitrogen-containing heterocyclyl, 5-6-membered saturated heterocyclyl, and the like. In addition, it can also be 3-14 membered oxygen-containing heterocyclyl, 3-14 membered nitrogen-containing heterocyclyl, 3-12 membered oxygen-containing heterocyclyl, 3-12 membered sulfur-containing heterocyclyl, 3-12 membered sulfuryl(S(O ) ₂ )-containing heterocyclyl, 3-12-membered sulfoxide (S(O))-containing heterocyclyl, and the like. Examples of "heterocyclyl" include, without limitation, azacyclopropyl, oxacyclopropyl, thiacyclopropyl, azacyclobutyl, oxacyclobutyl, thiacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolalkyl, pyrazolalkyl, 1,2-oxazolalkyl, 1,3-oxazolalkyl, 1,2-thiazolalkyl, 1,3 -thiazolalkyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxacyclohexyl, 1,4-oxathiacyclohexyl; 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro- 1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl, 6H-1,3-oxazinyl, and the like.

Monovalent or (optionally) divalent polycyclic heterocycle or polycyclic heterocycle or higher valence heterocycle includes fused heterocyclyl, spiroheterocyclyl and bridged heterocyclyl which may be saturated, partially saturated or unsaturated, but not aromatic. The polycyclic heterocyclyl may be a heterocyclyl obtained by the condensation of the above heterocyclyl with a 6-14 membered aryl (e.g., benzene ring), a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-14 membered heterocyclyl, or a 3-14 -membered heteroaryl, 5-6-membered monocyclic cycloalkyl, 5-6-membered monocyclic cycloalkenyl, 5-6-membered monocyclic heterocyclyl or 5-6-membered monocyclic heteroaryl, 5-6-membered monocyclic heterocyclyl.

Said fused heterocyclyl may be a 6-12 membered fused ring group, a 7-10 membered fused ring group, a 6-10 membered fused ring group, or a 6-12 membered saturated fused ring group. Illustrative examples include, without limitation, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl , octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro- 1H-indolyl, octahydrobenzofuranyl, octahydrocyclopenta[c]pyrrole, hexahydrocyclopenta[c]furan, 2,2-dioxohexahydrocyclopenta[c]thiophene, 2-imino-2-oxo-octahydrocyclopenta[c]thiophene.

Said spiroheterocyclyl may be a monovalent group obtained by removing one hydrogen atom from a 6-12 membered spiroheterocycle, a 7-11 membered spiroheterocycle, a 6-12 membered saturated spiroheterocycle, or a 7-membered saturated spiroheterocycle, or optionally a divalent group or group with a higher valency value, obtained by removing hydrogen atoms from the same carbon atom or different carbon atoms of the spiroheterocycle. Examples of the spiro heterocycle include, without limitation And

Said bridged heterocyclyl may be a monovalent group obtained by removing one hydrogen atom from a 6-12 membered bridged heterocycle, a 7-11 membered bridged heterocycle, a 6-12 membered saturated heterocycle, bridged heterocycle, or a 7-8 membered saturated bridged heterocycle, or optionally a divalent group or a higher valence group obtained by removing hydrogen atoms from the same carbon atom or different carbon atoms of a bridged heterocycle connection. Examples of a bridged heterocycle include, without limitation And

In accordance with the present invention, "aromatic ring" refers to a carbocyclic hydrocarbon having aromatic properties. A monovalent or divalent group or a group with a higher valence value (if necessary) is obtained by derivatization from an aromatic carbocyclic hydrocarbon. Said aromatic carbocyclic hydrocarbon includes a 6-14 membered aromatic ring, a 6-10 membered aromatic ring, a 6-8 membered monocyclic aromatic hydrocarbon, and an 8-14 membered polycyclic aromatic hydrocarbon. A 6-8 membered monocyclic aryl is, for example, phenyl. An 8-14 membered polycyclic aryl is, for example, naphthalenyl, phenanthrenyl, anthracenyl, and the like. In the case of a divalent group, phenylene, naphthalenediyl, and the like can be illustrated.

As used in the present invention, "aryl" or "aromatic group" (hereinafter collectively referred to as "aryl" in this document) refers to a monovalent or divalent group or a group with a higher valence value (if necessary) obtained by derivatizing from an aromatic carbocyclic hydrocarbon. It includes 6-14 membered aryl or 6-10 membered aryl. 6-14 membered aryl is, for example, phenyl, naphthalenyl, phenanthrenyl and anthracenyl. 6-10 membered aryl is, for example, phenyl and naphthalene. In the case of a divalent group, phenylene, naphthalenediyl, and the like can be illustrated.

As used herein, "heteroaromatic ring" refers to a cyclic hydrocarbon having an aromatic property and containing at least one (for example, 1-5, 1-4, 1-3, 1-2 or 1) heteroatom, which is ring selected from O, S and N. This may be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic cyclic group, preferably containing 1-3 heteroatoms. In addition, the heteroaromatic ring of the present invention may be a monocyclic system, and may also be a polycyclic system (in the form of a fused ring, a spiro ring, and a bridged ring). In particular, a monocyclic heteroaromatic ring such as pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole can be illustrated. , oxadiazole; optionally illustrating a polycyclic heteroaromatic ring such as isoindole, indazole, indolizine, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzoimidazole, benzoisoxazole, benzooxazole, benzooxadiazole, benzoisothiazole, benzothiazole, benzothiadiazol, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazolopyridine, triazolopyridine, imidazolothiazole, pyrazinopyridazine, benzoimidazoline.

As used herein, "heteroaryl" or "heteroaromatic group" (hereinafter collectively referred to as "heteroaryl" herein) refers to a monovalent or higher valency group derived from the above "heteroaromatic ring". In addition, as indicated in the present invention, "heteroaryl" may also be an aromatic cyclic hydrocarbyl containing at least one heteroatom selected from O, S and N, and containing the number of atoms forming the ring, constituting 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14. Namely, we can talk about 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl. Heteroaryl may contain 1, 2, 3, 4 or 5 heteroatoms as a ring atom. In addition, heteroaryl also includes such a state in which a carbon atom or a sulfur atom is oxidized or nitrated, for example, a carbon or sulfur atom is replaced by C(=O), S(=O), S(=O) ₂ or S(= O)(=N). Heteroaryl includes monocyclic heteroaryl and polycyclic heteroaryl. Unless otherwise indicated, X-membered heteroaryl includes all possible monocyclic and polycyclic rings that are fully aromatic or partially aromatic. Monocyclic heteroaryl may be 5-7 membered heteroaryl or 5-6 membered heteroaryl. Examples thereof include, without limitation, furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiophenyl, triazolyl, and triazinyl. In some embodiments, a polycyclic heteroaryl refers to a group obtained by fusing a monocyclic heteroaromatic ring with phenyl, cycloalkenyl, heteroaryl, or cycloalkyl, heterocyclyl. The polycyclic heteroaryl may be 8-12 membered fused heteroaryl or 9-10 membered fused heteroaryl. Examples thereof include, without limitation, benzoimidazolyl, benzofuranyl, benzothiophenyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl , purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8 -tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H )-he-il. Said heteroaryl may also be a divalent group derived from the above groups.

As used in the present invention, "5-14 membered cyclic group" refers to a group containing 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms forming a ring, which may be a group containing 5-14 ring-forming atoms as defined above for the cycloalkyl, cycloalkenyl, heterocyclic group, aromatic cyclic group or heteroaromatic group of the present invention. In particular, it may be a 5-10 membered cyclic group or a 5-6 membered cyclic group. In addition, as indicated in the present invention, "5-6 membered cyclic group" refers to a cyclic structure containing 5-6 chemically valid ring atoms, and the ring atom may optionally be selected from C, N, O, S, C( =O), S(=O), S(=O) ₂ and S(=O)(=N). The resulting ring structure may be a monocyclic ring or a polycyclic ring, which may be saturated, partially saturated or aromatic. Examples thereof include, without limitation, a group derived from pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, 1,4-dioxane, oxathiolane, tetrahydrothiopyran, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, benzene, and the like. Preferably it is a 5-6 membered oxygen containing cyclic group, i.e. a cyclic group having at least one oxygen atom, and the number of atoms forming the ring is 5 or 6.

As used in the present invention, "one or more" means that the number of substituents may be the number of all positions in which the group to be substituted may be chemically substituted, preferably 1-6, more preferably 1-5, more preferably 1 -3, even more preferably 1-2, even more preferably 1.

As used herein, in the term "optionally substituted with a substituent", the number of substituents may be 0 (i.e., no substitution) or 1 to the number of all positions at which the group to be substituted may be chemically substituted, preferably 1 -6, more preferably 1-5, more preferably 1-4, even more preferably 1-3, even more preferably 1-2, even more preferably 1.

In particular, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

where W is selected from hydrogen or C _1-6 alkyl optionally substituted with a substituent;

R is a group represented by the following general formula (a'), (b') or (c'):

while in the formula (a') ring A is a 6-10-membered aromatic ring, a 5-6-membered heteroaromatic ring containing 1-3 heteroatoms selected from NR ^b , O and S, or a 5-6-membered heterocyclic a ring containing 1-4 heteroatoms selected from NR ^b , O and S;

each Q is independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R', optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3- 12-membered cycloalkenyl optionally substituted with a substituent, 3-14-membered heterocyclyl optionally substituted with a substituent, 6-14-membered aryl optionally substituted with a substituent, or 5-10-membered heteroaryl optionally substituted with a substituent;

in formula (a') fragment attached via a linking group to a fragment ;

in formula (a'), each of X ⁶ and X ⁷ is independently selected from CR ^a R ^a , C=O and NR ^b and at least one of X ⁶ and X ⁷ is C=O;

in formula (b') fragment attached via a linking group to a fragment ;

in formula (c') fragment attached via a linking group to a fragment ; each of X ¹ , X ² and X ³ is independently selected from CR ^a R ^a , C=O and NR ^b and at least one of X ¹ , X ² and X ³ is C=O;

each of X ⁴ and X ⁵ is independently selected from CR ^a or N;

each of M ¹ and M ² is independently selected from H, C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted substituent, -C _1-6 alkyl-R' optionally substituted by a substituent, -C _1-6 alkoxy-R' optionally substituted by a substituent, or M ¹ and M ² together with the atoms to which they are attached can form 3-8 -membered cycloalkyl optionally substituted with a substituent, or fragment may correspond to a hydrogen atom;

Cy ² is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ² , 3-12 membered cycloalkenyl optionally substituted with one or more R ² , 3-14 membered heterocyclyl optionally substituted with one or more R ² , 6 -14 membered aryl optionally substituted with one or more R ² , or 5-10 membered heteroaryl optionally substituted with one or more R ² , each R ² being independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro , -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _{2 -8} alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R' optionally substituted with a substituent, -O-R', -C(O)-R' , -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted a substituent, a 6-14 membered aryl optionally substituted with a substituent, or a 5-10 membered heteroaryl optionally substituted with a substituent;

Cy ³ is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ³ , 3-14 membered heterocyclyl optionally substituted with one or more R ³ , or 5-10 membered heteroaryl optionally substituted with one or more R ³ , each R ³ is independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O) NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _{1 -6} alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R ' optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent; if X ¹ or X ² is NR ^b , Cy ³ may also be a 6-14 membered aromatic group optionally substituted with one or more R ³ ;

Cy ⁴ is selected from 3-12 membered cycloalkyl optionally substituted with one or more R ⁴ , 3-14 membered heterocyclyl optionally substituted with one or more R ⁴ , 5-14 membered heteroaryl optionally substituted with one or more R ⁴ , and 6-14 membered aryl optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl- R', optionally substituted with a substituent, -C _1-6 alkoxy-R', optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O) -R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5 -10-membered heteroaryl optionally substituted with a substituent, or two R ⁴ together with the atoms to which they are attached, can form a 5-14-membered cyclic group;

L is selected from -NR ^b -, -O-, -S- and -(CR ^a R ^a ) _m -, where m is an integer 1-3;

R ^a is absent or independently selected from H, cyano, hydroxy, mercapto, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -OC (O)NR ^b R ^c , -NR ^b C(O)R ^d , -SO ₂ -NR ^b R ^c , -SO ₂ R ^d , -NR ^b SO ₂ R ^d , C _1-6 alkyl optionally substituted with a substituent , C _1-6 alkoxy optionally substituted with a substituent, C _2-8 alkenyl optionally substituted with a substituent, C _2-8 alkynyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R' optionally substituted with a substituent, -O-R', -C(O)-R', -SO ₂ -R', -NR ^b C(O)-R', 3-12 membered cycloalkyl, optional substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

each of R ^b and R ^c is absent, or in each occurrence each is independently selected from H, hydroxy, C _1-6 alkyl optionally substituted with a substituent, -C _1-6 alkyl-R' optionally substituted with a substituent, -C(O )-R', -SO ₂ -R', 3-12-membered cycloalkyl, optionally substituted by a substituent, 3-12-membered cycloalkenyl, optionally substituted by a substituent, 3-14-membered heterocyclyl, optionally substituted by a substituent, 6-14-membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

R ^d is absent or independently selected at each occurrence from hydroxy, halogen, amino, -amino(C _1-6 alkyl optionally substituted with a substituent) ₂ , C _1-6 alkyl optionally substituted with a substituent, C _1-6 alkoxy optionally substituted with a substituent , -C _1-6 alkyl-R' optionally substituted with a substituent, -C _1-6 alkoxy-R' optionally substituted with a substituent, -O-R', 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12- a membered cycloalkenyl optionally substituted with a substituent, a 3-14 membered heterocyclyl optionally substituted with a substituent, a 6-14 membered aryl optionally substituted with a substituent, or a 5-10 membered heteroaryl optionally substituted with a substituent;

each R' is independently selected from 3-12 membered cycloalkyl optionally substituted with a substituent, 3-12 membered cycloalkenyl optionally substituted with a substituent, 3-14 membered heterocyclyl optionally substituted with a substituent, 6-14 membered aryl optionally substituted with a substituent, or 5-10 membered heteroaryl optionally substituted with a substituent;

q is an integer 0-4;

n is an integer 0-4;

each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alksfamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _{1- 6} alkylcarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonamido, haloC _1-6 alkyl, haloC _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl and oxo;

in the groups represented by formula (a'), formula (b') and formula (c'), is a double bond moiety, which is optionally present in the cyclic structure;

provided that in the groups represented by formula (a') and formula (c'), the fragment does not correspond to a hydrogen atom;

with the proviso that, in the group represented by formula (b'), if X ¹ and X ³ are C=O and X ⁴ is N, R ² as the Cu ² substituent is not a halogen atom.

In another embodiment of the present invention, the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, is represented by the following formula (II).

In another embodiment of the present invention, the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, is represented by the following formula (III).

Where

each of Y ² and Y ³ is independently selected from CH or N, and at least one of Y ² and Y ³ is N;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5.

In another embodiment of the present invention, the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, is represented by the following formula (IV).

Where

each of Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ⁶ and Y ⁷ is N;

each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5.

In one embodiment of the present invention, each of M ¹ and M ² is independently selected from H, C _1-6 alkyl optionally substituted with a substituent, and C _2-8 alkenyl optionally substituted with a substituent, or M ¹ and M ² together with the atoms to to which they are attached may form a 3-8 membered cycloalkyl optionally substituted with a substituent, or a moiety may correspond to a hydrogen atom.

In one embodiment of the present invention, M ¹ and M ² are each independently C _1-6 alkyl optionally substituted with a substituent, or M ¹ and M ² together with the atoms to which they are attached may form a 3-8 membered cycloalkyl, optionally substituted with a substituent, or fragment may correspond to a hydrogen atom.

In one embodiment of the present invention, M ¹ and M ² are each independently C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached can form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In one embodiment of the present invention, X ¹ is NR ^b , X ² is CR ^a R ^a , and X ³ is C=O.

In one embodiment of the present invention, X ¹ is CR ^a R ^a , X ² is NR ^b , and X ³ is C=O.

In one embodiment of the present invention, X ¹ is C=0, X ² is CR ^a R ^a , and X ³ is C=O.

In one embodiment of the present invention, X ¹ is CR ^a R ^a , X ² is C=O, and X ³ is C=O.

In one embodiment of the present invention, X ¹ is CR ^a R ^a , X ² is CR ^a R ^a , and X ³ is C=O.

In one embodiment of the present invention, X ¹ is C=O, X ² is CR ^a R ^a , and X ³ is CR ^a R ^a .

In one embodiment of the present invention, X ¹ is CR ^a R ^a , X ² is C=O, and X ³ is CR ^a R ^a .

In one embodiment of the present invention, X ⁴ is N and X ⁵ is CR ^a .

In one embodiment of the present invention, X ⁴ is CR ^a and X ⁵ is CR ^a .

In one embodiment of the present invention, X ⁴ is N and X ⁵ is N.

In one embodiment of the present invention, X ⁴ is CR ^a and X ⁵ is N.

In one embodiment of the present invention, X ⁶ is C=O and X ⁷ is CR ^a R ^a .

In one embodiment of the present invention, X ⁶ is CR ^a R ^a and X ⁷ is C=O.

In one embodiment of the present invention, X ⁶ is C=O and X ⁷ is NR ^b .

In one embodiment of the present invention, X ⁶ is NR ^b and X ⁷ is C=O.

In one embodiment of the present invention, in formula (a'), ring A is a 6-10 membered aromatic ring.

In one embodiment of the present invention, in formula (a'), ring A is a benzene ring, a naphthalene ring.

In one embodiment of the present invention, in formula (a'), ring A is a benzene ring, a naphthalene ring, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, a thiazole ring, an imidazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, pyran ring, thiopyran ring, pyrrolidine ring, pyrroline ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring or tetrahydropyran ring.

In one embodiment of the present invention, in formula (a'), each Q is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy, optionally substituted with a substituent.

In one embodiment of the present invention, Cy ² is selected from 6-14 membered aryl optionally substituted with one or more R ² , or 5-10 membered heteroaryl optionally substituted with one or more R ² .

In one embodiment of the present invention, Cy ² is selected from phenyl or naphthalene, both of which are optionally substituted with one or more R ² .

In one embodiment of the present invention, Cy ³ is selected from 3-8 membered cycloalkyl optionally substituted with one or more R ³ , or 5-10 membered heteroaryl optionally substituted with one or more R ³ when X ¹ or X ² is NR ^b , Cy ³ may also be a 6-10 membered aromatic group optionally substituted with one or more R ³ .

In one embodiment of the present invention, Cy ³ is selected from 3-6 membered cycloalkyl optionally substituted with one or more R ³ , or 5-6 membered heteroaryl optionally substituted with one or more R ³ when X ¹ or X ² is NR ^b , Cy ³ may also be selected from phenyl or naphthalene, both of which are optionally substituted with one or more R ³ .

In one embodiment of the present invention, Cy ³ is selected from pyrrolyl optionally substituted with one or more R ³ , pyridinyl optionally substituted with one or more R ³ , pyrimidinyl optionally substituted with one or more R ³ , pyridazinyl optionally substituted with one or more R ³ , or pyrazinyl optionally substituted with one or more R ³ .

In one embodiment of the present invention, Cy ³ is the group represented by optionally substituted with one or more R ³ , wherein is a single bond or a double bond, each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CR ^a R ^a and NR ^b , and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is is NR ^b .

In one embodiment of the present invention, Cy ³ is the group represented by optionally substituted with one or more R ³ , each of Y ² , Y ³ , Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N.

In one embodiment of the present invention, Cy ³ is selected from the following groups, optionally substituted with one or more R ³ :

In one embodiment of the present invention, Cy ³ is selected from the following groups, optionally substituted with one or more R ³ : the * end is attached to N and the ⋅ end is attached to L.

In one embodiment of the present invention, Cy ⁴ is selected from 5-10 membered heterocyclyl optionally substituted with one or more R ⁴ , 5-10 membered heteroaryl optionally substituted with one or more R ⁴ , and 6-10 membered aryl optionally substituted one or more R ⁴ .

In one embodiment of the present invention, Cy ⁴ is selected from 9-10 membered heteroaryl, optionally substituted with one or more R ⁴ , and phenyl or naphthalene, both of which are optionally substituted with one or more R ⁴ .

In one embodiment of the present invention, Cy ⁴ is the group represented by optionally substituted with one or more R ⁴ , wherein is a single bond or a double bond, each of Y ⁴ and Y ⁵ is independently selected from CR ^a R ^a and NR ^b and at least one of Y ⁴ and Y ⁵ is NR ^b , ring B is a benzene ring, naphthalene ring or 5-6 membered heteroaromatic ring.

In one embodiment of the present invention, Cy ⁴ is the group represented by optionally substituted with one or more R ⁴ , Y ⁴ and Y ⁵ are each independently selected from CH or N, and at least one of Y ⁴ and Y ⁵ is N.

In one embodiment of the present invention, ring B is a benzene ring or a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms selected from NR ^b , O and S.

In one embodiment of the present invention, Cy ⁴ is selected from the following groups, optionally substituted with one or more R ⁴ :

In one embodiment of the present invention, Cy ⁴ is selected from the following group, optionally substituted with one or more R ⁴ :

In one embodiment of the present invention, each R ² is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C (O)OR ^d , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent.

In one embodiment of the present invention, each R ² is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _{1 -6} alkoxy; preferably each R ² is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl.

In one embodiment of the present invention, each R ³ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C (O)R ^d , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent.

In _one embodiment of the present invention, each R ³ is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC 1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, or haloC _{1 -6} alkoxy; preferably each R ³ is independently selected from H, hydroxy, fluorine, chlorine, bromine, or C _1-4 alkyl.

In one embodiment of the present invention, each R ⁴ is independently selected from H, hydroxy, halogen, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C (O)R ^d , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent, or two R ⁴ together with the atoms to which they are attached, may form a 5-6 membered cyclic group.

In one embodiment of the present invention, preferably each R ⁴ is independently selected from H, hydroxy, halogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy,

C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylC _1-6 alkoxy and C _1-6 alkoxyC _1-6 alkoxy, or two together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group.

In one embodiment of the present invention, R ⁴ is selected from H, hydroxy, mercapto, halogen, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkylC _1-4 alkoxy, C _1-4 alkoxyC _1-4 alkoxy and haloC _1-4 alkoxy, or two R ⁴ together with the atoms to which they are attached, can form a 5-6 membered oxygen-containing cyclic group.

In one embodiment of the present invention, R ^a is absent or in each occurrence is independently selected from H, halogen, hydroxy, carboxyl, nitro, -NR ^b R ^c , -C(O)R ^d , -C(O)NR ^b R ^c , -NR ^b C(O)R ^d , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent.

In one embodiment of the present invention, R ^a is absent or independently selected from H, hydroxy, halogen, carboxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy, or haloC _1-6 alkyl at each occurrence.

In one embodiment of the present invention, R ^a is absent or in each occurrence is independently selected from H, C _1-6 alkyl, and C _1-6 alkoxy.

In one embodiment of the present invention, R ^b and R ^c are absent, or in each case each is independently selected from H or C _1-6 alkyl optionally substituted with a substituent.

In one embodiment of the present invention, R ^b and R ^c are absent, or in each case each is independently selected from H, C _1-6 alkyl, or haloC _1-6 alkyl.

In one embodiment of the present invention, R ^b and R ^c are absent, or in each case each is independently selected from H or C _1-6 alkyl.

In one embodiment of the present invention, R ^d is absent or independently selected from hydroxy, halogen, amino, -amino(C _1-6 alkyl optionally substituted with a substituent) _1-2 , C _1-6 alkyl optionally substituted with a substituent, and C _1-6 alkoxy optionally substituted with a substituent.

In one embodiment of the present invention, R ^d is absent or independently selected from hydroxy, amino, -amino(C _1-6 alkyl) _1-2 , C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkoxy.

In one embodiment of the present invention, R ^d is absent or in each occurrence independently selected from hydroxy, amino, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy.

In one embodiment of the present invention, R' is selected from 3-8 membered cycloalkyl optionally substituted with a substituent, 3-8 membered cycloalkenyl optionally substituted with a substituent, 3-10 membered heterocyclyl optionally substituted with a substituent, 6-10 membered aryl, optionally substituted with a substituent, or 5-6 membered heteroaryl optionally substituted with a substituent.

In one embodiment of the present invention, R' is selected from 3-6 membered cycloalkyl optionally substituted with a substituent, 4-7 membered heterocyclyl optionally substituted with a substituent, 6-10 membered aryl optionally substituted with a substituent, or 5-6 membered heteroaryl , optionally substituted with a substituent.

In one embodiment of the present invention, R' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalene, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, oxacycloheptyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl.

In one embodiment of the present invention, each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkylC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _{1- 6} alkyl) ₂ aminocarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonamido, haloC _1-6 alkyl, haloC _1-6 alkoxy, C _1-6 alkylsulfonyl, C _{1 -6} alkylthio, 3-8 membered cycloalkyl, 6-10 membered aryl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl and oxo.

In one embodiment of the present invention, each substituent on said "optionally substituted substituent" is independently selected from hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _{1 -4} alkoxy, C _1-4 alkylC _1-4 alkoxy, C _1-4 alkoxyC _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylaminocarbonyl, (C _{1- 4} alkyl) ₂ aminocarbonyl, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonamido, haloC _1-4 alkyl, haloC _1-4 alkoxy, C _1-4 alkylsulfonyl, C _{1 -4} alkylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthalenyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, oxacycloheptyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidine silt, pyridazinyl and oxo.

In one embodiment of the present invention, n is 0, 1, 2, 3, or 4.

In one embodiment of the present invention, q is 0, 1, 2, 3, or 4.

In one embodiment of the present invention, L is selected from -NR ^b -, -O- or -S-.

In one embodiment of the present invention, R is a group represented by formula (b'), wherein the six-membered ring in the group represented by formula (b') is represented by any of the following, wherein is a single bond or a double bond,

In the present invention in the groups represented by formula (a'), formula (b') and formula (c'), is a double bond moiety, which is optionally present in the cyclic structure, provided that the valency requirement of each atom is satisfied.

In one embodiment of the present invention, in the compound represented by the formula (I) of the present invention, there is no such state in which three or more nitrogen atoms as ring-forming atoms are directly connected.

In one embodiment of the present invention, in the compound represented by the formula (I) of the present invention, there is no such state in which two or more carbonyl groups (C=O) are directly connected in the ring.

In one embodiment of the present invention, only one C=O group is present in the ring of formula (a').

In one embodiment of the present invention, only one C=O group is present in the ring of formula (b').

In one embodiment of the present invention, only one C=O group is present in the ring of formula (c').

In one embodiment of the present invention, X ¹ and X ² are each independently selected from CR ^a R ^a and NR ^b , X ³ is C=O.

In one embodiment of the present invention, if X ¹ or X ² is C=O, X ⁴ is not NR ^b .

In one embodiment of the present invention, X ⁴ is not NR ^b .

In one embodiment of the present invention, either X ¹ or X ² is NR ^b , X ³ is C=O.

As referred to in the present invention, "ester" means a pharmaceutically acceptable ester derived from the compound of the present invention, more particularly an ester such as formic acid ester, acetic acid ester, propionic acid ester, butyric acid ester, acrylic acid and an ester of ethyl succinic acid with the compound of the present invention, without limitation.

As used herein, "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid and base addition salt or solvate thereof. Such a pharmaceutically acceptable salt includes an acid salt such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid and alkanoic acid (such as acetic acid, HOOC-(CH ₂ ) _n -COOH (where n is 0-4)); base salt: sodium salt, potassium salt, calcium salt, ammonium salt, and the like. A person skilled in the art is aware of a variety of non-toxic, pharmaceutically acceptable addition salts.

A hydrogen atom, a fluorine atom, a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, and the like. in the present invention also include their respective radioisotopes or stable isotopes.

In accordance with the present invention, "tumor" includes sarcoma, lymphoma and cancer, and in particular, may include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine carcinoma, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ , lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharynx cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colonic villus adenoma, melanoma cell tumor and sarcoma.

"Relevant diseases caused by NTRK" referred to in the present invention include non-small cell lung cancer, colorectal cancer, secretory breast carcinoma analog, sarcoma, astrocytoma, glioblastoma, spiceoid melanoma, cholangiocarcinoma, papillary thyroid cancer, secretory breast cancer, breast cancer unknown pathological type, etc.

According to the present invention, the expression of "A/ and B" refers only to A or both A and B. For example, "TAM/ family kinase and CSF1R kinase" refers only to "TAM family kinase", or both "kinase of the TAM family" and "kinase CSF1R".

"Stereoisomers" of the compounds of formulas (I), (II), (III) and (IV) of the present invention means that if an asymmetric atom is present in the compounds of formulas (I), (II), (III) and (IV), then enantiomers can be formed; if a carbon-carbon double bond or a cyclic structure is present in the compounds, cis- and trans-isomers will be formed. All enantiomers, diastereomers, racemic isomers, cis and trans isomers, geometric isomers, epimers of the compounds of formulas (I), (II), (III) and (IV) and mixtures thereof are within the scope of the present invention. The definition of a compound of the present invention includes all possible stereoisomers and mixtures thereof. In particular, it includes racemic forms and isolated optical isomers having the indicated activity. The racemic form can be resolved by physical means such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate using conventional methods such as salt formation with an optically active acid followed by crystallization.

"Tautomers" of the compounds of formulas (I), (II), (III) and (IV) according to the present invention means that if a certain atom in the compounds of formulas (I), (II), (III) and (IV) rapidly moves between two positions, then isomers of functional groups will be formed, which are called tautomers; if the hydrogen at the α-position of the functional group containing the carbonyl group is attached to the α-carbon, then a ketoautomer will be formed, and if the hydrogen at the α-position of the functional group containing the carbonyl group is attached to the oxygen atom of the carbonyl group, then an alcohol tautomer will be formed .

The pharmaceutical composition of the present invention contains at least one of the compounds represented by formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof.

The pharmaceutical composition of the present invention contains compounds represented by formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, and optionally one or more pharmaceutically acceptable carriers .

The pharmaceutical composition of the present invention can be administered by any suitable means known in the art, for example, orally, parenterally (including subcutaneously, intramuscularly, intravenously, intraarterially, intradermally, intrathecally and epidurally), transdermally, rectally, nasally, transpulmonary, topically (including orally and sublingually), vaginally, intraperitoneally, intrapulmonary and intranasally, to a patient or subject in need of such prevention and/or treatment.

The pharmaceutical composition of the present invention may be in the form of conventional solid preparations such as tablets, capsules, pills and granules; or may also be presented as liquid oral preparations such as oral solutions, oral suspensions and syrups. For oral preparations, one or more of an excipient, diluent, sweetener, solubilizer, lubricant, binder, tablet disintegrant, stabilizer, preservative, or encapsulating material may be added as appropriate. For parenteral administration, the pharmaceutical composition may be in the form of injections, including a sterile powder for injection and a concentrated solution for injection. In the case of injection, conventional methods of preparation known in the pharmaceutical field can be used, and when formulating an injection, no additive may be added, or a suitable additive may be added according to the properties of the drug. For rectal administration, the pharmaceutical composition may be in the form of suppositories and the like. For transpulmonary administration, the pharmaceutical composition may be in the form of inhalation preparations or aerosols, and the like. In accordance with the present invention, suitable solid carriers include, without limitation, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, gum , sodium alginate, parabens, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. Suitable liquid carriers include, without limitation, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, glyceride, and mixtures thereof.

Methods for preparing the pharmaceutical composition of the present invention are well known. The preparation of the pharmaceutical composition of the present invention in a known manner includes conventional methods of mixing, granulating, tableting, coating, dissolving or lyophilizing.

The pharmaceutical composition is preferably presented in unit dosage form. In this form, the formulation is divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be packaged in a package containing individual amounts of the formulation, such as a packaged tablet, capsule or powder in a vial or ampoule.

The dosage of the drug to be administered depends on various factors including the age, weight and condition of the patient and the route of administration. The exact dosages to be administered will be determined based on the judgment of the attending physician. Typical dosages for administering the active compound are, for example, from about 0.01 to about 100 mg per day, from about 0.05 to about 75 mg per day, from about 0.1 to about 50 mg per day, or from about 5 to about 5 to approximately 10 mg per day. The required dosage will also depend on the particular compound used, the severity of the disease, the route of administration, the weight and health of the patient, and the judgment of the attending physician.

Process for the preparation of a compound of general formula (I) according to the present invention

Compounds of the present invention can be obtained in a variety of ways, including standard chemical methods. Unless otherwise specified, any previously defined variables will continue to have the previously defined value. Illustrative general synthesis methods are presented in the schemes below and can be easily modified to obtain other compounds of the present invention. Those skilled in the art can carry out the following reactions in accordance with conventional methods set forth in the art (eg, Organic Synthesis 2 ^nd , Michael B. Smith etc.). Specific compounds of the present invention, in particular, obtained in the section Examples.

A method for producing a compound represented by the general formula (I) includes the following steps:

adding a compound of formula (I-a) to a solvent, then adding a peptide bond coupling reagent, a base and a compound of formula (I-b), allowing the resulting mixture to react completely with stirring, and performing separation to obtain a compound of formula (I); or

adding a compound of formula (I-a) and a compound of formula (I-b) to a base, then dropwise adding a coupling reagent, allowing the resulting mixture to react completely with stirring, and performing separation to obtain formula (I),

where M ¹ , M ² , R, n, W, Cy ³ , L and Cy ⁴ are defined above.

The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, 1,2- dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, water, and mixtures thereof;

the base is selected from methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, and mixtures thereof;

peptide bond coupling reaction reagent selected from 2-(7-azabenzotriazol-1-yl)-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2 -(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and mixtures thereof;

the coupling reagent is selected from phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, 1-n-propylphosphoric anhydride, and mixtures thereof.

Intermediates for the preparation of a compound of general formula (I) have structures represented by formula (I-a) or (I-c):

where R ¹ is C _1-6 alkyl,

X ¹ , X ² , X ³ , X ⁴ , X ⁵ , M ¹ , M ² , R, Su ² , n and defined above.

Reaction formula

A compound of formula (I) can be prepared by allowing a compound of formula (I-a) to react with a compound of formula (I-b):

where M ¹ , M ² , R, n, W, Cy ³ , L and Cy ⁴ are defined above.

Those skilled in the art can prepare a compound of formula (I) from a compound of formula (I-a) and a compound of formula (I-b) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I) by providing a reaction compounds of formula (I-a) with a compound of formula (I-b).

For example, a compound of formula (I-a) is added to a suitable solvent (e.g. tetrahydrofuran N,N-dimethylformamide N,N-dimethylacetamide and the like, preferably N,N-dimethylformamide) to which a suitable coupling reagent is added to form a peptide bond (preferably 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) followed by the addition of a suitable base (e.g. triethylamine, pyridine, N,N-diisopropylethylamine and etc., preferably N,N-diisopropylethylamine). The resulting mixture is cooled to a suitable temperature (eg 0° C.) and stirred for a suitable period of time (eg 10-30 minutes). Add the compound of formula (I-b) and the resulting mixture is stirred at a suitable temperature (eg, from 0°C to ambient temperature) for a suitable period of time (eg, 1-16 hours). The reaction liquid is concentrated under reduced pressure. An appropriate amount of water is added and the resulting mixture is extracted with a suitable extractant (eg ethyl acetate). The extract is concentrated. The crude product is separated using a standard purification method (eg silica gel column chromatography) to give a compound of formula (I).

Also by way of example, a compound of formula (I-a) and a compound of formula (I-b) are added to a suitable base (eg pyridine) and the resulting mixture is cooled to a suitable temperature (eg 0°C). A coupling reagent (eg phosphorus oxychloride) is added dropwise. After the addition is complete, the resulting mixture is stirred for a suitable period of time (eg 0.5-3 hours) until the reaction is complete. The reaction liquid is concentrated under reduced pressure. An appropriate amount of water is added and the resulting mixture is extracted with a suitable extractant (eg ethyl acetate). The extract is concentrated. The crude product is separated using a standard purification method (eg silica gel column chromatography) to give a compound of formula (I).

The compound of formula (I-a) can be obtained from the compound of formula (I-c):

where R ₁ is C _1-6 alkyl and M ¹ , M ² , R and n are as defined above.

Those skilled in the art can prepare a compound of formula (I-a) from a compound of formula (I-c) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-a) from a compound of formula (I-c).

For example, a compound of formula (I-c) is dissolved in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane, etc., preferably methanol) and a suitable base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) is added. ., preferably lithium hydroxide). The resulting mixture is stirred at a suitable temperature (eg room temperature) for a suitable period of time (eg 0.5-3 hours). After completion of the reaction, the mixture is concentrated under reduced pressure, adjusted with an aqueous solution of a suitable acid (such as hydrochloric acid and citric acid) to an appropriate pH range (eg 2-5) and filtered to obtain a compound of formula (I-a).

A compound of formula (I-c) can be prepared by allowing a compound of formula (I-d) to react with a compound of formula (I-e):

where R and R ₁ are defined above; LG is a leaving group such as chlorine, bromine, iodine, mesylate or benzenesulfonate, or boric acid or borate; M ¹ , M ² and n are defined above.

Those skilled in the art can prepare a compound of formula (I-c) from a compound of formula (I-d) and a compound of formula (I-e) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-c) by providing a reaction compounds of formula (I-d) with a compound of formula (I-e).

For example, a compound of formula (I-d) and a compound of formula (I-e) (LG is a leaving group) are dissolved in a suitable solvent (eg, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, etc., preferably N,N- dimethylformamide) and add a suitable base (eg sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate). The resulting mixture is reacted at a suitable temperature (eg 50° C.) with stirring for a suitable period of time (eg 10-16 hours). After completion of the reaction, water and a suitable extractant are added. The crude product is separated using standard purification means (eg silica gel column chromatography) to give the compound of formula (I-c).

Also by way of example, a compound of formula (I-d) and a compound of formula (I-e) (LG is boric acid or borate) are dissolved in a suitable solvent (e.g., acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethylformamide, etc. ., preferably N,N-dimethylformamide) and add a suitable base (eg triethylamine, pyridine, etc.) and a suitable catalyst (eg, copper acetate, copper chloride, etc.). The resulting mixture is reacted under air or oxygen conditions at a suitable temperature (eg room temperature to 50° C.) for a suitable period of time (eg 14 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (such as extraction and concentration) to give the crude product. The crude product is subjected to standard purification (eg silica gel column chromatography) to give the product.

The compound of formula (I-b) can be obtained by allowing the compound of formula (I-b') to react with W-LG:

where Cy ³ , L, Cy ⁴ , W and LG are defined above.

Those skilled in the art can prepare a compound of formula (I-b) from a compound of formula (I-b') according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-b) from a compound of formula (I-b'). ).

For example, a compound of formula (I-b') and a compound of formula W-LG are dissolved in a suitable solvent (eg, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, etc., preferably N,N-dimethylformamide) and a suitable base is added (eg sodium carbonate, potassium carbonate, cesium carbonate and the like, preferably potassium carbonate). The resulting mixture is reacted at a suitable temperature (eg 50° C.) with stirring for a suitable period of time (eg 10-16 hours). After completion of the reaction, water and a suitable extractant are added. The crude product is separated using standard purification means (eg silica gel column chromatography) to give the compound of formula (I-b).

The compound of formula (I-b) can be obtained from the compound of formula (I-f):

where Cy ³ , L and Cy ⁴ are defined above.

Those skilled in the art can prepare a compound of formula (I-b) from a compound of formula (I-f) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-b) from a compound of formula (I-f).

For example, a compound of formula (I-f) and a suitable reducing agent (for example, iron powder, zinc powder, stannous chloride, sodium dithionite, and the like, preferably iron powder) are added to a suitable solvent (for example, ethanol, ammonium chloride aqueous solution, acetic acid, a mixture of ethanol and an aqueous ammonium chloride solution, etc.). The resulting mixture is reacted at a suitable temperature (eg 80° C.) for a suitable period of time (eg 4 hours). After completion of the reaction, the mixture is filtered, concentrated under reduced pressure, extracted with a suitable extractant (eg dichloromethane) and concentrated under reduced pressure to obtain the product.

A compound of formula (I-f) can be prepared by allowing a compound of formula (I-g) to react with a compound of formula (I-h):

where L, Cy ⁴ , Cy ³ and LG are defined above.

Those skilled in the art can prepare a compound of formula (I-f) from a compound of formula (I-g) and a compound of formula (I-h) according to standard methods in the art, and the following is a schematic representation of a method for preparing a compound of formula (I-f) from a compound of formula (I-g). ) and compounds of formula (I-h).

For example, a compound of formula (I-g) and a compound of formula (I-h) are added to a suitable solvent (e.g. tetrahydrofuran acetonitrile N,N-dimethylformamide N,N-dimethylacetamide and the like, preferably N,N-dimethylformamide) and a suitable base is added (eg potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine and the like, preferably potassium carbonate). The resulting mixture is stirred at a suitable temperature (eg room temperature to 80° C.) for a suitable period of time (eg 14 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, etc.) to obtain a crude product. The crude product is separated using standard purification means (eg silica gel column chromatography) to give the product.

In some embodiments, the implementation of the compound of formula (I-b) can be obtained through the following reactions:

where LG, Cy ³ , L, Cy ⁴ and W are defined above. Those skilled in the art can prepare a compound of formula (Ib) from a compound of formula (Il) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (Ib) from a compound of formula (Il).

For example, a compound of formula (I-l) and a compound of formula (I-k) are added to a suitable solvent (eg, toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, preferably xylene). The resulting mixture is heated to a suitable temperature (eg 140° C.) and stirred for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, etc.) to obtain a compound of formula (I-i). The compound of formula (I-i) and the compound of formula (I-j) are added to a suitable solvent (eg ethanol, water, etc.). The resulting mixture is heated to a suitable temperature (eg 90°C). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, concentration, extraction, filtration, etc.) to obtain a compound of formula (I-b).

In particular, if R is a group represented by the general formula (b), the compound of formula (I-c) can be obtained by the following reaction.

In some embodiments, the implementation of the compound of formula (I-c) can be obtained through the following reactions:

where each of X ¹ , X ² , X ⁵ and X ⁴ is independently selected from C, CH or CH ₂ ; X ³ represents C=O; R ² is alkoxy or disubstituted amino; Cy ² , R ¹ , M ¹ , M ² and n are defined above.

Those skilled in the art can prepare a compound of formula (I-c) from a compound of formula (I-m) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-c) from a compound of formula (I-m).

For example, a compound of formula (I-m) is added to a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, preferably toluene) and an appropriate reagent is added (e.g., N, N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate and the like, preferably N,N-dimethylformamide dimethyl acetal). The resulting mixture is heated to a suitable temperature (eg 100° C.) and stirred for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) to obtain a compound of formula (I-n).

The compound of formula (I-n) and the compound of formula (I-o) are added to a suitable solvent (eg ethanol, isopropanol, toluene, etc.). The resulting mixture is heated to a suitable temperature (eg 100° C.) and reacted for a suitable period of time (eg 3 hours). After completion of the reaction, the mixture is subjected to standard purification (eg silica gel column chromatography) to obtain a compound of formula (I-c).

In some other embodiments, the implementation of the compound of formula (I-c) can be obtained through the following reactions:

where each of X ¹ , X ⁵ and X ⁴ is independently selected from C, CH or CH ₂ ; X ³ represents C=O; Cy ² , R ¹ , M ¹ , M ² and n are defined above.

Those skilled in the art can prepare a compound of formula (I-c) from a compound of formula (I-p) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-c) from a compound of formula (I-p).

For example, a compound of formula (I-p) and a compound of formula (I-q) are added to a suitable solvent (e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc., preferably dichloromethane) and the resulting mixture is cooled to a suitable temperature (e.g. , 0°С). A suitable base (eg potassium carbonate, sodium carbonate, sodium hydroxide and the like, preferably potassium carbonate) is added and the resulting mixture is slowly warmed to room temperature and reacted for a suitable period of time (eg 3-15 hours). After completion of the reaction, the mixture is subjected to conventional purification (eg silica gel column chromatography) to obtain a compound of formula (I-r).

The compound of formula (I-r) is added to a suitable solvent (for example, toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably toluene) and a suitable reagent is added (for example, N,N- dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate and the like, preferably N,N-dimethylformamide dimethyl acetal). The resulting mixture is heated to a suitable temperature (eg 110° C.) and stirred for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, silica gel column chromatography) to obtain a compound of formula (I-c).

In some other embodiments, the implementation of the compound of formula (I-c) can be obtained in accordance with the following reaction scheme:

where each of X ² , X ⁵ and X ⁴ is independently selected from C, CH or CH ₂ ; X ³ represents C=O; Cy ² , R ¹ , M ¹ , M ² and n are defined above.

Those skilled in the art can prepare a compound of formula (I-c) from a compound of formula (I-s) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-c) from a compound of formula (I-s).

For example, a compound of formula (I-s) and a compound of formula (I-t) are added to a suitable solvent (eg, methanol, ethanol, isopropanol, etc., preferably ethanol). The resulting mixture is reacted at a suitable temperature (eg 80° C.) for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard purification (eg silica gel column chromatography) to obtain a compound of formula (I-u).

The compound of formula (I-u) is added to a suitable solvent (for example, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, etc., preferably 2-methyltetrahydrofuran) and the resulting mixture is cooled to a suitable temperature (for example, 0°C). A suitable base (eg sodium hydride, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, etc., preferably potassium t-butoxide) is added. After the addition is complete, the resulting mixture is heated to a suitable temperature (eg, room temperature) and stirred for a suitable period of time (eg, 15 hours). After completion of the reaction, the reaction liquid is adjusted to a suitable pH value (for example, 5-6). The mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, silica gel column chromatography) to give a compound of formula (I-v).

The compound of formula (I-v) is added to a suitable solvent (eg acetonitrile) and a suitable oxidizing agent (eg copper chloride) is added. The resulting mixture is heated to a suitable temperature (eg 80° C.) and reacted for a suitable period of time (eg 2-4 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, silica gel column chromatography) to obtain a compound of formula (I-c).

The compound of formula (I-t) can be prepared according to the following reaction scheme:

where each of X ² and X ⁵ is independently selected from CH or CH ₂ ; PG is a protecting group (eg, t-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.); R ¹ , M ¹ , M ² and n are defined above, with n≥1.

Those skilled in the art can prepare a compound of formula (I-t) from a compound of formula (I-w) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-t) from a compound of formula (I-w).

For example, a compound of formula (I-w) and a compound of formula (I-x) are added to a suitable solvent (e.g., dichloromethane, methanol, ethanol, and the like, preferably dichloromethane) to which an appropriate acid (e.g., acetic acid) is added, and a dehydrating agent (eg, magnesium sulfate), and then a suitable reducing agent (eg, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) is added. The resulting mixture is reacted at a suitable temperature (eg room temperature) for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) to obtain a compound of formula (I-y).

The compound of formula (I-y) and the compound of formula (I-z) are added to a suitable solvent (eg ethanol). The resulting mixture is reacted at a suitable temperature (eg 80° C.) for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, silica gel column chromatography) to obtain a compound of formula (I-a1).

The compound of formula (I-a1) is treated with a suitable deprotection method (e.g., acid, base, hydrogenation, oxidation, etc.) and then subjected to standard post-treatment (e.g., filtration, extraction, concentration, and etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-t).

In some other embodiments, the implementation of the compound of formula (I-a1) can be obtained in accordance with the following reaction scheme:

where each of X ² and X ⁵ is independently selected from CH or CH ₂ ; PG is a protecting group (eg, t-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.); LG is a leaving group (eg, benzenesulfonate, mesylate, etc.); R ¹ , M ¹ , M ² and n are defined above.

Those skilled in the art can prepare a compound of formula (I-a1) from a compound of formula (I-o) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-a1) from a compound of formula (I -O).

For example, a compound of formula (I-o) is dissolved in a suitable solvent (eg ethanol) and a compound of formula (I-z) is added at an appropriate temperature (eg 0° C. to room temperature). The resulting mixture is subjected to the reaction for a suitable period of time (2-15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-a2).

The compound of formula (I-a2) is added to a suitable solvent (e.g., dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.) and a suitable base (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, etc.) is added. ). The resulting mixture is cooled to a suitable temperature (eg -5°C). A compound of formula (I-a3) is added and the resulting mixture is warmed to room temperature and reacted for a suitable period of time (eg 14 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-a1).

If R is a group represented by the general formula (b),

where each of X ¹ , X ⁴ and X ⁵ is independently selected from C, CH or CH ₂ ; X ² is N; X ³ represents C=O; and Cy ² is defined above, then the compound of formula (Id) can be prepared according to the following reaction scheme:

where LG is a leaving group (eg chlorine); PG is a protecting group (preferably t-butoxycarbonyl); and R ¹ is defined above.

Those skilled in the art can prepare a compound of formula (I-d) from a compound of formula (I-d3) according to standard methods in the art, and the following is a schematic representation of a process for preparing a compound of formula (I-d) from a compound of formula (I-d3).

For example, a compound of formula (I-d3) is dissolved in a suitable solvent (eg ethyl acetate). The resulting mixture is cooled to a suitable temperature (eg 0°C). A compound of formula (I-d4) is added and the resulting mixture is warmed to room temperature and reacted for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is quenched by adding a suitable base (for example, potassium carbonate) and then subjected to standard post-treatment (for example, filtration, extraction, concentration, etc.) and purification (for example, recrystallization, silica gel column chromatography, etc. .) to give a compound of formula (I-d5).

The compound of formula (I-d5) is dissolved in a suitable solvent (eg methyl tert-butyl ether) and the resulting mixture is cooled to a suitable temperature (eg 0°C). A suitable reducing agent (eg triphenylphosphine, tri-n-butylphosphine and the like, preferably tri-n-butylphosphine) is added and the resulting mixture is warmed to room temperature and reacted for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-d6).

The compound of formula (I-d6) is dissolved in a suitable solvent (eg dichloromethane, tetrahydrofuran, etc.) and the resulting mixture is cooled to a suitable temperature (eg 0°C). A suitable base (eg triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate and the like, preferably triethylamine) and a suitable protecting group agent (eg di-t-butyl dicarbonate) are added. The resulting mixture is warmed to room temperature and reacted for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-d7).

The compound of formula (I-d7) is added to a suitable solvent (e.g. toluene, xylene, trimethylbenzene N,N-dimethylformamide N-dimethylacetamide and the like, preferably toluene) and an appropriate reagent is added (e.g. N,N-dimethylformamide- dimethyl acetal, trimethyl orthoformate, triethyl orthoformate and the like, preferably N,N-dimethylformamide dimethyl acetal). The resulting mixture is heated to a suitable temperature (eg 60°C) and stirred for a suitable period of time (eg 15 hours). After completion of the reaction, the mixture is subjected to standard post-treatment (eg, filtration, extraction, concentration, etc.) and purification (eg, recrystallization, silica gel column chromatography, etc.) to obtain a compound of formula (I-d).

When synthesizing the compound of the present invention, a solvent commonly used in the art can be used as the reaction solvent, including but not limited to ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, alcohols, and the like. Specifically, the following solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (for example, toluene, benzene, xylene, trimethylbenzene, and the like), saturated hydrocarbons (for example, , cyclohexane, hexane, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (for example, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane and etc.), esters (for example, methyl acetate, ethyl acetate, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), nitriles (for example, acetonitrile, etc.), alcohols (for example, , methanol, ethanol, isopropanol, tert-butanol, etc.), water and mixed solvents based on them.

When synthesizing the compound of the present invention, the base used may be a base commonly used in the art, including an organic base and an inorganic base. As an example of an organic base, methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, and the like; as an example of an inorganic base, alkali metal hydroxide, carbonate and bicarbonate (eg lithium, sodium, potassium and cesium) can be given; hydroxide, carbonate and bicarbonate of alkaline earth metal (magnesium, calcium, strontium and barium); sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and the like.

When synthesizing the compound of the present invention, the acid used may be an acid commonly used in the art, including an organic acid and an inorganic acid. Examples of organic acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid. acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methylsulfonic acid and ethylsulfonic acid; as an example of an inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid and the like can be mentioned.

In synthesizing the compound of the present invention, the reducing agent used may be a reducing agent commonly used in the art, including, but not limited to, triphenylphosphine, tri-n-butylphosphine, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, iron powder, zinc powder, divalent chloride tin, sodium dithionite, hydrogen, etc.

When synthesizing the compound of the present invention, the oxidizing agent used may be an oxidizing agent commonly used in the art, including, but not limited to, copper chloride, manganese dioxide, permanganate, dichromate, peracetic acid, peroxybenzoic acid, and the like.

In synthesizing the compound of the present invention, the catalyst used may be a catalyst commonly used in the art, including but not limited to, for example, copper acetate, copper chloride, palladium-carbon, iron chloride, palladium acetate, dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium and the like.

Examples

The present invention can be better understood from the following examples and analyzes. It will be readily understood by those skilled in the art that the contents of these examples and analyzes are only intended to illustrate the present invention, and the invention claimed in the appended claims cannot and should not be limited to these examples and analyzes.

In case specific reaction conditions are not indicated in the examples, these examples are carried out in accordance with the usual conditions or conditions recommended by the manufacturer. In the event that the manufacturers of the reagents or instruments used are not indicated, these reagents or instruments are conventional products that are commercially available.

In the present invention, unless otherwise indicated, (i) the temperature is expressed in degrees Celsius (°C) and, unless otherwise indicated, the procedure is carried out at room temperature; (ii) the reaction is monitored by thin layer chromatography (TLC) or LC-MS; (iii) end products have clear proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS) data. Abbreviations and expressions in English used in the present invention have the following meanings.

DAST: diethylaminosulfur trifluoride

DCM: dichloromethane

-Boc: tert-butoxycarbonyl

TEA: triethylamine

TBSCl: tert-butyldimethylchlorosilane

TBS-: tert-butyldimethylsilyl

DMSO: dimethyl sulfoxide

NaHMDS: sodium hexamethyldisilazide

TBAF: tetrabutylammonium fluoride

MsCl: methanesulfonyl chloride

TFA: trifluoroacetic acid

DMF: N,N-dimethylformamide

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium

conc. HCl: concentrated hydrochloric acid

NBS: N-bromosuccinimide

AIBN: Azodiisobutyronitrile

THF: tetrahydrofuran

TMSCN: trimethylsilyl cyanide

CPBA: m-chloroperoxybenzoic acid

TMSI: trimethylsilylimidazole

BHT: dibutylhydroxytoluene

Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine)dichloropalladium

EA: ethyl acetate

EtOH: ethanol

MTBE: methyl tert-butyl ether

PE: petroleum ether

HATU: 2-(7-azabenzotriazol-1-yl)-tetramethyluronium hexafluorophosphate

reflux heating: reflux heating

pyridine: pyridine

toluene: toluene

PBu3:tributylphosphine

1,4-dioxane: 1,4-dioxane

DMF-DMA: N,N-dimethylformamide dimethyl acetal

DIPEA/DIEA: N,N-diisopropylethylamine

DEC: dichloroethane

Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ : complex of dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium and dichloromethane

DMAP: 4-dimethylamino pyridine

rt: room temperature.

Example 1 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridine-3-carboxamide (compounds 14)

Scheme:

Stage 1. Synthesis of 2-(4-fluorophenyl)acetyl chloride

2-(4-Fluorophenyl)acetic acid (50.0 g, 324.380 mmol, 1.0 eq.) and thionyl chloride (77.18 g, 648.761 mmol, 2.0 eq.) were dissolved in dichloromethane (250.0 ml) . The mixture was heated to 60° C. under nitrogen protection and subjected to reflux for 3 hours. TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure, an appropriate amount of dichloromethane was added thereto, and the resulting mixture was concentrated. The above process was repeated twice to give a yellow oily product.

Stage 2. Synthesis of 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

2,2-Dimethyl-1,3-dioxane-4,6-dione (56.10 g, 389.3 mmol, 1.2 eq) and triethylamine (78.78 g, 7798.5 mmol, 2.4 eq.) was dissolved in dichloromethane (250.0 ml). The mixture was cooled to 0° C. under a protective nitrogen atmosphere. The crude product 2-(4-fluorophenyl)acetyl chloride obtained in the above step was diluted with dichloromethane (100.0 ml) and slowly added dropwise to the reaction liquid. After completion of the dropwise addition, the resulting mixture was warmed to room temperature. After 3 hours, detection by TLC showed completion of the reaction. The reaction liquid was washed three times with 1 mol/l HCl, and the pH of the aqueous phase was 3-4. The reaction liquid was washed twice with a saturated aqueous NaCl solution, dried, and concentrated under reduced pressure to give a yellow oily product.

Stage 3. Synthesis of ethyl 4-(4-fluorophenyl)-3-oxobutanoate

5-(2-(4-Fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was dissolved in ethanol (250.0 ml). The mixture was heated to 100°C and subjected to reaction under reflux for 3 hours. TLC showed the incompleteness of the reaction. Added concentrated HCl (10.0 ml). After 2 hours, TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=75:1-10:1) to obtain a yellow oily product (35.0 g, three-step yield: 48.1%).

Stage 4. Synthesis of ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-4-(4-fluorophenyl)-3-oxopent-4-enoate

Ethyl 4-(4-fluorophenyl)-3-oxobutanoate (2.0 g, 8.92 mmol, 1.0 eq) was dissolved in toluene (20.0 ml) and DMF-DMA (3.188 g, 26. 76 mmol, 3.0 eq.). The mixture was heated to 100° C. and reacted overnight. TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure to obtain a product (2.5 g, crude product).

Stage 5. Synthesis of ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate

Ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-4-(4-fluorophenyl)-3-oxopent-4-enoate (3.5 g, crude product) was dissolved in ethanol (20.0 ml) and isopropylamine (791.0 mg, 13.38 mmol, 1.5 eq.) was added. The mixture was heated to 100° C. and reacted for 3 hours. TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=50:1-2:1) to obtain a product (1.0 g, two-step yield: 50%).

Stage 6. Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.0 g, 3.297 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10.0 ml ) and 1 mol/l LiOH aqueous solution (5.0 ml) was added. The mixture was stirred at room temperature for 0.5 hour. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure and the pH was adjusted to 4-5. A large amount of solid precipitated and the mixture was suction filtered. The filter cake was dried to give a white solid (700.0 mg, yield: 70%).

Step 7. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridine-3-carboxamide

5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (250.0 mg, 0.91 mmol, 1.0 eq) and N,N-diisopropylethylamine ( 352.0 mg, 2.72 mmol, 3.0 eq.) was dissolved in N,N-dimethylformamide (2.5 ml) and the mixture was cooled to 0°C. HATU (518.0 mg, 1.362 mmol, 1.5 eq.) was added under nitrogen protection and the mixture was stirred for 0.5 hour. 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (270.0 mg, 0.908 mmol, 1.0 eq) was added and the mixture was slowly warmed to room temperature. After 1 hour, TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure. Ethyl acetate was added and the mixture was washed twice with saturated aqueous NaHCO ₃ , washed with water four times, dried and concentrated under reduced pressure to give a crude product which was worked up by silica gel column chromatography (DCM:MeOH=150:1-30:1). The resulting solid was dissolved in tetrahydrofuran and 1 mol/l HCl was added to adjust the pH to 7-8. The mixture was stirred for 0.5 hour and suction filtered. The filter cake was washed with water and dried to give the product (313.0 mg, yield: 62.0%).

¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 13.47(s, 1H), 8.80 (s, 1H), 8.69-8.68 (d, 1H), 8.48 -8.44 (m, 2H), 8.28 (s, 1H), 7.94-7.92 (m, 1H), 7.75 (s, 2H), 7.67 (s, 1H), 7.52 (s, 1H), 7.31-7.27 (m, 2H), 6.84 (s, 1H), 4.66 (m, 1H), 4.01 (s, 6H), 1 .54-1.52 (d, 6H).

Molecular formula: C ₃₁ H ₂₇ FN ₄ O ₅ , molecular weight: 554.58, LC-MS (positive ion mass/charge)=555.35 [M+H] ⁺ .

Example 2 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine- 3-carboxamide (compounds 1)

Stage 1. Synthesis of ethyl 1-isopropyl-4-okeo-5-p-tolyl-1,4-dihydropyridine-3-carboxylate

Ethyl 4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylate (2.00 g, 7.77 mmol, 1.0 eq.), isopropyl bromide (1.15 g, 9.33 mmol , 1.2 eq.) and potassium carbonate (3.22 g, 23.32 mmol, 3.0 eq.) were added in DMF (20 ml). The mixture was reacted at 50° C. with stirring overnight. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filter cake was eluted with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (20 ml). The mixture was washed successively with distilled water (10 ml×4) and brine (10 ml), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=4:1-1:4) to obtain a product (1.60 g, yield: 68.8%).

Stage 2. Synthesis of 1-isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid

Ethyl 1-isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylate (1.60 g, 5.34 mmol, 1.0 eq.) was dissolved in methanol (20 ml) and an aqueous solution (10 ml) of lithium hydroxide monohydrate (1.01 g, 24.05 mmol, 4.5 eq.) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. A solid precipitated out. Water was added and the mixture was stirred until the solid dissolved. The pH of the mixture was adjusted to 3-4 with concentrated HCl under ice bath conditions and stirred for 30 minutes. The mixture was filtered and the filter cake was dissolved in dichloromethane. The mixture was dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure to obtain a product (1.00 g, yield: 69.0%).

Stage 3. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine- 3-carboxamide

1-Isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid (200.0 mg, 0.74 mmol, 1.2 eq.) was dissolved in DMF (2 ml). HATU (350.4 mg, 0.62 mmol, 1.5 eq) and DIPEA (238.2 mg, 1.84 mmol, 3.0 eq) were added. The mixture was stirred for 10 minutes and then 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (182.6 mg, 0.62 mmol, 1.0 eq.) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (10 ml). The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (developing agent: ethyl acetate) to give the product (216 mg, yield: 53.2%).

¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 13.47 (s, 1H), 8.78-8.77 (d, 1H), 8.51-8.50 (d, 1H), 8.45-8.43(d, 1H), 8.38-8.37(d, 1H), 8.22-8.21(d, 1H), 7.87-7.84(m, 1H ), 7.61-7.59 (d, 2H), 7.55 (s, 1H), 7.42 (s, 1H), 7.27-7.25 (d, 2H), 6.58- 6.56 (d, 1H), 4.68-4.62(m, 1H), 3.96-3.95 (d, 6H), 2.35 (s, 3H), 1.53-1, 52(d, 6H).

Molecular formula: C ₃₂ H ₃₀ N ₄ O ₅ , molecular weight: 550.61, LC-MS (positive ion mass/charge)=551.38[M+H] ⁺ .

Example 3 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridazine-3-carboxamide (compounds 15)

Stage 1. Synthesis of 6,7-dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline

6,7-Dimethoxyquinolin-4-ol (15.00 g, 73.10 mmol, 1.0 eq.), 5-chloro-2-nitropyridine (11.60 g, 73.10 mmol, 1.0 eq. ) and potassium carbonate (20.20 g, 146.11 mmol, 2.0 eq.) were added in DMF (120 ml). The mixture was reacted at 80° C. overnight with stirring under a protective nitrogen atmosphere. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filter cake was eluted with dichloromethane. The filtrate was concentrated under reduced pressure and dissolved in dichloromethane (50 ml). The mixture was washed successively with distilled water (20 ml×4 ml) and brine (20 ml), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=1:9-EA) to give the product (4.70 g, yield: 19.6%).

Stage 2. Synthesis of 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-2-amine

6,7-Dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline (4.70 g, 14.36 mmol, 1.0 eq.), reduced iron powder (4.81 g, 86, 16 mmol, 6.0 eq.) and NH ₄ Cl (9.22 g, 172.32 mmol, 12.0 eq.) were added to a mixed solvent of ethanol (100 ml) and water (40 ml). The mixture was reacted at 80° C. with stirring for 4 hours. Detection by TLC demonstrated completion of the reaction. The mixture was filtered hot and the filter cake was eluted with dichloromethane. The filtrate was concentrated under reduced pressure. The aqueous phase was extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a product (4.07 g, yield: 95.3%).

Step 3. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridazine-3-carboxamide

1-Isopropyl-4-oxo-5-(4-fluorophenyl)-1,4-dihydropyridazine-3-carboxylic acid (149.0 mg, 0.54 mmol, 1.0 eq.) and 5-((6, 7-dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (192.4 mg, 0.65 mmol, 1.2 eq.) was dissolved in anhydrous pyridine (2 ml) and the mixture was stirred for 10 minutes. POCl ₃ was slowly added dropwise until the solid dissolved. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Ethyl acetate (10 ml) was added to dissolve the solid and the mixture was washed successively with 1 mol/l HCl (5 ml), saturated aqueous NaHCO ₃ (5 ml), water (5 ml × 2) and brine (5 ml ), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to give the product (151 mg, yield: 50.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.08 (s, 1H), 8.94 (s, 1H), 8.52-8.50 (d, 1H), 8.44 -8.42 (t, 2H), 7.98-7.95 (m, 2H), 7.91-7.88 (q, 1H), 7.55 (s, 1H), 7.42 (s , 1H), 7.37-7.33 (t, 2H), 6.60-6.58 (d, 1H), 4.80-4.74 (m, 1H), 3.96-3.95 (d, 6H), 1.54-1.53 (d, 6H).

Molecular formula: C ₃₀ H ₂₆ FN ₅ O ₅ , molecular weight: 555.57, LC-MS (positive ion mass/charge)=556.33 [M+H] ⁺ .

Example 4 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridazine-3-carboxamide (compounds 16)

Stage 1. Synthesis of 2-(4-fluorophenyl)acetyl chloride

2-(4-Fluorophenyl)acetic acid (100.0 g, 0.649 mol, 1.0 eq) was dissolved in dichloromethane (200 ml) and thionyl chloride (193.0 g, 1.62 mol, 2.5 eq) was added. ). The mixture was reacted at 50° C. with stirring for 2 hours. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure to give the product (116.0 g, crude product).

Stage 2. Synthesis of ethyl 2-diazo-4-(4-fluorophenyl)-3-oxobutanoate

2-(4-Fluorophenyl)acetyl chloride (116.0 g, crude) was dissolved in ethyl acetate (50 mL) and ethyl 2-diazoacetate (153.3 g, 1344 mmol, 2.0 eq) was added under ice bath conditions . The mixture was gradually warmed to room temperature and stirred overnight. Detection by TLC demonstrated completion of the reaction. Saturated aqueous potassium carbonate solution (100 ml) was added dropwise under ice bath conditions. The mixture was stirred for 20 minutes and subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-60:1) to give the product (60.3 g, yield over two steps: 37.1%).

Stage 3. Synthesis of ethyl 4-(4-fluorophenyl)-2-hydrazono-3-oxobutanoate

Ethyl 2-diazo-4-(4-fluorophenyl)-3-oxobutanoate (57.1 g, 228 mmol, 1.0 eq) was dissolved in methyl t-butyl ether (270.0 ml) and tributylphosphine ( 55.4 g, 273 mmol, 1.2 eq) under ice bath conditions. The mixture was gradually warmed to room temperature and stirred overnight. Detection by TLC demonstrated completion of the reaction. Ethyl acetate (150 ml) and water (200 ml) were added and the mixture was subjected to liquid separation. The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to give the product (125.3 g, crude product).

Stage 4. Synthesis of tert-butyl-2-(1-ethoxy-4-(4-fluorophenyl)-1,3-dioxobutan-2-ylidene)hydrazine-1-carboxylate

Ethyl 4-(4-fluorophenyl)-2-hydrazono-3-oxobutanoate (93.0 g, crude product) was dissolved in tetrahydrofuran (150 ml). The mixture was cooled in an ice bath to 0°C. Triethylamine (37.2 g, 368 mmol) and di-tert-butyl dicarbonate (96.5 g, 442.0 mmol) were added and DMAP (13.4 g, 110.0 mmol) was added intermittently. The mixture was gradually warmed to room temperature and stirred overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Ethyl acetate (300 ml) and water (500 ml) were added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to give the product (52.0 g, crude product).

Stage 5. Synthesis of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate

tert-Butyl 2-(1-ethoxy-4-(4-fluorophenyl)-1,3-dioxobutan-2-ylidene)hydrazine-1-carboxylate (52.0 g, crude product) was dissolved in toluene (100 ml) . N,N-dimethylformamide dimethyl acetal (35.1 g, 338 mmol, 2.0 eq.) was added. The mixture was stirred at 60° C. overnight. Detection by LC-MS demonstrated completion of the reaction. The system was cooled to room temperature. The mixture was suction filtered. The filter cake was dried to give the product (22.1 g, three-step yield: 49.8%).

Stage 6. Synthesis of ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate

Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.80 g, 33.5 mmol, 1.0 eq.) was dissolved in DMF (30 ml). Potassium carbonate (9.26 g, 67.0 mmol, 2.0 eq) and bromisopropane (6.18 g, 50.3 mmol, 1.5 eq) were added. The mixture was stirred at 50° C. under a protective nitrogen atmosphere overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure.

Ethyl acetate (150 ml) and water (200 ml) were added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a product (8.49 g, yield: 84.0%).

Stage 7. Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

Ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (7.47 g, 24.0 mmol, 1.0 eq) was dissolved in methanol (30, 0 ml). An aqueous solution (15.0 ml) of lithium hydroxide monohydrate (3.08 g, 73.0 mmol, 3.0 eq.) was added. The mixture was reacted at room temperature with stirring for 0.5 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure, adjusted to pH with HCl (1 mol/l, 4.0 ml) to approximately 4, stirred for 20 minutes and filtered by suction. The filter cake was dried to give the product (6.29 g, yield: 94.8%).

Step 8. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridazine-3-carboxamide

5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (2.0 g, 7.23 mmol, 1.0 eq.) and 5-((6, 7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (2.15 g, 7.23 mmol, 1.0 eq.) was added to pyridine (8 ml) and phosphorus oxychloride (0.5 ml) was added dropwise ). The mixture was stirred for 30 minutes. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Water (50 ml) was added. The mixture was extracted with ethyl acetate (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1-60:1) to give the product (2.1 g, yield: 51.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.89 (s, 1H), 8.89 (s, 1H), 8.80 (s, 2H), 8.50-8, 51 (m, 1H), 7.93-7.97 (m, 2H), 7.55 (s, 1H), 7.43 (s, 1H), 7.31-7.35 (m, 2H) , 6.68-6.69 (d, 1H), 4.72-4.75 (m, 1H), 3.95-3.96 (m, 6H), 1.50-1.52 (m, 6H).

Molecular formula: C ₂₉ H ₂₅ FN ₆ O ₅ , molecular weight: 556.55, LC-MS (positive ion mass/charge) = 551.38 [M+H] ⁺ .

Example 5 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridine-3-carboxamide (compounds 20)

Step 1. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4- dihydropyridine-3-carboxamide

5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (450.0 mg, 1.63 mmol, 1.0 eq.) and 5-((6, 7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (487.31 mg, 1.63 mmol, 1.0 eq.) was added to pyridine (18 mL) and phosphorus oxychloride (0.2 ml) in an ice bath. The mixture was slowly warmed to room temperature and reacted for 3 hours. Detection by TLC demonstrated completion of the reaction. Ethyl acetate (10 ml) and water (20 ml) were added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-10:1) to give the product (200.0 mg, yield: 22.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.67 (s, 1H), 8.80 (s, 2H), 8.77-8.76 (d, 1H), 8.52 -8.51 (d, 1H), 8.28 (s, 1H), 7.77-7.73 (m, 2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.31-7.27(m, 2H), 6.71-6.70(d, 1H), 4.68-4.65(t, 1H), 3.97-3.96(d, 6H ), 1.53-1.52 (d, 6H).

Molecular formula: C ₃₀ H ₂₆ FN ₅ O ₅ , molecular weight: 555.57, LC-MS (positive ion mass/charge) = 556.3 [M+H] ⁺ .

Example 6 Synthesis of N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-1-isopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridazine -3-carboxamide (compounds 29)

Stage 1. Synthesis of 6,7-dimethoxy-4-((5-nitropyridin-2-yl)oxy)quinoline

6,7-Dimethoxyquinolin-4-ol (5.00 g, 24.36 mmol, 1.0 eq.), 2-chloro-5-nitropyridine (3.86 g, 24.36 mmol, 1.0 eq. ) and potassium carbonate (6.73 g, 48.73 mmol, 2.0 eq.) were added in DMF (50 mL). The mixture was reacted at 40° C. with stirring under a protective nitrogen atmosphere overnight. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filter cake was eluted with dichloromethane. The filtrate was concentrated under reduced pressure. Dichloromethane (20 ml) and methanol (20 ml) were added to dissolve the crude product. The mixture was dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=80:1-30:1) to obtain a product (0.60 g, yield: 7.52%).

Stage 2. Synthesis of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-3-amine

6,7-Dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline (366.0 mg, 1.12 mmol, 1.0 eq.), reduced iron powder (374.7 mg, 6, 71 mmol, 6.0 eq.) and NH ₄ Cl (717.8 mg, 13.42 mmol, 12.0 eq.) were added to a mixed solvent of ethanol (10 ml) and water (5 ml). The mixture was reacted at 80° C. with stirring for 4 hours. Detection by TLC demonstrated completion of the reaction. Celite was added to the solution and the mixture was filtered hot and the filter cake was eluted with EtOH. The filtrate was concentrated under reduced pressure and extracted with dichloromethane (5 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a product (188.0 mg, yield: 56.6%).

Stage 3. Synthesis of N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-1-isopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridazine -3-carboxamide

1-Isopropyl-4-oxo-5-p-fluorophenyl-1,4-dihydropyridazine-3-carboxylic acid (184.6 mg, 0.66 mmol, 1.1 eq.) was dissolved in DMF (2 ml). HATU (346.4 mg, 0.91 mmol, 1.5 eq) and DIPEA (235.4 mg, 1.82 mmol, 3.0 eq) were added. The mixture was stirred for 10 minutes. 6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-3-amine (180.6 mg, 0.61 mmol, 1.0 eq) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (10 ml). The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (230 mg, yield: 67.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.38 (s, 1H), 8.92 (s, 1H), 8.63-8.62 (d, 1H), 8.59 -8.58 (d, 1H), 8.40-8.37 (t, 1H), 7.97-7.94 (m, 2H), 7.43 (s, 1H), 7.39-7 .32 (m, 4H), 6.91-6.90 (d, 1H), 4.78-4.71(m, 1H), 3.96 (s, 3H), 3.89 (s, 3H ), 1.53-1.51 (d, 6H).

Molecular formula: C ₃₀ H ₂₆ FN ₅ O ₅ , molecular weight: 555.57, LC-MS (positive ion mass/charge) = 556.28 [M+H] ⁺ .

Example 7 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine -3-carboxamide (compounds 30)

Stage 1. Synthesis of ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-4-p-fluorophenyl-3-oxopentane-4-enoate

Ethyl 4-p-fluorophenyl-3-oxobutanoate (5.00 g, 22.30 mmol, 1.0 eq.) and DMF-DMA (15.94 g, 133.79 mmol, 6 eq.) were added to toluene (50 ml). The mixture was reacted at 100° C. with stirring overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure to give a crude product which was directly used in the next step without purification.

Stage 2. Synthesis of ethyl 1-cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine-3-carboxylate

The crude product from the previous step, ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-4-p-fluorophenyl-3-oxopentane-4-enoate and cyclopropylamine (1.91 g, 33.45 mmol , 1.5 eq.) was added to EtOH (30 ml). The mixture was reacted at 80° C. with stirring overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (20 ml). The mixture was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (2.67 g, two-step yield: 39.7%).

Stage 3. Synthesis of 1-cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine-3-carboxylic acid

Ethyl 1-cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine-3-carboxylate (2.67 g, 8.86 mmol, 1.0 eq.) was dissolved in methanol (40 ml). An aqueous solution (20 ml) of lithium hydroxide monohydrate (1.67 g, 39.87 mmol, 4.5 eq.) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Water was added with stirring until complete dissolution of the solid. The pH of the mixture was adjusted to 3-4 with concentrated HCl under ice bath conditions and stirred for 30 minutes. The solid was filtered off and dissolved in dichloromethane. The mixture was dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure to obtain a product (1.25 g, yield: 51.6%).

Step 4 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine -3-carboxamide

1-Cyclopropyl-4-oxo-5-para-fluorophenyl-1,4-dihydropyridine-3-carboxylic acid (150.0 mg, 0.55 mmol, 1.1 eq) was dissolved in DMF (1.5 ml) . HATU (285.0 mg, 0.75 mmol, 1.5 eq) and DIPEA (193.0 mg, 1.50 mmol, 3.0 eq) were added. The mixture was stirred for 10 minutes. 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (148.0 mg, 0.50 mmol, 1.0 eq) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (10 ml). The mixture was washed successively with saturated sodium bicarbonate solution (5 ml), saturated ammonium chloride solution (5 ml), water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (140.0 mg, yield: 50.7%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.29 (s, 1H), 8.66 (s, 1H), 8.50-8.49 (d, 1H), 8, 43-8.37 (m, 2H), 8.14 (s, 1H), 7.86-7.84 (d, 1H), 7.75 (s 2H), 7.54 (s, 1H), 7.42(s, 1H), 7.30-7.28(d, 2H), 6.57-6.56(d, 1H), 3.95(d, 7H), 1.26(s, 2H), 1.11(s, 2H).

Molecular formula: C ₃₁ H ₂₅ FN ₄ O ₅ , molecular weight: 552.56, LC-MS (positive ion mass/charge) = 553.25 [M+H] ⁺ .

Example 8 Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridine-3-carboxamide (compounds 32)

Step 1. Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridine-3-carboxamide

1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (227.0 mg, 0.83 mmol, 1.0 eq) and 5-((6, 7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (247.8 mg, 0.83 mmol, 1.0 eq.) was added to pyridine (4 ml) and phosphorus oxychloride (0.3 ml) was added dropwise ). The mixture was stirred for 30 minutes. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Ethyl acetate (20 ml) and water (15 ml) were added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=15:1) to give the product (110.0 mg, yield: 23.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.53 (s, 1H), 8.80 (s, 2H), 8.63 (m, 1H), 8.51-8, 52 (m, 1H), 8.13-8.14 (m, 1H), 7.73-7.76 (m, 2H), 7.55 (s, 1H), 7.43 (s, 1H) , 7.26-7.30(m, 2H), 6.69-6.71(m, 1H), 3.95-3.96(s, 6H), 3.88-3.91(m, 1H). 1.23-1.25(m, 2H), 1.08-1.09(m, 2H).

Molecular formula: C ₃₀ H ₂₄ FN ₅ O ₅ , molecular weight: 553.55, LC-MS (positive ion mass/charge) = 554.26 [M+H] ⁺ .

Example 9 Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethylquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-4-o xo-1,4 -dihydropyridazine-3-carboxamide (compounds 31)

Stage 1. Synthesis of ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate

Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.627 mmol, 1.0 eq.), cyclopropylboronic acid (1.965 g, 22.880 mmol, 3, 0 eq.), triethylamine (3.858 g, 38.133 mmol, 5.0 eq.), pyridine (4.826 g, 61.013 mmol, 8.0 eq.) and copper acetate (1.385 g, 7.627 mmol, 1.0 eq.) was dissolved in DMF (20.0 ml) and the mixture was subjected to reaction at 50°C overnight under oxygen atmosphere. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure. Added water. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=40:1) to give the product (38.0 mg, yield: 1.65%).

Stage 2. Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

Ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (38.0 mg, 0.126 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (1.0 ml ). An aqueous solution of LiOH (1 mol/l) was added. The mixture was reacted at room temperature for 1 hour. TLC showed completion of the reaction. The reaction liquid was concentrated under reduced pressure. Water (15.0 ml) was added. The mixture was extracted with ethyl acetate (6.0 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (59.0 mg, crude product).

Step 3. Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethylquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridazine-3-carboxamide

1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (59.0 mg, crude) and N,N-diisopropylethylamine (48.7 mg, 0.377 mmol, 3.0 eq.) was dissolved in DMF (1.0 ml). The mixture was cooled to 0°C. HATU (71.7 mg, 0.188 mmol, 1.5 eq.) was added under nitrogen protection. The mixture was stirred at 0°C for 0.5 hour. 5-((6,7-Dimethoxyquinolin-4-yloxy)pyridine-2-amine (37.0 mg, 0.126 mmol, 1.0 eq) was added. The mixture was reacted at room temperature for 3 hours. TLC showed completion The reaction liquid was poured into water (20.0 ml) The mixture was extracted with ethyl acetate (10.0 ml × 2) The organic phase was washed successively with saturated aqueous sodium carbonate solution (3.0 ml), saturated aqueous NH ₄ Cl (3 0 ml) and saturated aqueous sodium chloride solution (3.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The crude product was purified using preparative thin layer chromatography plate (DCM : MeOH = 20:1) with product (40.0 mg, yield over two steps: 57.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.98 (s, 1H), 8.94 (s, 1H), 8.52-8.50 (m, 1H), 8, 43-8.40(m, 2H), 7.97-7.93(m, 2H), 7.91-7.87(m, 1H), 7.55(s, 1H), 7.42( s, 1H), 7.37-7.32 (m, 2H), 6.60-6.57 (m, 1H), 4.17-4.11 (m, 1H), 3.97-3, 95 (d, 6H), 1.35-1.23 (m, 2H), 1.15-1.14 (m, 2H).

Molecular formula: C ₃₀ H ₂₄ FN ₅ O ₅ , molecular weight: 553.55, LC-MS (positive ion mass/charge) = 554.32 [M+H] ⁺ .

Example 10 Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridazine-3-carboxamide (compounds 33)

Step 1. Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethylquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridazine-3-carboxamide

1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (200.0 mg, 0.729 mmol, 1.0 eq.) and 5-((6.7- dimethoxyquinolin-4-yloxy)pyrimidin-2-amine (217.5 mg, 0.729 mmol, 1.0 eq.) was dissolved in pyridine (4.0 ml) The mixture was cooled to 0° C. Phosphorus oxychloride (0 .2 ml) under nitrogen protection The mixture was reacted at room temperature for 0.5 hour TLC showed completion of the reaction The reaction liquid was poured into water (20.0 ml) and the pH was adjusted to 6-7 The mixture was extracted with ethyl acetate (10.0 ml x 2) The organic phase was washed with 2 mol/l HCl solution (2.0 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was purified by silica gel column chromatography (DCM : MeOH=100:1-20:1) to give the product (200.0 mg, yield: 49.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.82 (s, 1H), 8.90 (s, 1H), 8.86-8.80 (m, 2H), 8, 52-8.50 (m, 1H), 7.95-7.93 (m, 2H), 7.55 (s, 1H), 7.44 (s, 1H), 7.36-7.31 ( m, 2H), 6.70-6.69 (m, 1H), 4.11-4.10 (m, 1H), 3.97-3.95 (d, 6H), 1.31-1, 24 (m, 2H), 1.13-1.11 (m, 2H).

Molecular formula: C ₂₉ H ₂₃ FN ₆ O ₅ , molecular weight: 554.54, LC-MS (positive ion mass/charge) = 554.66 [M+H] ⁺ .

Example 11 Synthesis of N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-5-p-fluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazin- 3-carboxamide (compounds 34)

Stage 1. Synthesis of 6,7-dimethoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline

6,7-Dimethoxyquinolin-4-ol (3.86 g, 18.81 mmol, 1.0 eq.), 2-chloro-5-nitropyrimidine (3.00 g, 18.81 mmol, 1.0 eq. ) and triethylamine (2.28 g, 22.57 mmol, 1.2 eq.) were added in DMF (60 mL). The mixture was reacted at room temperature with stirring under a protective nitrogen atmosphere overnight. Detection by TLC demonstrated completion of the reaction. A saturated aqueous solution of NH ₄ Cl (30 ml) was added. The mixture was concentrated under reduced pressure. Saturated brine (30 ml) was added. The mixture was extracted with dichloromethane (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by 200-300 mesh silica gel column chromatography (DCM:MeOH=150:1-120:1) to give the product (1.70 g, yield: 27.5%).

Stage 2. Synthesis of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine

6,7-Dimethoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline (1.70 g, 5.18 mmol, 1.0 eq.), reduced iron powder (1.74 g, 31, 07 mmol, 6.0 eq.) and NH ₄ Cl (3.32 g, 62.14 mmol, 12.0 eq.) were added to a mixed solvent of ethanol (30 ml) and water (15 ml). The mixture was reacted at 80° C. with stirring for 2 hours. Detection by TLC demonstrated completion of the reaction. The mixture was filtered hot and the filter cake was eluted with dichloromethane. The mixture was concentrated under reduced pressure and extracted with dichloromethane (10 ml x 3). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a product (0.93 g, yield: 60.2%).

Step 3. Synthesis of N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-5-p-fluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazin- 3-carboxamide

5-p-Fluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (947.4 mg, 3.43 mmol, 1.1 eq.) was dissolved in DMF (12 ml). DIPEA (1208.8 mg, 9.35 mmol, 3.0 eq.) and HATU (1778.2 mg, 4.68 mmol, 1.5 eq.) were added sequentially with ice bath cooling. The mixture was stirred for 10 minutes and then 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine (930.0 mg, 3.12 mmol, 1.0 eq.) was added. The mixture was warmed to room temperature and reacted with stirring overnight. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. Ethyl acetate (20 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (10 ml), saturated aqueous NH ₄ Cl (10 ml), distilled water (10 ml × 4) and brine (10 ml), dried over anhydrous sodium sulfate and filtered by suction . The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (oxidizing agent is DCM:MeOH = 15:1) to give the product (1410.0 mg, yield: 81.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.50 (s, 1H), 9.08 (s, 2H), 8.93 (s, 1H), 8.68-8, 67 (d, 1H), 7.97-7.93 (m, 2H) 7.46 (s, 1H), 7.36-7.32 (t, 2H), 7.23-7.20 (t , 2H), 4.78-4.72(m, 1H), 3.96(s, 3H), 3.85(s, 3H), 1.52-1.51(d, 6H).

Molecular formula: C ₂₉ H ₂₅ FN ₆ O ₅ , molecular weight: 556.55, LC-MS (positive ion mass/charge) = 557.31 [M+H] ⁺ .

Example 12 Synthesis of ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate as an intermediate

Stage 1. Synthesis of 1-cyclopropylurea

Cyclopropylamine (10.0 g, 0.175 mol) and potassium cyanate (16.8 g, 0.21 mol) were added to water (60 ml). The mixture was subjected to reaction at 100°C under reflux for 30 minutes. The mixture was concentrated under reduced pressure. Isopropyl alcohol was added. The mixture was heated to 85°C and stirred for 30 minutes. The mixture was filtered and the filter cake washed with isopropyl alcohol. The filtrate was concentrated under reduced pressure to obtain a product (6.0 g, yield: 34.3%).

Stage 2. Synthesis of 1-cyclopropyl-1-nitrosourea

1-Cyclopropylurea (6.0 g, 60 mmol) and sodium nitrite (8.7 g, 126 mmol) were added to water (42 ml). The mixture was cooled in an ice bath to 0° C. and concentrated HCl (13.44 ml) was slowly added dropwise. The mixture was subjected to reaction at 0°C for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was filtered to give the product (3.5 g, yield: 45.2%).

Stage 3. Synthesis of ethyl 2-(2-cyclopropylhydrazino)-4-(4-fluorophenyl)-3-oxobutanoate

1-Cyclopropyl-1-nitrosourea (3.33 g, 25.8 mmol) and ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.82 g, 21.5 mmol) were added to dichloromethane (33.3 ml). The mixture was cooled in an ice bath to 0° C. and potassium carbonate (8.92 g, 77.3 mmol) was added. The mixture was slowly warmed to room temperature and reacted for 3 hours. TLC showed completion of the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 15:1-10:1) to give the product (1.5 g, yield: 19.92%).

Stage 4. Synthesis of ethyl 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-4-(4-fluorophenyl)-3-oxopent-4-enoate

Ethyl 2-(2-cyclopropylhydrazino)-4-(4-fluorophenyl)-3-oxobutanoate (1.5 g, 5.13 mmol) and DMF-DMA (917.8 mg, 7.7 mmol) were added to toluene (10 ml). The mixture was heated to 110°C and subjected to reaction under reflux overnight. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure to give the product (1.8 g, crude).

Stage 5. Synthesis of ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate

Ethyl 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-4-(4-fluorophenyl)-3-oxopent-4-enoate (1.8 g, crude) was added to ethanol (15 ml). The mixture was heated to 80° C. and reacted overnight. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure to give the product (1.56 g, crude).

Example 13 Synthesis of 1-cyclopropyl-N-(6-((6,7-dimethylquinolin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridazine-3-carboxamide (compounds 36)

Stage 1. Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

Ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (1.17 g, 3.87 mmol, 1.0 eq.) was added to methanol (10 ml ). After the mixture was stirred to dissolve the solid, an aqueous solution (4 ml) of lithium hydroxide monohydrate (487.0 mg, 11.6 mmol, 3.0 eq.) was added. The mixture was stirred at room temperature for 2 hours. Detection by TLC showed completion of the reaction, and then the mixture was concentrated under reduced pressure, adjusted with 2 mol/l HCl (5 ml) to pH 3-4 and extracted with DCM (100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (903.5 mg, yield: 85%).

Step 2. Synthesis of 1-cyclopropyl-N-(6-((6,7-dimethylquinolin-4-yl)oxy)pyridin-3-yl)-5-(4-fluorophenyl)-4-oxo-1,4- dihydropyridazine-3-carboxamide

To pyridine (4 ml) was added 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (230.0 mg, 0.84 mmol, 1.0 eq.) and 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-3-amine (274.2 mg, 0.92 mmol, 1.1 eq) and phosphoroxychloride (0.1 ml) was added dropwise . The mixture was stirred for 5 minutes. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Ethyl acetate (50 ml) and water (70 ml) were added and the mixture was subjected to liquid separation. The organic phase was washed with saturated aqueous sodium chloride solution (50 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane:methanol = 20:1) to give the product (122.0 mg, yield over two steps: 26.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.92 (s, 1H), 8.57-8.60 (m, 2H), 8, 36-8.39 (m, 1H), 7.92-7.96 (m, 2H), 7.42 (s, 1H), 7.31-7.42 (m, 4H), 6.89- 6.90 (m, 1H), 4.08-4.12 (m, 1H), 3.95 (s, 3H), 3.89-3.91 (s, 3H), 1.30-1, 31 (m, 2H). 1.10-1.12 (m, 2H).

Molecular formula: C ₃₀ H ₂₄ FN ₅ O ₅ , molecular weight: 553.55, LC-MS (positive ion mass/charge) = 553.80 [M+H] ⁺ .

Example 14 Synthesis of 1-cyclopropyl-N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-5-p-fluorophenyl-4-oxo-1,4-dihydropyridazin- 3-carboxamide (compounds 37)

Step 1. Synthesis of 1-cyclopropyl-N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-5-p-fluorophenyl-4-oxo-1,4-dihydropyridazine -3-carboxamide

1-Cyclopropyl-5-p-fluorophenyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (190.0 mg, 0.69 mmol, 1.0 eq.) was dissolved in DMF (3 ml). DIPEA (211.5 mg, 2.08 mmol, 3.0 eq.) and HATU (395.1 mg, 1.04 mmol, 1.5 eq.) were added sequentially with ice bath cooling. The mixture was stirred for 10 minutes and then 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine (207.0 mg, 0.69 mmol, 1.0 eq.) was added. The mixture was warmed to room temperature and reacted with stirring overnight. Detection by TLC demonstrated completion of the reaction.

The solvent was removed by evaporation under reduced pressure. Ethyl acetate (10 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), distilled water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction . The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (oxidizing agent is DCM:MeOH = 15:1) to give the product (90.0 mg, yield: 23.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.41 (s, 1H), 9.08 (s, 2H), 8.93 (s, 1H), 8.68-8, 67 (d, 1H), 7.94 (s, 2H) 7.46 (s, 1H), 7.36-7.32 (t, 2H), 7.23-7.21 (t, 2H), 4.12 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 1.31-1.24 (d, 2H), 1.12-1.10 (d, 2H).

Molecular formula: C ₂₉ H ₂₃ FN ₆ O ₅ , molecular weight: 554.54, LC-MS (positive ion mass/charge) = 554.79 [M+H] ⁺ .

Example 15 Synthesis of N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-6-p-fluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazin- 4-carboxamide (compounds 38)

Step 1. Synthesis of N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-6-p-fluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazin- 4-carboxamide

6-p-Fluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (150.0 mg, 0.54 mmol, 1.0 eq.) was dissolved in DMF (3 ml). DIPEA (164.8 mg, 1.63 mmol, 3.0 eq.) and HATU (309.7 mg, 0.81 mmol, 1.5 eq.) were added successively with ice bath cooling. The mixture was stirred for 10 minutes and then 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-3-amine (177.6 mg, 0.59 mmol, 1.1 eq.) was added. The mixture was warmed to room temperature and reacted with stirring overnight. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. Ethyl acetate (10 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), distilled water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction . The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (205.0 mg, yield: 68.0%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.34 (s, 1H), 9.23 (s, 1H), 8.64-8.63 (d, 1H), 8.60 -8.59 (d, 1H), 8.42-8.40 (dd, 1H), 8.21-8.18 (q, 2H), 7.43 (s, 1H), 7.40-7 .35 (m, 4H), 6.92-6.91 (d, 1H), 4.91-4.85 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H ), 1.51-1.50 (d, 6H).

Molecular formula: C ₃₀ H ₂₆ FN ₅ O ₅ , molecular weight: 555.57, LC-MS (positive ion mass/charge) = 556.26 [M+H] ⁺ .

Example 16 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5- dihydropyridazine-4-carboxamide (compounds 39)

Step 1. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5- dihydropyridazine-4-carboxamide

6-(4-Fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (100.0 mg, 0.36 mmol, 1.0 eq.) was added to pyridine (3 ml) . The mixture was stirred to dissolve the solid and then 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (118.7 mg, 0.39 mmol, 1.1 eq) and phosphoroxychloride ( 0.2 ml). The mixture was stirred at room temperature for 10 minutes. After detection by TLC showed completion of the reaction, water (40 ml) and ethyl acetate (60 ml) were added to the system and the system was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (123.0 mg, yield: 61.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.95 (s, 1H), 9.21 (s, 1H), 8.84 (s, 2H), 8.51-8, 53 (m, 1H), 8.18-8.22 (m, 2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.34-7.38 (m, 2H) , 6.71-6.73 (m, 1H), 4.89-4.92 (m, 1H), 3.96 (s, 6H), 1.50-1.52 (m, 6H).

Molecular formula: C ₂₉ H ₂₅ FN ₆ O ₅ , molecular weight: 556.55, LC-MS (positive ion mass/charge) = 557.24 [M+H] ⁺ .

Example 17 Synthesis of N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5- dihydropyridazine-4-carboxamide (compounds 40)

Step 1. Synthesis of N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5- dihydropyridazine-4-carboxamide

6-(4-Fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (101.9 mg, 0.37 mmol, 1.1 eq) was dissolved in DMF (3 ml) . DIPEA (101.8 mg, 1.01 mmol, 3.0 eq.) and HATU (191.3 mg, 0.50 mmol, 1.5 eq.) were added sequentially with ice bath cooling. The mixture was stirred for 10 minutes and then 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine (100.0 mg, 0.34 mmol, 1.0 eq.) was added. The mixture was warmed to room temperature and reacted with stirring overnight. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. Ethyl acetate (10 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), distilled water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate and filtered by suction . The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (90.0 mg, yield: 48.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.29 (s, 1H), 9.23 (s, 1H), 9.10 (s, 2H), 8.68-8, 67 (d, 1H), 8.22-8.18 (q, 2H), 7.46 (s, 1H), 7.39-7.34 (t, 2H), 7.22-7.20 ( d, 2H), 4.90-4.84(m, 1H), 3.96(s, 3H), 3.85(s, 3H), 1.51-1.50(d, 6H).

Molecular formula: C ₂₉ H ₂₅ FN ₆ O ₅ , molecular weight: 556.55, LC-MS (positive ion mass/charge) = 557.23[M+H] ⁺ .

Example 18 Synthesis of 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid as an intermediate

Stage 1. Synthesis of tert-butyl-2-isopropylhydrazine-1-carboxylate

tert-Butylhydrazine carboxylate (20.0 g, 0.151 mol), acetone (9.26 g, 0.16 mol), acetic acid (2 ml), magnesium sulfate (10.0 g) and sodium triacetoxyborohydride (96.64 g, 0.456 mol) was added to dichloromethane (100 ml). The mixture was reacted at room temperature overnight. Detection by TLC demonstrated completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a product (25 g, yield: 95.6%).

Stage 2. Synthesis of tert-butyl-2-(3-ethoxy-3-oxopropyl)-2-isopropylhydrazine-1-carboxylate

tert-Butyl-2-isopropylhydrazine-1-carboxylate (19.0 g, 0.109 mmol) and ethyl acrylate (12.01 g, 0.12 mol) were added to ethanol (60 ml). The mixture was heated to 80° C. and reacted overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Added water. The mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (DCM:MeOH=200:1-80:1) to give the product (24.2 g, yield: 81.0%).

Stage 3. Synthesis of ethyl 3-(1-isopropylhydrazinyl)propionate

tert-Butyl-2-(3-ethoxy-3-oxopropyl)-2-isopropylhydrazine-1-carboxylate (24.1 g, 0.088 mol) was added to dichloromethane (75 ml). The mixture was cooled in an ice bath to 0°C. Trifluoroacetic acid (35 ml) was added. The mixture was slowly warmed to room temperature overnight. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure to give the product (18.9 g, crude product).

Stage 4. Synthesis of ethyl 2-(4-fluorophenyl)-2-oxoacetate

p-Fluoriodobenzene (10.0 g, 0.0451 mol) was added to 2-methyltetrahydrofuran (10 ml). The mixture was cooled in an ice bath to 0°C. Isopropyl magnesium chloride (2 mol/l, 24.78 ml, 0.049 mol) was added. The mixture was reacted at 0° C. with stirring for 30 minutes. The above reaction liquid was added dropwise to a solution of diethyl oxalate (7.25 g, 0.0496 mol) in 2-methyltetrahydrofuran (50 ml). The mixture was slowly warmed to room temperature overnight. TLC showed completion of the reaction. The reaction liquid was added to an aqueous citric acid solution. The pH of the mixture was maintained at 5-6. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 120:1-40:1) to give the product (8 g, yield: 90.5%).

Stage 5. Synthesis of ethyl 3-(2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylidene)-1-isopropylhydrazinyl)propionate

Ethyl 2-(4-fluorophenyl)-2-oxoacetate (4.43 g, 22.6 mmol) and ethyl 3-(1-isopropylhydrazinyl) propionate (11.81 g, crude) were added to ethanol (10 ml ). The mixture was heated to 80° C. and reacted overnight. TLC showed completion of the reaction. The mixture was suction filtered. Water was added to the filtrate. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 60:1-10:1) to give the product (2.3 g, yield: 28.9%).

Stage 6. Synthesis of ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

Ethyl 3-(2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylidene)-1-isopropylhydrazinyl)propionate (2.27 g, 6.45 mmol) was added to 2-methyltetrahydrofuran (10 ml) . The mixture was cooled in an ice bath to 0°C. Potassium tert-butoxide (1.81 g, 16.11 mmol) was added. The mixture was slowly warmed to room temperature overnight. TLC showed completion of the reaction. The reaction liquid was added to an aqueous citric acid solution. The pH of the mixture was maintained at 5-6. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a product (1.27 g, yield: 64.5%).

Stage 7. Synthesis of ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylate

Ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxy t (1.2 g, 3.92 mmol) and copper chloride dihydrate (2, 67 g, 15.68 mmol) was added to acetonitrile (10 ml). The mixture was subjected to reaction at 80°C for 4 hours. TLC showed completion of the reaction. Water was added to the reaction liquid. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 100:1-40:1) to give the product (730.0 mg, yield: 61.2%).

Stage 8. Synthesis of 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid

Ethyl 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylate (700.0 mg, 2.3 mmol) was added to a mixed solvent of methanol (6 ml) and water (5 ml) and lithium hydroxide monohydrate (284.4 mg, 6.91 mmol) was added. The mixture was stirred at room temperature for 1 hour. TLC showed completion of the reaction. The pH value of the mixture was adjusted to 2-3 with citric acid. A solid precipitated out. The mixture was suction filtered. Dichloromethane was added to dissolve the precipitate on the filter. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a product (600.0 mg, yield: 94.5%).

Example 19 Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxco-2.5 -dihydropyridazine-4-carboxamide (compounds 41)

Step 1. Synthesis of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxco-2,5 -dihydropyridazine-4-carboxamide

6-(4-Fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (50.0 mg, 0.181 mmol, 1.0 eq) and DIPEA (70.0 mg, 0.543 mmol, 3.0 eq.) was dissolved in DMF (1.0 ml). HATU (103.0 mg, 0.272 mmol, 1.5 eq.) was added at 0° C. under nitrogen protection. The mixture was stirred for 0.5 hour. 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (54.0 mg, 0.181 mmol, 1.0 eq) was added. The mixture was slowly warmed to room temperature overnight. TLC showed completion of the reaction. Ethyl acetate (30.0 ml) was added to the reaction liquid, and the mixture was washed successively with a saturated aqueous sodium carbonate solution (2.0 ml), a saturated aqueous NH ₄ Cl solution (2.0 ml), and a saturated aqueous sodium chloride solution (2.0 ml ). The organic phase was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-30:1) to give the product (75.0 mg, yield: 74.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.75 (s, 1H), 9.25 (s, 1H), 8.51-8.49 (d, 1H), 8.45 -8.42(m, 2H), 8.23-8.19(m, 2H), 7.92-7.88(m, 1H), 7.55(s, 1H), 7.43-7 .34 (m, 3H), 6.59-6.57 (d, 1H), 4.93-4.86 (m, 1H), 3.96-3.95 (d, 6H), 1.53 -1.50 (d, 6H).

Molecular formula: C ₃₀ H ₂₆ FN ₅ O ₅ , molecular weight: 555.57, LC-MS (positive ion mass/charge) = 556.28 [M+H] ⁺ .

Example 20 Synthesis of 2-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-6-(4-fluorophenyl)-5-oxo-2,5- dihydropyridazine-4-carboxamide (compounds 42)

Stage 1. Synthesis of tert-butyltosyloxycarbamate

tert-Butylhydroxycarbamate (230.0 g, 1.72 mol, 1.0 eq.) was dissolved in methyl tert-butyl ether (1.15 L). 4-Methylbenzene-1-sulfonyl chloride (329.3 g, 1.72 mol, 1.0 eq.) was added. Triethylamine (182.7 g, 1.80 mol, 1.05 eq.) was added dropwise with stirring under ice bath conditions. The mixture was gradually warmed to room temperature and stirred for 14 hours. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was suspended in n-hexane (200 ml) and filtered. The filter cake was dried to give the product (411.0 g, yield: 83.1%).

Stage 2. Synthesis of tert-butyl-2-cyclopropyl-2-(3-ethoxy-3-oxopropyl)hydrazine-1-carboxylate

Ethyl 3-(cyclopropylamino)propionate (156.5 g, 0.99 mol, 1.2 eq) was dissolved in DCM (700 ml). The mixture was cooled to -5° C. in an ice salt bath. N-methylmorpholine (100.7 g, 0.99 mol, 1.2 eq.) was added and tert-butyltosyloxycarbamate (240 g, 0.83 mol, 1.0 eq.) was added in portions. The mixture was gradually warmed to room temperature and stirred for 14 hours. Detection by TLC demonstrated completion of the reaction. Water (500 ml) was added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-15:1) to obtain a product (71.30 g, yield: 31.5%).

Stage 3. Synthesis of ethyl 3-(1-cyclopropylhydrazine)propionate

tert-Butyl-2-cyclopropyl-2-(3-ethoxy-3-oxopropyl)hydrazine-1-carboxylate (71.30 g 0.26 mol, 1.0 eq.) was dissolved in DCM (136.0 ml). Trifluoroacetic acid (91.0 ml) was added dropwise with ice bath cooling. After completion of the dropwise addition, the mixture was gradually warmed to room temperature and stirred for 14 hours. Detection by TLC demonstrated completion of the reaction. The system was concentrated under reduced pressure to give the product (88.1 g, crude).

Stage 4. Synthesis of ethyl 2-(4-fluorophenyl)-2-oxoacetate

para-Fluoriodobenzene (400.0 g, 1.8 mol, 1.0 eq.) was added to 2-methyltetrahydrofuran (2 L) and isopropylmagnesium chloride (2 mol/L, 990.0 ml) was added dropwise under ice-cold bath conditions. salt. The mixture was stirred for 30 minutes. The above reaction liquid was added dropwise to a solution of diethyl oxalate (289.7 g, 1.98 mol, 1.1 eq.) in 2-methyltetrahydrofuran (2.0 L). The mixture was gradually warmed to room temperature and stirred for 15 hours. Detection by TLC demonstrated completion of the reaction. The reaction liquid was added to a saturated aqueous citric acid solution, and the pH was controlled to be 5-6. Ethyl acetate (2.0 L) was added and the mixture was subjected to liquid separation. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 120:1-40:1) to obtain a product (282.4 g, yield: 80%).

Stage 5. Synthesis of ethyl 3-(1-cyclopropyl-2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylidene)hydrazinyl)propionate

Ethyl 3-(1-cyclopropylhydrazine)propionate (88.1 g, 0.26 mol, 1.0 eq) and ethyl 2-(4-fluorophenyl)-2-oxoacetate (61.4 g, 0.31 mol, 1.19 eq.) was added to ethanol (105.0 ml). The mixture was subjected to reaction at 80°C for 15 hours. Detection by TLC demonstrated completion of the reaction. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1-15:1) to give the product (5.76 g, yield over two steps: 6.3%).

Stage 6. Synthesis of ethyl 2-cyclopropyl-6-(4-fluorophenyl)-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

Ethyl 3-(1-cyclopropyl-2-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylidene)hydrazinyl)propionate (5.76 g, 0.01 mol, 1.0 eq) was added to 2-methyltetrahydrofuran (33.0 ml). Potassium tert-butoxide (4.6 g, 0.04 mol, 2.5 eq.) was added portionwise under ice bath conditions. The mixture was gradually warmed to room temperature and stirred for 15 hours. Detection by TLC demonstrated completion of the reaction. The reaction liquid was added to an aqueous solution of citric acid (10%) and the pH was controlled at 5-6. Ethyl acetate (70 ml) was added and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1-10:1) to obtain a product (2.81 g, yield: 56.2%).

Stage 7. Synthesis of ethyl 2-cyclopropyl-6-(4-fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate

Ethyl 2-cyclopropyl-6-(4-fluorophenyl)-5-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (2.81 g, 9.23 mmol, 1.0 eq) and monohydrate copper chloride (6.28 g, 36.9 mmol, 4.0 eq.) was added to acetonitrile (18 ml). The mixture was subjected to reaction at 80°C for 2 hours. Detection by TLC demonstrated completion of the reaction. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=60:1-30:1) to give the product (1.5 g, yield: 53.7%).

Stage 8. Synthesis of 2-cyclopropyl-6-(4-fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid

Ethyl 2-cyclopropyl-6-(4-fluorophenyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate (1.5 g, 4.96 mmol, 1.0 eq.) was added to methanol (22 ml ) and water (12 ml) and lithium hydroxide monohydrate (624.3 mg, 14.8 mmol, 3.0 eq.) was added. The mixture was reacted at room temperature for 2 hours. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The pH of the aqueous phase was adjusted to 4 with 2 mol/l HCl. A white solid precipitated. The mixture was stirred for 0.5 hour and suction filtered. The filter cake was dried to give the product (1.3 g, yield: 95.5%).

Step 9. Synthesis of 2-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-6-(4-fluorophenyl)-5-oxo-2,5- dihydropyridazine-4-carboxamide

2-Cyclopropyl-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (250.0 mg, 0.91 mmol, 1.0 eq) was dissolved in DMF (5 ml) and added DIPEA (353.2 mg, 2.73 mmol, 3.0 eq.) and HATU (519.5 mg, 1.36 mmol, 1.5 eq.) at 0°C. The mixture was stirred at 0°C for 2 hours. 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (298.1 mg, 1.0 mmol, 1.1 eq) was added. The mixture was reacted at room temperature with stirring for 13 hours. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=60:1-30:1) to give the product (220.0 mg, yield: 43.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 12.68 (s, 1H), 9.02 (s, 1H), 8.53-8.55 (m, 1H), 8.45- 8.47(m, 1H), 8.35(m, 1H), 8.22-8.25(m, 2H), 7.57-7.61(m, 2H), 7.46(s, 1H), 7.15-7.20 (s, 2H), 6.49-6.50 (m, 1H), 4.08 (m, 6H), 3.84-3.88 (m, 1H) , 1.37-1.39 (m, 2H), 1.27 (m, 2H).

Molecular formula: C ₃₀ H ₂₄ FN ₅ O ₅ , molecular weight: 553.55, LC-MS (positive ion mass/charge) = 554.45 [M+H] ⁺ .

Example 21 Synthesis of 2-cyclopropyl-N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazin- 4-carboxamide (compounds 43)

Stage 1. Synthesis of 6,7-dimethoxy-4-((5-nitropyridin-2-yl)oxy)quinoline

6,7-Dimethoxyquinolin-4-ol (5.00 g, 24.36 mmol, 1.0 eq.), 2-chloro-5-nitropyridine (3.86 g, 24.36 mmol, 1.0 eq. ) and potassium carbonate (6.73 g, 48.73 mmol, 2.0 eq.) were added in DMF (50 mL). The mixture was reacted at 40° C. with stirring under a protective nitrogen atmosphere overnight. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filter cake was eluted with dichloromethane and methanol. The filtrate was concentrated under reduced pressure. Dichloromethane (20 ml) and methanol (20 ml) were added to dissolve the solid. The mixture was dried over anhydrous sodium sulfate, filtered by suction and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=80:1-30:1) to give the product (0.60 g, yield: 7.52%).

Stage 2. Synthesis of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridine-3-amine

6,7-Dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline (366.0 mg, 1.12 mmol, 1.0 eq.), reduced iron powder (374.7 mg, 6, 71 mmol, 6.0 eq.) and NH ₄ Cl (717.8 mg, 13.42 mmol, 12.0 eq.) were added to a mixed solvent of ethanol (10 ml) and water (5 ml). The mixture was reacted at 80° C. with stirring for 4 hours. Detection by TLC demonstrated completion of the reaction. Celite was added to the solution and the mixture was filtered hot and the filter cake was eluted with EtOH. The filtrate was concentrated under reduced pressure. The residual aqueous phase was extracted with dichloromethane (5 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a product (188.0 mg, yield: 56.6%).

Step 3. Synthesis of 2-cyclopropyl-N-(6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-3-yl)-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazin- 4-carboxamide

2-Cyclopropyl-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (250 mg, 0.91 mmol, 1.0 eq.) was dissolved in DMF (2 ml). DIPEA (353.4 mg, 2.73 mmol, 3.0 eq.) and HATU (519.9 mg, 1.37 mmol, 1.5 eq.) were added and the mixture was stirred for 10 minutes. 6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-3-amine (271.0 mg, 0.91 mmol, 1.0 eq) was added. The mixture was reacted at room temperature with stirring for 1 hour. After detection by TLC showed completion of the reaction, the solvent was removed by evaporation under reduced pressure. Dichloromethane (10 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml) and brine (5 ml × 3). The organic phase was dried over anhydrous sodium sulfate. The mixture was suction filtered. The filtrate was added to methanol (5 ml) and the mixture was concentrated under reduced pressure until a solid began to precipitate. The mixture was left to stand at room temperature for 1 hour. The solid was filtered off, washed with methyl tert-butyl ether and dried to give the product (292.7 mg, yield: 58.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 12.29 (s, 1H), 9.04 (s, 1H), 8.66-8.63 (m, 2H), 8.39- 8.36 (m, 1H), 8.16-8.12 (m, 2H), 7.48-7.46 (d, 2H), 7.23-7.16 (m, 3H), 6, 85-6.83 (d, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.89-3.86 (m, 1H), 1.40-1.37( m, 2H), 1.27-1.21 (m, 2H).

Molecular formula: C ₃₀ H ₂₄ FN ₅ O ₅ , molecular weight: 553.55, LC-MS (positive ion mass/charge) = 553.84 [M+H] ⁺ .

Example 22 Synthesis of 2-cyclopropyl-N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazin- 4-carboxamide (compounds 44)

Stage 1. Synthesis of 6,7-dimethoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline

6,7-Dimethoxyquinolin-4-ol (3.86 g, 18.81 mmol, 1.0 eq.), 2-chloro-5-nitropyrimidine (3.00 g, 18.81 mmol, 1.0 eq. ) and triethylamine (2.28 g, 22.57 mmol, 1.2 eq.) were added in DMF (60 mL). The mixture was reacted at room temperature with stirring under a protective nitrogen atmosphere overnight. Detection by TLC demonstrated completion of the reaction. A saturated aqueous solution of NH ₄ Cl (30 ml) was added. The solvent was removed by evaporation under reduced pressure. Saturated brine (30 ml) was added. The mixture was extracted with dichloromethane (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=150:1-120:1) to give the product (1.70 g, yield: 27.5%).

Stage 2. Synthesis of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine

6,7-Dimethoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline (1.70 g, 5.18 mmol, 1.0 eq.), reduced iron powder (1.74 g, 31, 07 mmol, 6.0 eq.) and NH ₄ Cl (3.32 g, 62.14 mmol, 12.0 eq.) were added to a mixed solvent of ethanol (30 ml) and water (15 ml). The mixture was reacted at 80° C. with stirring for 2 hours. Detection by TLC demonstrated completion of the reaction. The mixture was filtered hot and the filter cake was eluted with dichloromethane. The filtrate was concentrated under reduced pressure. The residual aqueous phase was extracted with dichloromethane (10 ml x 3). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a product (0.93 g, yield: 60.2%).

Stage 3. Synthesis of 2-cyclopropyl-N-(2-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-5-yl)-6-para-fluorophenyl-5-oxo-2,5-dihydropyridazine -4-carboxamide

2-Cyclopropyl-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (250 mg, 0.91 mmol, 1.0 eq.) was dissolved in DMF (2 ml). DIPEA (353.4 mg, 2.73 mmol, 3.0 eq.) and HATU (519.9 mg, 1.37 mmol, 1.5 eq.) were added and the mixture was stirred for 10 minutes. 2-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-5-amine (271.9 mg, 0.91 mmol, 1.0 eq) was added. The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. Dichloromethane (10 ml) was added to dissolve the residue. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml) and brine (5 ml × 3). The organic phase was dried over anhydrous sodium sulfate. The mixture was suction filtered. The filtrate was added to methanol (5 ml) and the mixture was concentrated under reduced pressure until a solid began to precipitate. The mixture was left to stand at room temperature for 1 hour. The solid was filtered off, washed with methyl tert-butyl ether and dried to give the product (372.9 mg, yield: 73.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 12.36 (s, 1H), 9.07 (s, 2H), 9.03 (s, 1H), 8.75-8.74 ( d, 1H), 8.15-8.12 (m, 2H), 7.49 (s, 1H), 7.38 (s, 1H), 7.23-7.18 (m, 2H), 7 .15-7.13(d, 1H), 4.07(s, 3H), 3.99(s, 3H), 3.89-3.85(m, 1H), 1.41-1.37 (m, 2H), 1.28-1.21 (m, 2H).

Molecular formula: C ₂₉ H ₂₃ FN ₆ O ₅ , molecular weight: 554.54, LC-MS (positive ion mass/charge) = 554.65 [M+H] ⁺ .

Example 23 Synthesis of 2-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-6-(4-fluorophenyl)-5-oxo-2,5- dihydropyridazine-4-carboxamide (compounds 45)

Stage 1. Synthesis of 4-((2-chloropyrimidin-5-yl)oxy)-6,7-dimethoxyquinoline

2-Chloropyrimidin-5-ol (50.0 g, 0.38 mol, 1.0 eq.) was added to xylene (300 ml) and 4-chloro-6,7-dimethoxyquinoline (85.6 g, 0. 38 mol, 1.0 eq.). The mixture was stirred at 140° C. under reflux for 15 hours. Detection by TLC demonstrated completion of the reaction. The mixture was cooled to room temperature and filtered. The filter cake was dried to give the product (24.6 g, crude product).

Stage 2. Synthesis of 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine

4-((2-Chloropyrimidin-5-yl)oxy)-6,7-dimethoxyquinoline (24.6 g, crude) was added to aqueous ammonia (200 ml) and the mixture was reacted at 90° C. in a closed flask for 15 hours. Detection by TLC demonstrated completion of the reaction. The mixture was cooled to room temperature and concentrated under reduced pressure to give the product (18.3 g, yield over two steps: 16.1%).

Step 3. Synthesis of 2-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-6-(4-fluorophenyl)-5-oxo-2,5- dihydropyridazine-4-carboxamide

2-Cyclopropyl-6-p-fluorophenyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (250.0 mg, 0.91 mmol, 1.0 eq.) was dissolved in pyridine (7 ml). 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (272.0 mg, 0.91 mmol, 1.0 eq) was added and phosphoroxychloride (0.5 ml) was added. The mixture was stirred at room temperature for 30 minutes. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. DCM (50 ml) and water (100 ml) were added and the mixture was subjected to liquid separation. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=60:1-30:1) to give the product (155.0 mg, yield: 30.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 13.00 (s, 1H), 9.06 (s, 1H), 8.66 (s, 2H), 8.56-8.58 (d , 1H), 8.20-8.24 (m, 2H), 7.54 (s, 1H), 7.47(s, 1H), 7.16-7.20 (t, 2H), 6, 49-6.51 (d, 1H), 4.08-4.09 (m, 6H), 3.88 (m, 1H), 1.39-1.41 (m, 2H), 1.24- 1.27 (m, 2H).

Molecular formula: C ₂₉ H ₂₃ FN ₆ O ₅ , molecular weight: 554.54, LC-MS (positive ion mass/charge) = 554.79 [M+H] ⁺ .

Example 24 Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-5-p-tolyl-1,4-dihydropyridazin- 3-carboxamide (compounds 46)

Stage 1. Synthesis of para-methylbenzeneacetyl chloride

para-methylbenzoacetic acid (50.0 g, 0.33 mol) and thionyl chloride (78.52 g, 0.66 mol) were added to dichloromethane (100 ml). The mixture was heated to 45°C and subjected to reaction under reflux for 6 hours. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure to give the product (55.6 g, crude product).

Stage 2. Synthesis of 2,2-dimethyl-5-(2-(p-tolyl)acetyl)-1,3-dioxane-4,6-dione

A solution of p-methylbenzeneacetyl chloride (55.4 g, crude product) in dichloromethane (100 ml) was added dropwise to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (47.6 g, 0.33 mol) and triethylamine (66.8 g, 0.66 mol) in dichloromethane (100 ml). During the dropwise addition, the reaction system was maintained in an ice bath at a temperature of 0-5°C. The mixture was slowly warmed to room temperature overnight. Detection by TLC demonstrated completion of the reaction. The reaction system was washed successively with saturated aqueous NH ₄ Cl, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product (101.0 g, crude product).

Stage 3. Synthesis of ethyl 3-oxo-4-(para-tolyl)butanoate

2,2-Dimethyl-5-(2-(p-tolyl)acetyl)-1,3-dioxane-4,6-dione (101.0 g, crude product) was added to ethanol (200 ml). The mixture was heated under reflux overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 40:1-20:1) to give the product (11.5 g, three step yield: 15.8%).

Stage 4. Synthesis of ethyl 2-(2-cyclopropylhydrazono)-3-oxo-4-(p-tolyl)butanoate

1-Cyclopropyl-1-nitrosourea (3.36 g, 26.0 mmol) and ethyl 3-oxo-4-(para-tolyl)butanoate (4.8 g, 22.0 mmol) were added to dichloromethane (30 ml ) and the mixture was cooled to 0° C. under ice bath conditions. Potassium carbonate (9.12 g, 66.0 mmol) was added and the mixture was slowly warmed from 0° C. to room temperature and reacted overnight. Detection by TLC demonstrated completion of the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE : EA = 40-10:1) to give the product (460.0 mg, yield: 7.3%).

Stage 5. Synthesis of ethyl 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-3-oxo-4-(p-tolyl)pent-4-enoate

Ethyl 2-(2-cyclopropylhydrazono)-3-oxo-4-(p-tolyl)butanoate (460.0 mg, 1.6 mmol) and DMF-DMA (285.9 mg, 2.4 mmol) were added to toluene (3 ml). The mixture was heated to 110°C and subjected to reaction under reflux overnight. TLC showed completion of the reaction. The mixture was concentrated under reduced pressure to give the product (549.5 mg, crude product).

Stage 6. Synthesis of ethyl 1-cyclopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridazine-3-carboxylate

Ethyl 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-3-oxo-4-(p-tolyl)pent-4-enoate (549.1 mg, 1.6 mmol) was added to ethanol (6 ml) . The mixture was heated under reflux overnight. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure. Water and ethyl acetate were added and the mixture was subjected to liquid separation. The organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (450.0 mg, yield over two steps: 94.3%).

Stage 7. Synthesis of 1-cyclopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridazine-3-carboxylic acid

Ethyl 1-cyclopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridazine-3-carboxylate (450.0 mg, 1.51 mmol, 1.0 eq.) was dissolved in methanol (6 ml). A solution of lithium hydroxide monohydrate (284.8 mg, 6.79 mmol, 4.5 eq.) was added to water (3 ml). The mixture was reacted at room temperature with stirring for 1 hour. Detection by TLC demonstrated completion of the reaction. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (3 ml). The aqueous phase was stirred and the pH was adjusted to 3-4 with concentrated HCl. A white solid precipitated. The dense liquid mixture was extracted with dichloromethane (3 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered and concentrated under reduced pressure to give the product (300.0 mg, yield: 73.6%).

Step 8. Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-5-p-tolyl-1,4-dihydropyridazin- 3-carboxamide

1-Cyclopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridazine-3-carboxylic acid (300 mg, 1.11 mmol, 1.0 eq.) was dissolved in DMF (4 ml). The mixture was cooled in an ice bath to 0°C. DIPEA (430.3 mg, 3.33 mmol, 3.0 eq.) and HATU (633.1 mg, 1.66 mmol, 1.5 eq.) were added sequentially. The mixture was stirred for 10 minutes. 5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridine-2-amine (363.0 mg, 1.22 mmol, 1.1 eq) was added. The mixture was warmed to room temperature and reacted with stirring overnight. Detection by TLC demonstrated completion of the reaction. The solvent was removed by evaporation under reduced pressure. Ethyl acetate (10 ml) was added to dissolve the solid. The mixture was washed successively with saturated aqueous NaHCO ₃ (5 ml), saturated aqueous NH ₄ Cl (5 ml), distilled water (5 ml × 4) and brine (5 ml), dried over anhydrous sodium sulfate, filtered by suction and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=15:1) to give the product (334.9 mg, yield: 54.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 13.22 (s, 1H), 8.58-8.54 (t, 2H), 8.34 (s, 1H), 8.25 ( s, 1H), 7.70-7.68 (d, 2H), 7.61-7.58 (d, 2H), 7.49 (s, 1H), 7.32-7.28 (t, 2H), 6.52-6.51 (d, 1H), 4.08 (s, 6H), 3.92 (s, 1H), 2.43 (s, 3H), 1.45 (s, 2H ), 1.28-1.26 (d, 2H).

Molecular formula: C ₃₁ H ₂₇ N ₅ O ₅ , molecular weight: 549.59, LC-MS (positive ion mass/charge) = 549.90 [M+H] ⁺ .

Assay 1 Stability Evaluation of Compounds of the Invention in Liver Microsomes in Mice and Dogs

Test Substances: Compounds of the present invention, the structure and preparation of which are described above.

The composition of the system for incubation

Obtaining Test Substances

An appropriate amount of the compound was accurately weighed and dissolved in DMSO to give a 5.0 mM stock solution. The 5.0 mM stock solution was diluted to 1.0 mM with DMSO and finally diluted with water to 10 µM test substance working solution for use (DMSO content in the reaction system was 0.1%).

Stages of Analysis

(1) Liver microsomes (20mg protein/ml) were removed from the -80°C refrigerator, pre-incubated at 37°C with a shaker in a constant temperature water bath for 3 minutes, and melted for use.

(2) For analysis, a mixed solution of the incubation system (free of compounds and β-NADPH) corresponding to the above "composition of the incubation system" was prepared and pre-incubated at 37° C. temperature for 2 minutes.

(3) Control group (not containing β-NADPH). 30 µl of water and 30 µl of compound working solution (10 µM) were added to 240 µl of the mixed solution of the incubation system from step (2) and vortexed for 30 seconds to ensure thorough mixing. The total volume of the reaction mixture was 300 μl. The sample was received in duplicate. The sample was incubated at 37°C using a shaker in a water bath while maintaining a constant temperature. Started the countdown, and were set to the following points in time, which carried out the sampling, 0 minutes and 60 minutes.

(4) Group containing sample. 70 μl of β-NADPH solution (10 mM) and 70 μl of compound working solution (10 μM) were added to 560 μl of the mixed solution from step (2). The total volume of the reaction mixture was 700 µl. The resulting mixture was vortexed for 30 seconds to ensure thorough mixing. The sample was received in duplicate. The sample was incubated at 37°C using a shaker in a water bath while maintaining a constant temperature. The timing was started and the following times were set at which sampling was performed, 0 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes and 60 minutes after the timing.

(5) After vortexing for 3 minutes, the sample was centrifuged at 4000 rpm for 10 minutes.

(6) 50 µl of the supernatant was removed and 150 µl of water was added. The resulting mixture was vortexed to ensure thorough mixing and analyzed by LC/MS/MS.

Data analysis

The half-life (t _1/2 ) and the clearance rate (Cl) were calculated using the following first order kinetic equation:

V _d \u003d 1 / protein content in liver microsomes

Note: k was the slope of the logarithm of the residual compound versus time, and V _d was the apparent volume of distribution.

The test results are shown in Table 1 below.

Test Conclusion: As can be seen from the test results in Table 1, the compounds of the present invention have a lower clearance and a longer half-life, and are highly stable in liver microsomes, indicating that the compounds of the present invention are excellent in metabolic stability.

Assay 2 PK assessment of the compounds of the present invention in rats

Animal Administration and Sample Collection

Test Compounds 14, 15, 16, 20, 29, 30, 31, 32, 33, 34, 36, 37, 47 and 48 were dissolved in 5% DMSO + 20% (30% solutol) + 75% saline to give solutions connections. Each of the compound solutions was intragastrically administered to SD rats at a dose of 5.0 mg/kg. Blood sampling was carried out at the following time points: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours and 48 hours.

Test compounds 38, 39, 40 and 41 were dissolved in 5% NMP + 5% Tween-80 + 90% saline to give compound solutions. Each of the compound solutions was intragastrically administered to SD rats at a dose of 5.0 mg/kg. Blood sampling was carried out at the following time points: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours and 48 hours.

Test Compounds 14, 15, 16, 20, 29, 30, 31, 32, 33, 34, 36, 37, 47 and 48 were dissolved in 5% DMSO + 20% (30% solutol) + 75% saline to give solutions connections. Each of the compound solutions was administered by intravenous bolus injection to SD rats at a dose of 1 mg/kg. Blood sampling was carried out at the following time points: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours.

Test compounds 38, 39, 40 and 41 were dissolved in 5% NMP + 5% Tween-80 + 90% saline to give compound solutions. Each of the compound solutions was administered by intravenous bolus injection to SD rats at a dose of 1 mg/kg. Blood sampling was carried out at the following time points: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours.

The animal was fixed. The tail was heated in a water bath tank for 10 minutes before each time point. Approximately 100 µl of blood was collected through the tail vein. Blood was collected and placed in an anticoagulant tube containing EDTA-K ₂ . The blood sample was centrifuged at 8000 rpm for 6 minutes at 4°C to obtain a blood plasma sample. Blood plasma was obtained within 30 minutes after blood sampling. Blood plasma was stored in a refrigerator at -80° C. prior to testing.

Sample analysis method

The sample to be tested was removed from the 80° C. refrigerator, allowed to thaw naturally at room temperature, and vortexed for 5 minutes. Using a pipette, 20 μl of the blood plasma sample was accurately measured into a 1.5 ml centrifuge tube. 200 µl of a working solution of an internal standard (a solution of tolbutamide in methanol) at a concentration of 100 ng/ml was added and thoroughly mixed. The mixture was vortexed for 5 minutes and centrifuged at 12,000 rpm for 5 minutes. Using a pipette, 50 μl of the supernatant was accurately measured into a 96-well plate pre-filled with water at 150 μl/well. The plate was vortexed for 5 minutes and thoroughly mixed and then detected and analyzed by LC-MS/MS.

Data processing method

Derivation of test substance concentration values was performed using Analyst 1.6.3 from AB Company. Parameters such as mean, standard deviation, and coefficient of variation were calculated using Microsoft Excel (no direct calculation of output values from Analyst 1.6.3) and PK parameters were calculated using NCA from Pharsight Phoenix 6.1 software (T _max was median).

The results are shown in Table 2 below.

As can be seen from the test results in Table 2, the compounds of the present invention have good pharmacokinetic properties and good drug-forming properties.

Assay 3: Enzymatic activity testing of the compounds of the present invention

Test Substances: Compounds of the present invention, the structure and preparation of which are described above.

Test method

(1) Preparation of compound stock solution

The compound was dissolved in 100% DMSO to obtain a stock solution with a maximum concentration of 500 μm.

(2) Obtaining a working solution of the compound

The compound stock solution was diluted to final concentrations of 500, 150, 50, 15, 5, 1.5, 0.5, 0.15, and 0.05 μM, which became compound working solutions (50x).

(3) Preparation of reaction solutions with different enzymes

a) Axl (people)

Axl enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA and 250 μM KKSRGDYMTMQIG to give an enzyme solution having a final concentration of 1.7 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

b) Mer (people)

Mer enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 30 mM NaCl and 250 μM GGMEDIYFEFMGGKKK to give an enzyme solution having a final concentration of 3.1 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

c) Tyro-3 (man)

Tyro3 enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 1 mM MnCl ₂ and 250 μM KVEKIGEGTYGVVYK to give an enzyme solution having a final concentration of 38 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

d) CSF1R (human)

CSF1R enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA and 250 μM KKSRGDYMTMQIG to give an enzyme solution having a final concentration of 64 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

(4) Enzymatic reaction

Compound working solution was added to a 384-well plate to final concentrations of 10,000, 3,000, 1,000, 300, 100, 30, 10, 3, and 1 nM. Then the reaction solutions with different enzymes prepared according to the above conditions were added. Incubation was carried out for 40 minutes at room temperature. Testing was completed by adding a 0.5% phosphoric acid solution. 10 μl of the reaction solution was taken and transferred as a drop onto P30 filter paper. The filter paper was washed 4 times with 0.425% phosphoric acid and once with methanol and then placed on a scintillation counter. Analysis of the results represented by a grayscale image was performed using Image J software and IC ₅₀ values were calculated using GraphPad 5.0 software.

The test results are shown in Table 3 below.

As can be seen from the test results in Table 3, the compounds of the present invention have adequate inhibitory activity against Axl (Human), Mer (Human), Tyro3 (Human) and CSF1R (Human), and thus the compounds of the present invention are useful in the prevention and/or treatment of diseases mediated by Axl (human), Mer (human), Tyro-3 (human) and CSF1R (human).

Assay 4: Testing the Enzymatic Activity of a Compound of the Invention

Test Substances: Compounds of the present invention, the structure and preparation of which are described above.

Test method

Obtaining the stock solution of the compound

The compound was dissolved in 100% DMSO to obtain a stock solution with a maximum concentration of 500 μm.

Obtaining a working solution of the compound

The compound stock solution was diluted to final concentrations of 500, 150, 50, 15, 5, 1.5, 0.5, 0.15, and 0.05 μM, which became compound working solutions (50x).

Preparation of reaction solutions with different TrkA enzymes (persons)

The TrkA enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA and 250 μM KKKSPGEYVNIEFG to give an enzyme solution having a final concentration of 1.7 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

TrkB (people)

The TrkB enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA and 0.1 mg/ml poly(Glu, Tyr) 4:1 to give an enzyme solution having a final concentration of 3.1 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

TrkC (person)

The TrkC enzyme (human) was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA and 500 μM GEEPLYWSFPAKKK to give an enzyme solution having a final concentration of 38 nM. The enzymatic reaction was activated by applying 10 mM magnesium acetate and 10 μM [γ- ³³ P]-ATP to form a mixed Mg/ATP solution.

enzymatic reaction

Compound working solution was added to a 384-well plate to final concentrations of 10,000, 3,000, 1,000, 300, 100, 30, 10, 3, and 1 nM. Then the reaction solutions with different enzymes prepared according to the above conditions were added. Incubation was carried out for 40 minutes at room temperature. Testing was completed by adding a 0.5% phosphoric acid solution. 10 μl of the reaction solution was taken and transferred as a drop onto P30 filter paper. The filter paper was washed 4 times with 0.425% phosphoric acid and once with methanol and then placed on a scintillation counter. Analysis of the results represented by a grayscale image was performed using Image J software and IC ₅₀ values were calculated using GraphPad 5.0 software.

The test results are shown in Table 4 below.

As can be seen from the test results in Table 4, the compounds of the present invention have adequate inhibitory activity against TrkA (human), TrkB (human) and TrkC (human), and thus the compounds of the present invention are suitable for prevention and/or treatment of diseases mediated by TrkA (human), TrkB (human) and TrkC (human).

Assay 5. Testing the inhibitory activity of the compounds of the present invention against cellular pAxl

H1299 is a non-small cell lung cancer cell.

Test substances: compounds of the present invention, the structures of which are described above.

Test equipment: protein electrophoresis apparatus (manufactured by Bio Rad), transfer unit (manufactured by Bio Rad), exposure unit (manufactured by Tanon), CO ₂ cell incubator (manufactured by Thermo).

Test method

H1299 cells were inoculated into a 6-well plate (containing 1640 medium with 10% FBS, based on 5×10 ⁵ cells per well), and adherent cells were cultured at 37°C under 5% CO ₂ for 18 hours. Cells were starved overnight. Compounds were added at different concentrations. The final compound concentrations were 1.1, 3.3, 10 and 30 nM and the final DMSO content was 1%. The negative control wells contained medium containing 1% DMSO. After incubation at 37° C. under 5% CO ₂ for 60 minutes, hGAS6 (R&D, final concentration 200 ng/ml) was added to each well. After an additional incubation for 60 minutes, total cellular protein was extracted for Western blotting and IC ₅₀ values were calculated using GraphPad 5.0 software. The inhibitory activity of the compound against cellular pAxl was studied.

The test results are shown in Table 5 below.

As can be seen from the test results in Table 5, the compounds of the present invention have a significant inhibitory effect on pAxl of H1299 cells, indicating that the compounds of the present invention can provide effective inhibition of Axl activity at the cellular level and are excellent inhibitors of Axl.

Assay 6: Testing the inhibitory activity of the compounds of the present invention against cellular pMer

H1299 is a non-small cell lung cancer cell.

Test substances: compounds of the present invention, the structures of which are described above.

Test equipment: protein electrophoresis apparatus (manufactured by Bio Rad), transfer unit (manufactured by Bio Rad), exposure unit (manufactured by Tanon), CO ₂ cell incubator (manufactured by Thermo).

Test method

H1299 cells were inoculated into a 6-well plate (containing 1640 medium with 10% FBS, based on 5×10 ⁵ cells per well), and adherent cells were cultured at 37°C under 5% CO ₂ for 18 hours. Cells were starved overnight. Compounds were added at different concentrations. The final compound concentrations were 0.35, 1.1, 3.3 and 10 nM and the final DMSO content was 1%. The negative control wells contained medium containing 1% DMSO. After incubation at 37° C. under 5% CO ₂ for 60 minutes, human MerMab (R&D, final concentration 200 ng/ml) was added to each well. After an additional incubation for 60 minutes, total cellular protein was extracted for Western blotting and IC ₅₀ values were calculated using GraphPad 5.0 software. The inhibitory activity of the compound against cellular pMer was studied.

The test results are shown in Table 6 below.

As can be seen from the test results in Table 6, the compounds of the present invention have a significant inhibitory effect on pMer of H1299 cells, indicating that the compounds of the present invention can effectively inhibit Mer activity at the cellular level and are excellent Mer inhibitors.

Assay 7. Testing the inhibitory activity of the compounds of the present invention against cellular pCSF1R

HEK293T is a human renal epithelial cell.

Plasmid with CSF1R.

Test substances: compounds of the present invention, the structures of which are described above.

Test equipment: protein electrophoresis apparatus (manufactured by Bio Rad), transfer unit (manufactured by Bio Rad), exposure unit (manufactured by Tanon), CO ₂ cell incubator (manufactured by Thermo).

Test method

HEK293T cells were inoculated into a 6-well plate (containing DMEM medium with 10% FBS, based on 4×10 ⁵ cells per well), and adherent cells were cultured at 37°C under 5% CO ₂ for 6 hours. Each well was transfected with 2 μg of CSF1R plasmid and cells were cultured at 37°C under 5% CO ₂ overnight. Compounds at different concentrations were added to the administration group 24 hours after transfection. The final compound concentrations were 30, 100, 300 and 1000 nM and the final DMSO content was 1%. The negative control wells contained medium containing 1% DMSO. After incubation at 37° C. in 5% CO ₂ for 120 minutes, total cellular protein was extracted for Western blotting, analysis of the results presented in grayscale images was performed using Image J software, and IC ₅₀ values were calculated using software GraphPad 5.0 software. The inhibitory activity of the compound against cellular pCSF1R was studied.

Test Results: The inhibitory activity of the compounds of the present invention against cellular pCSF1R was determined, and their IC ₅₀ values ranged from greater than 0 to 300 nM or less.

The results show that the compounds of the present invention have a significant inhibitory effect on HEK293T cells transfected with pCSF1R, and the level of inhibitory effect increases with increasing dose. This indicates that the compounds of the present invention can provide effective inhibition of CSF1R activity at the cellular level and are excellent inhibitors of CSF1R.

Assay 8 Cell Viability Testing with Compounds of the Invention

Ba/F3 LMNA-NTRK1 is a wild-type NTRK1 cell;

Ba/F3 ETV6-NTRK2 is a wild-type NTRK2 cell;

Ba/F3 LMNA-NTRK1 G667C and Ba/F3 LMNA-NTRK1-V573M are cells with a mutation in the NTRK1 gene.

Test substances: compounds of the present invention, the structures of which are described above.

Instrument used for testing: SpectraMax multi-channel microplate reader.

Test method

Each of the cell types was inoculated into a 96-well plate and adherent cells were cultured overnight. Compounds were added at various concentrations (9 dose groups, 3.16-fold serial dilution with DMSO) to give a final concentration of 0.1-1000 nM and a final DMSO content of 1%. The negative control wells contained medium containing 1% DMSO. Cells were incubated at 37° C. under 5% CO ₂ and 95% humidity for 72 hours for use. An equal volume of CTG reagent was added to each well, and cells were allowed to lyse by shaking for 5 minutes on an orbital shaker, and incubated for 20 minutes at room temperature to stabilize the luminescent signal. The luminescent signal was read using a microplate reader. The data was analyzed using GraphPad Prism 5.0 software, and data fitting was performed using non-linear S-curve regression to obtain a dose-response curve, and thereby IC ₅₀ values were calculated.

The test results are shown in Table 8.

As can be seen from the test results in Table 8, the compounds of the present invention have adequate inhibitory activity against wild-type NTRK cells such as Ba/F3 LMNA-NTRK1 and Ba/F3 ETV6-NTRK2, and even higher inhibitory activity against cells with a mutation in the NTRK gene, such as Ba/F3 LMNA-NTRK1 G667C and Ba/T3 LMNA-NTRK1-V573M, indicating that the compounds of the present invention can be used to treat tumors associated with NTRK gene fusion and tumors drug-resistant due to NTRK mutations, and they have a very high clinical value.

Industrial Applicability

The present invention provides a novel compound which is an inhibitor of TAM family kinases. Said compound has a high kinase inhibitory activity and can be used to prevent and/or treat diseases mediated by abnormal expression of TAM family receptor kinases and/or their ligands. Moreover, the compound of the present invention can also target CSF1R kinase and can be used to prevent and/or treat diseases mediated by abnormal expression of TAM/family kinases and CSF1R receptor kinases and/or their ligands. In addition, the compound of the present invention can inhibit the growth, migration and/or drug resistance of tumors mediated by the TAM/ family kinase and CSF1R kinase. In addition, the compound of the present invention can be used to treat and/or prevent relevant diseases caused by NTRK, in particular relevant drug-resistant diseases caused by NTRK mutations. In addition, the compound of the present invention has a long in vivo half-life, excellent metabolic stability in vivo, and therefore, the compound of the present invention can provide an improvement in the therapeutic effect of a drug, reduce the patient's burden of administration, and provide an improvement in compliance. patient treatment regimen.

Claims (129)

1. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof: , (I) where W is selected from hydrogen; R is a group represented by the following general formula (b): in formula (b) fragment attached via a linking group to groups M ¹ and M ² ; each of X ¹ and X ² is independently selected from CR ^a and NR ^b and X ³ is C=O; each of X ⁴ and X ⁵ is independently selected from C; each of M ¹ and M ² independently selected from hydrogen and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-8-membered cycloalkyl; Cy ² is selected from 6-14 membered aryl which is optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, halogen and C _1-6 alkyl; Cy ³ is optionally substituted with one or more R ³ ; Y ² , Y ³ , Y ⁶ and Y ⁷ are each independently selected from CH or N, and at least one of Y ² , Y ³ , Y ⁶ and Y ⁷ is N, with each R ³ independently selected from hydrogen; Cy ⁴ selected from optionally substituted with one or more R ⁴ , Y ⁴ and Y ⁵ are independently selected from CH or N and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl; each R ⁴ is independently selected from hydrogen, -NR ^b R ^c and C _1-6 alkoxy; L is -O- R ^a is absent, or in each case each is independently selected from hydrogen; R ^b and R ^c are absent, or in each case each is independently selected from hydrogen; n is an integer 0-4; in the groups represented by formula (b), is a double bond moiety which is optionally present in the cyclic structure. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the structure represented by the following general formula (II), X ¹ is N, X ² is CR ^a , and X ³ is C=O; or X ¹ is CR ^a , X ² is N, and X ³ is C=O; or X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O; represents a fragment with a double bond, which is not necessarily present in the cyclic structure. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where each of M ¹ and M ² is independently selected from hydrogen and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6 membered cycloalkyl. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the structure represented by the general formula (III), where each of X¹And X² independently selected from CR^a and NR^b, and X³ is C=O; Cy ² is selected from phenyl; each of Y ² and Y ³ is independently selected from CH or N, and at least one of Y ² and Y ³ is N; Cy ⁴ is Y ⁴ and Y ⁵ are independently selected from CH or N and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl; each of M ¹ and M ² is independently selected from hydrogen and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, may form a 3-6 membered cycloalkyl; preferably M ¹ and M ² together with the atoms to which they are attached, can form cyclopropyl; each R ² is independently selected from hydrogen, halogen and C _1-6 alkyl; preferably the halogen atom is a fluorine atom; each R ³ is independently selected from hydrogen; each R ⁴ is independently selected from hydrogen, -NR ^b R ^c and C _1-6 alkoxy; L is selected from -O-; R ^a is absent, or in each case each is independently selected from hydrogen; R ^b and R ^c are absent, or in each case each is independently selected from hydrogen; n is an integer 0-2; each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5; represents a fragment with a double bond, which is not necessarily present in the cyclic structure; preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O; preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O; preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the structure represented by the general formula (IV), where each of X ¹ and X ² is independently selected from CR ^a and NR ^b and X ³ is C=O; Cy ² is selected from phenyl; each of Y ⁶ and Y ⁷ is independently selected from CH or N, and at least one of Y ⁶ and Y ⁷ is N; Cy ⁴ is Y ⁴ and Y ⁵ are independently selected from CH or N and at least one of Y ⁴ and Y ⁵ is N, ring B is phenyl; each of M ¹ and M ² is independently selected from hydrogen and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, may form a 3-6 membered cycloalkyl; preferably M ¹ and M ² together with the atoms to which they are attached, can form cyclopropyl; each R ² is independently selected from hydrogen, halogen and C _1-6 alkyl; preferably the halogen atom is a fluorine atom; each R ³ is independently selected from hydrogen; each R ⁴ is independently selected from hydrogen, -NR ^b R ^c and C _1-6 alkoxy; L is selected from -O-; R ^a is absent, or in each case each is independently selected from hydrogen; R ^b and R ^c are absent, or in each case each is independently selected from hydrogen; n is an integer 0-2; each of t ² , t ³ and t ⁴ is independently selected from an integer 1-5; represents a fragment with a double bond, which is not necessarily present in the cyclic structure; preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O; preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O; preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O. 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where Cy ³ is optionally substituted with one or more R ³ ; Y ² and Y ³ are independently selected from CH or N and at least one of Y ² and Y ³ is N, each of Y ⁶ and Y ⁷ is independently selected from CH or N; Cy ⁴ is selected from the following groups, optionally substituted with one or more R ⁴ : , ; each of M ¹ and M ² is independently selected from hydrogen and C _1-6 alkyl, or M ¹ and M ² together with the atoms to which they are attached, may form a 3-6 membered cycloalkyl; each R ² is independently selected from hydrogen, halogen and C _1-6 alkyl; each R ³ is independently selected from hydrogen; each R ⁴ is independently selected from hydrogen, -NR ^b R ^c and C _1-6 alkoxy; L is selected from -O-; R ^a is absent, or in each case each is independently selected from hydrogen; R ^b and R ^c are absent, or in each case each is independently selected from hydrogen; n is an integer 0-1; preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O; preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O; preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O. 7. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein each of M ¹ and M ² independently selected from hydrogen or C _1-4 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6-membered cycloalkyl; Cy ² selected from which is optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, fluorine, chlorine, bromine, or C _1-4 alkyl; Cy ³ selected from , , , or all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen; Cy ⁴ is selected from the following groups, optionally substituted with one or more R ⁴ : , , each R ⁴ is independently selected from hydrogen and C _1-4 alkoxy; L is -O-; R ^a is absent, or in each case each is independently selected from hydrogen; R ^b is absent or in each case each is independently selected from hydrogen; n is an integer 0-1; preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O; preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O; preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O. 8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, where W is hydrogen; each of M ¹ and M ² independently selected from hydrogen or C _1-4 alkyl, or M ¹ and M ² together with the atoms to which they are attached, can form a 3-6-membered cycloalkyl; ^Cy2 is , optionally substituted with one or more R ² , each R ² being independently selected from hydrogen, fluorine, chlorine, or C _1-4 alkyl; Cy ³ selected from , , , or , all of which are optionally substituted with one or more R ³ , each R ³ being independently selected from hydrogen; Cy ⁴ is optionally substituted with one or more R ⁴ , each R ⁴ being independently selected from hydrogen or C _1-4 alkoxy; L is -O-; R ^a is absent, or in each case each is independently selected from hydrogen; R ^b is absent or in each case each is independently selected from hydrogen; n is an integer 0-1; preferably X ¹ is N, X ² is CR ^a , and X ³ is C=O; preferably X ¹ is CR ^a , X ² is N, and X ³ is C=O; preferably X ¹ is CR ^a , X ² is CR ^a , and X ³ is C=O. 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where the compound is selected from compounds having the following structures: 10. Pharmaceutical composition containing a compound according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof having the property of an inhibitor of TAM, CSF1R and TRK family kinases. 11. The use of a compound according to any one of paragraphs. 1-9 or its pharmaceutically acceptable salt and pharmaceutical composition according to claim 10 in the manufacture of drugs intended for the treatment and / or prevention of the corresponding diseases associated with abnormal signaling pathways due to abnormal expression of TAM family receptors and / or their ligands, where these relevant diseases associated with abnormal signaling pathways due to abnormal expression of TAM family receptors and/or their ligands include tumors, adenomyosis, vascular disease/damage, psoriasis, visual impairment/impairment, rheumatoid arthritis and osteoporosis. 12. The use of a compound according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof and a pharmaceutical composition according to claim 10 in the manufacture of drugs intended for the treatment and/or prevention of relevant diseases associated with abnormal signaling pathways due to abnormal expression of TAM family kinases and CSF1R receptor kinases and/or their ligands, wherein said relevant diseases associated with abnormal signaling pathways due to abnormal expression of TAM family kinases and CSF1R receptor kinases and/or ligands thereof include tumors, adenomyosis, vascular disease/damage, psoriasis, visual impairment/impairment, rheumatoid arthritis, and osteoporosis . 13. The use of a compound according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof and a pharmaceutical composition according to claim 10 in the manufacture of medicaments intended for the treatment and/or prevention of respective diseases caused by NTRK, preferably the respective drug-resistant diseases caused by NTRK mutations. 14. A method for producing a compound represented by the general formula (I), including: adding a compound of formula (I-a) to a solvent, then adding a peptide bond coupling reagent, a base and a compound of formula (I-b), allowing the resulting mixture to react to obtain a compound represented by the general formula (I); or adding a compound of formula (I-a) and a compound of formula (I-b) to a base, then dropwise adding a coupling reagent, allowing the resulting mixture to react to obtain a compound represented by the general formula (I), where M ¹ , M ² , R, n, W, Cy ³ , L and Cy ⁴ are as defined in paragraph 1. 15. The method according to claim 14, where said solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, 1 ,2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, water, and mixtures thereof; said base is selected from one of methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, and mixtures thereof; said peptide bond coupling reagent is selected from one of 2-(7- aza -benzotriazol-1-yl)-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and mixtures thereof; And said coupling reagent is selected from one of phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, 1-n-propylphosphoric anhydride, and mixtures thereof. 16. An intermediate for the preparation of a compound of general formula (I), wherein the intermediate has the structure represented by the following formula (I-a) or (I-c): or where R ¹ is C _1-6 alkyl, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , M ¹ , M ² , R, Cy ² , n and are as defined in clause 1.