Novel inhibitors prepared from quinoline derivatives

Abstract

The present invention provides novel inhibitors prepared from quinoline derivatives, which have the structure shown in the following general formula (I). The compounds of the present invention can selectively inhibit tyrosine kinase TAM family / and CSF1R kinase and are used for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinase / and CSF1R kinase receptors and / or their ligands. Thus, the compounds of the present invention can be used for the treatment and / or prevention of associated diseases induced by NTRK, more specifically, for the treatment and / or prevention of drug-resistant associated diseases caused by NTRK mutations. The definitions of each group are as described in the specification. [Selection diagram] None

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field and specifically relates to TAM family kinase / and CSF1R kinase inhibitor compounds represented by general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, and drug compositions, drug formulations, and uses thereof. The compounds according to the present invention can selectively inhibit tyrosine kinase TAM family / and CSF1R kinase and are used for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinase / and CSF1R kinase receptors and / or their ligands. Accordingly, the compounds according to the present invention are used for the treatment and / or prevention of NTRK-induced related diseases, and more specifically, for the treatment and / or prevention of drug-resistant related diseases caused by NTRK mutations. [Background technology]

[0002] The TAM family comprises three members: Axl, Mer, and Tyro-3. This family includes an extracellular domain, a transmembrane domain, and a conservative intracellular kinase domain. The extracellular domain is composed of two immunoglobulin-like domains linking two type III fibronectin repeat units. The conserved amino acid sequence KW(I / L)A(I / L)ES of the intracellular kinase domain is a unique structural feature of the TAM family. The family possesses a common ligand, growth arrest-specific protein 6 (Gas6), which can bind to any TAM receptor, although the binding strength varies. In addition, the TAM family includes related receptors such as vitamin K-dependent protein S (ProS), tabby-like protein Tubby, recombinant human tabby-like protein 1 (Tulp1), and galectin-3 (Wu Yanjun, Chinese Journal of New Drugs, 2016; Lu Ping, Chinese Journal of Practical Diagnostics and Therapeutics, 2016).

[0003] Among these, Axl (also known as UFO, Ark, Tyro-7, JTK1), Mer (also known as c-Mer, Mertk, Eyk, Nyk, Tyro-12), Tyro-3 (also known as Sky, Byk, Rse, Dtk, etc.), galectin-3, Gas6, and ProS are all abnormally expressed in multiple types of solid tumors such as lung cancer, gastric cancer, and liver cancer, as well as multiple types of hematological malignancies such as AML, ALL, and CML, and are relatively strongly associated with poor disease prognosis, disease progression, tumor metastasis, and tumor drug resistance (Douglas K, Nature reviews, 2014). In particular, Axl, as a tyrosine kinase, has been proven to be one of the causes of EGFR inhibitor resistance in NSCLC and is deeply involved in the metastasis of various solid tumors. Drugs developed targeting this protein have been shown to inhibit Axl, thereby slowing EGFR inhibitor resistance and tumor metastasis (T. Jimbo, Annals of Oncology, 2017; Sacha J. Holland, American Association for Cancer Research, 2010). Simultaneously, Axl, Mer, Tryo-3, and TAM ligands also play a significant role in tumor immunity. Inhibition of the TAM family and its ligands can reverse the immunosuppressive environment of tumors and enhance the immune system's ability to attack tumor cells by promoting the polarization of macrophages into M1 macrophages, increasing the activation and efficacy of effector T cells, and strengthening the antitumor activity of NK cells (Yemsratch T. Akalu, Immunological Reviews, 2017; Greg Lemke, Nature Reviews Immunology, 2008). Therefore, developing such inhibitors can provide strong suppressive and therapeutic effects against various solid and hematological malignancies induced by this family, such as lung cancer, liver cancer, breast cancer, cerebral glioma, melanoma, AML, ALL, and CML.

[0004] In addition to the oncological diseases mentioned above, TAM family receptors and ligands can regulate multiple physiological functions, including vascular smooth muscle homeostasis, platelet aggregation, thrombus stabilization, erythrocyte production, oligodendrocyte survival, osteoclast function, apoptotic cell phagocytosis, inflammation, and innate immunity. Therefore, TAM family inhibitors are also used to treat related diseases such as ectopic endometriosis, vascular diseases / injuries, psoriasis, visual impairments / lesions (caused by macular degeneration, diabetes, and premature birth, etc.), kidney diseases, rheumatoid arthritis, and osteoporosis, which are caused by disruption of the TAM family signaling pathway.

[0005] The colony-stimulating factor 1 receptor (CSF1R), also known as c-FMS, FMS, FIM2, MCSF, and CD115, is a single-chain transmembrane glycoprotein consisting of 972 amino acid residues, and belongs to the type III receptor tyrosine kinase (RTK) family along with FLT-3, PDGFR, and KIT. CSF1R is expressed only on the surface of monocytes, such as macrophages. Currently reported CSF1R ligands include colony-stimulating factor 1 (CSF1, macrophage colony-stimulating factor, also known as M-CSF) and interleukin-34 (IL-34). CSF1 affects various cellular functions of monocytes by binding to CSF1R, and IL-34 can promote the survival, proliferation, and differentiation of monocytes by strongly binding to CSF1R. These constitute the CSF1 / IL-34 / CSF1R pathway.

[0006] In the CSF1 / CSF1R pathway, CSF1 and CSF1R form a signaling axis that promotes the growth of macrophages in the body and regulates the normal development of tissues and organs and internal homeostasis. However, when homeostasis is disrupted, it can induce various diseases, such as inflammation, immune system disorders, and tumors. Macrophages have the potential to attack tumor cells, but tumor-associated macrophages (TAMs) in the tumor tissue infiltration area exert a more immunosuppressive effect. In particular, myeloid-derived suppressor cells (MDSCs) exhibit high CSF1R expression, selectively causing macrophages to ignore the presence of tumor cells, further promoting tumor progression and metastasis. It has already been found that CSF1 / CSF1R expression is elevated in several types of tumors, including breast cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, and Hodgkin lymphoma (O'Brien J, Am J Pathol, 2010). Overexpression of CSF1 / CSF1R is associated with malignant invasiveness and poor prognosis of tumors. High expression of CSF1R in CSF1-induced fibroblasts and epithelial cells, and consequently tumor formation in nude mice, has been detected, indicating that the CSF1 / CSF1R axis promotes tumor cell proliferation and survival, playing a crucial role in tumor development and progression. Furthermore, in bone metastases, CSF1R plays a role in osteolytic bone destruction (Ohno, Mol. Cancer Ther, 2006). Therefore, inhibiting the CSF1 / IL-34 / CSF1R signaling pathway can mitigate the immunosuppressive effects of tumors and improve immune system activity, thereby suppressing tumor progression and metastasis; it has also been reported that CSF1R inhibitors can significantly reduce tumor volume, such as glioblastoma, and decrease tumor invasiveness and proliferation (Pyonteck Stephanie M, Nature Medicine, 2013). As described above, suppressing the CFS1R pathway has already become one of the main therapeutic goals for cancer.

[0007] Both TAM and CSF1R inhibitors can improve the immunosuppressive environment of tumors and enhance the immune system's ability to attack tumor cells. However, given the complexity of tumor pathogenesis, targeting both simultaneously can exert a dual effect on tumor immunotherapy. Currently, CSF1R inhibitors are mainly used in combination with PD-1 in clinical practice, and inhibitors that simultaneously target both TAM and CSF1R are not yet commercially available.

[0008] The NTRK gene comprises NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of tropomyosin-related kinase (TRK) family proteins TRKA, TRKB, and TRKC, respectively. Gene expression studies have shown that the NTRK gene is primarily expressed in the nervous system, and is expressed both during embryonic development and in adulthood. When activated by signaling, TRK is self-phosphorylatable and activates downstream signaling pathways to realize various physiological functions. Downstream signaling molecules of TRK include SHC, FRS2, PLCγ, MAPK, PI3K, and PKC, many of which are closely related to cellular energy exchange, survival, and proliferation. Dysfunction of TRK can lead to uncontrolled physiological functions of cells and potentially result in cancer cells. Therefore, when a chromosomal mutation occurs and an NTRK gene fusion takes place, the TRK fusion protein remains persistently active, inducing a permanent cascade reaction in the downstream signaling pathway, thereby promoting the spread and growth of TRK fusion tumors (Yekaterina B. Khotskaya, Pharmacology & Therapeutics, 2017).

[0009] NTRK gene fusions can occur in any part of the body and are expressed in multiple types of solid tumors in adults and children, including mammary gland-like secretory carcinoma (MASC), colon cancer, lung cancer, pancreatic cancer, thyroid cancer, and various types of sarcomas. NTRK fusions are expressed very infrequently in common cancer types, such as colon cancer and lung cancer, both at less than 5%; however, they have extremely high mutation rates in some rare cancer types, such as congenital kidney tumors, infantile sarcomas, salivary gland cancers, and secretory mammary gland cancers, with expression rates exceeding 90% in some cancer types (Journal of Clinical Pharmacy, 2017, Vol. 15, No. 12). Therefore, developing NTRK inhibitors has extremely high clinical value.

[0010] Currently, there are first-generation NTRK inhibitors targeting NTRK gene fusion, such as Larotrectinib and Entrectinib. However, TKI (tyrosine kinase inhibitor) therapies targeting NTRK face the problem of acquired drug resistance. It has now been discovered that some TRKs, such as NTRK1-LMNA-G667C and NTRK1-LMNA-V573M, undergo mutations in their kinase sites in patients treated with TRK inhibitors, leading to secondary drug resistance in cancer cells, including those of colon cancer and MASC (Mariangela Russo, American Association for Cancer Research, 2015; A. Drilon, Annals of Oncology, 2016). These newly emerging mutations prevent first-generation NTRK inhibitors Entrectinib and Larotrectinib from binding to the kinase, rendering them ineffective. Therefore, acquired drug resistance to treatment with first-generation NTRK inhibitors remains a persistent challenge, and the development of second-generation NTRK inhibitors to resolve some of these drug resistance issues is urgently needed. [Overview of the project]

[0011] The present invention provides novel inhibitory compounds and their pharmaceutically acceptable salts, esters, stereoisomers, and tautomers (hereinafter also referred to as "compounds according to the present invention"). Compounds according to the present invention have an inhibitory effect on TAM family kinases. Furthermore, compounds according to the present invention can target CSF1R kinase and have an inhibitory effect on CSF1R kinase. By using compounds according to the present invention, diseases mediated by the abnormal expression of TAM family kinase receptors and / or their ligands can be treated and / or prevented. By inhibiting TAM family kinases and CSF1R kinases, compounds according to the present invention reverse immunosuppression in the tumor microenvironment, suppressing tumor growth, metastasis, and / or drug resistance development, thereby exhibiting tumor immune and antitumor effects. Furthermore, compounds according to the present invention can treat and / or prevent NTRK-induced related diseases, particularly drug-resistant related diseases caused by NTRK mutations.

[0012] Specifically, the technical solutions of the present invention are as follows:

[0013] Compounds represented by general formula (I) or their pharmaceutically acceptable salts, esters, stereoisomers, and tautomers:

[0014] [ka]

[0015] However, W is either hydrogen or C 1-6 Selected from alkyl groups.

[0016] R is a group represented by the following general formula (a), (b), or (c):

[0017] [ka]

[0018] In formula (a), ring A is selected from a phenyl group, a 5- to 6-membered heteroaryl group, or a 5- to 6-membered heterocyclic group.

[0019] Each Q is independently hydrogen, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -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 , -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, cyano C 1-6 alkyl group, amino C 1-6 alkyl group, C 1-6 alkyl group amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxyl group, halogenated C 1-6 alkoxyl group, C 1-6 alkoxyl group C 1-6 alkyl group, C 1-6 alkoxyl group C 1-6 alkoxyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, -C 1-6 alkyl group -R', -C 1-6 alkoxyl group -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 14-membered heterocyclic group, a 6- to 14-membered aryl group, a 5- to 10-membered heteroaryl group.

[0020] q is an integer from 0 to 4.

[0021] In equations (a) and (b),

[0022] [ka]

[0023] The portion is bonded by an M 1 and M 2 It bonds with a base.

[0024] In equation (c),

[0025] [ka]

[0026] The portion is bonded by an M 1 and M 2 It bonds with a base.

[0027] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from O, and at least one of them is C=O.

[0028] X 4 , X 5 Each is independently selected from C or N.

[0029] M 1 M 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b Rc 、 -SO2R d 、 -NR b SO2R d 、 C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, cyano C 1-6 alkyl group, amino C 1-6 alkyl group, C 1-6 alkyl group amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy group C 1-6 alkyl group, C 1-6 alkoxy group C 1-6 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, -C 1-6 alkyl group -R', -C 1-6 alkoxy group -R', -O-R', -C(O)-R', -SO2-R', -NR b selected from C(O)-R', or M 1 and M 2 can form a 3-8 member cycloalkyl group with the atom to which they are attached; or,

[0030] [Chemical formula]

[0031] The moiety can be formed into a hydrogen atom.

[0032] Cy 2 is an optionally one or more R 2 substituted 3-12 member cycloalkyl group, 3-12 member cycloalkenyl group, 3-14 member heterocyclic group, 6-14 member aryl group, 5-10 member heteroaryl group selected from, R 2 are each independently hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, -NR b R c 、 -C(O)R<0​​​, -OC(O)NR b R c , -NR b , -NR d , -NR b , -SO2-NR d , R b , -SO2R c , -NR d , SO2R b , C d , alkyl group, hydroxyl C 1-6 , alkyl group, cyano C 1-6 , alkyl group, amino C 1-6 , alkyl group, C 1-6 , alkyl group, C 1-6 , alkyl group amino C 1-6 , alkyl group, halogenated C 1-6 , alkyl group, C 1-6 , alkoxy group, halogenated C 1-6 , alkoxy group, C 1-6 , alkoxy group C 1-6 , alkyl group, C 1-6 , alkoxy group C[[ID=4*7]] 1-6 , alkoxy group, C 2-8 , alkenyl group, C 2-8 , alkynyl group, -C 1-6 , alkyl group-R', -C 1-6 , alkoxy group-R', -O-R', -C(O)-R', -SO2-R', -NR b [[ID=5*8]], C(O)-R', a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 14-membered heterocyclic group, a 6- to 14-membered aryl group, or a 5- to 10-membered heteroaryl group. <(

[0033] Cy 3 is optionally a 3- to 12-membered cycloalkyl group, a 3- to 14-membered heterocyclic group, or a 5- to 10-membered heteroaryl group substituted with one or more R 3 , and R 3 are each independently hydrogen, cyano, hydroxyl, a halogen atom, carboxyl, nitro, -NR b R c , -C(O)R [[ID=7*3]] d , -C(O)NR b R c , -OC(O)NR b R c , -NRb C(O)OR d , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group; X 1 or X 2 is NR b If that is the case, Cy 3 This can be any one or more R 3 It may also be a 6-14 membered aryl group that is substituted.

[0034] Cy 4 R can be any one or more R 4 A 3-14 member heterocyclic group or a 5-14 member heteroaryl group is selected to be substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR bR c -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl alkyl, cyano C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', selected from a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group, or two R 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0035] L is -NR b -, -O-, -S-, -(CR a R a ) m - is chosen from, and m is chosen from integers 1-3.

[0036] R a Either they are absent, or each time they appear, they are independently hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR e R f , -SO2R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR e Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0037] R b , R c They are either absent, or each time they appear, they independently consist of hydrogen, a hydroxyl group, and -C(O)R. g -C(O)NR e R f -SO2-NR e R f , -SO2R g , C 1-6Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0038] R d They do not exist, or each time they appear, hydrogen and -NR are independently present. e R f , -NR e C(O)OR g , -NR e C(O)R g , -NR e SO2R f , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -NR e Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0039] R e, R f It is not present, or each time it appears, it independently contains hydrogen, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Selected from alkyl groups, 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0040] R g It does not exist, or each time it appears, hydrogen and C are independently present. 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 The group is selected from an alkoxyl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group.

[0041] R' is a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group.

[0042] n is an integer between 0 and 4.

[0043] In the groups shown in formulas (b) and (c)

[0044] [ka]

[0045] This indicates an arbitrary double bond region in the ring structure.

[0046] The conditions are as shown in the bases of formulas (a) and (c):

[0047] [ka]

[0048] The part does not form a hydrogen atom.

[0049] The condition is that in the base shown in equation (b), X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0050] In another embodiment, in the compound represented by formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0051] [ka]

[0052] However, W is either hydrogen or C 1-6 Selected from alkyl groups.

[0053] R is the group shown in the following formulas (a), (b), (b-1), (b-2), or (c):

[0054] [ka]

[0055] In formula (a), ring A is selected from a phenyl group, a 5-6 membered heteroaryl group, or a 5-6 membered heterocyclic group.

[0056] Q independently consists of hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxyl groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0057] q is an integer between 0 and 4.

[0058] In equations (a), (b), (b-1), and (b-2),

[0059] [ka]

[0060] The portion is bonded by an M 1 and M 2 It bonds with a base.

[0061] In equation (c),

[0062] [ka]

[0063] The portion is bonded by an M 1 and M 2 It bonds with a base.

[0064] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from O, and at least one of them is C=O.

[0065] M 1 M 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2Rd , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R'; or M 1 and M 2 They can form a 3-8 membered cycloalkyl group with the atoms they bond to; or,

[0066] [ka]

[0067] The portion can be formed from hydrogen atoms.

[0068] Cy 2 R can be any one or more R 2 The following are selected to be substituted: a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, and a 5-10 membered heteroaryl group, R 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c -OC(O)NR b R c , -NRb C(O)OR d , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0069] Cy 3 R can be any one or more R 3 Selected from a 3-12 membered cycloalkyl group, a 3-14 membered heterocyclic group, or a 5-10 membered heteroaryl group, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 , -NRb C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group; X 1 or X 2 is NR b If that is the case, Cy 3 This can be any one or more R 3 It may also be a 6-14 membered aryl group that is substituted.

[0070] Cy 4 R can be any one or more R 4 A 3-14 member heterocyclic group or a 5-14 member heteroaryl group is selected to be substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c -OC(O)NR bR c , -NR b C(O)OR d , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', selected from a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group, or two R 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0071] L is -NR b -, -O-, -S-, -(CR a R a ) m - is chosen from, and m is chosen from integers 1-3.

[0072] R a Each time it appears, it independently represents hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR e R f , -SO2R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0073] R b , R c Each time it appears, it independently forms a hydrogen atom, a hydroxyl group, and -C(O)R. g -C(O)NR e R f -SO2-NR e R f , -SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0074] R d Each time it appears, hydrogen and -NR appear independently. e R f , -NR e C(O)OR g , -NR e C(O)R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -NR e Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0075] R e , R f It is not present, or each time it appears, it independently contains hydrogen, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom, and C1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Selected from alkyl groups, 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0076] R g It does not exist, or each time it appears, hydrogen and C are independently present. 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 The group is selected from an alkoxyl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group.

[0077] R' is a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group.

[0078] n is an integer between 0 and 4.

[0079] In the base shown in formulas (b), (b-1), and (b-2)

[0080] [ka]

[0081] This indicates an arbitrary double bond region in the ring structure.

[0082] The conditions are as shown in the bases of formulas (a) and (c):

[0083] [ka]

[0084] The part does not form a hydrogen atom,

[0085] In the base shown in formula (b), X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2 R as a substituent 2 It does not show a halogen atom,

[0086] In the base shown in formula (b-1), X 1 and X 3 If C=O is chosen, Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0087] In another preferred embodiment, in the compound represented by formula (I) above, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

[0088] However, W is either hydrogen or C 1-6 Selected from alkyl groups.

[0089] R is the group shown in the following formula (a), (b-1), or (b-2):

[0090] [ka]

[0091] In formula (a), ring A is selected from a phenyl group, a 5-6 membered heteroaryl group, or a 5-6 membered heterocyclic group.

[0092] Q independently consists of hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxyl groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0093] q is an integer between 0 and 4.

[0094] In equations (a), (b-1), and (b-2),

[0095] [ka]

[0096] The portion is bonded by an M 1 and M 2 To bond with a base; X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from O, and at least one of them is C=O.

[0097] M 1 M 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', or M 1 and M 2 They can form a 3-8 membered cycloalkyl group with the atoms they bond to; or,

[0098] [ka]

[0099] The portion can be formed from hydrogen atoms.

[0100] Cy 2 R can be any one or more R 2 The following are selected from substituted 3-8 membered cycloalkyl groups, 3-8 membered cycloalkenyl groups, 3-10 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups, R 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0101] Cy 3 R can be any one or more R 3 Selected from a 3-8 membered cycloalkyl group, a 3-10 membered heterocyclic group, or a 5-10 membered heteroaryl group, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group; X 1 or X 2 is NR b If that is the case, Cy 3 This can be any one or more R 3 It may also be a 6-14 membered aryl group that is substituted.

[0102] Cy 4 R can be any one or more R 4 A 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group is selected to be substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', selected from a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group, or two R 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0103] L is -NR b It is selected from -, -O-, and -S-.

[0104] R a Either they are absent, or each time they appear, they are independently hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 df -SO2-NR e R f , -SO2R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl groups, 3-10 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0105] R b , R c They are either absent, or each time they appear, they independently consist of hydrogen, a hydroxyl group, and -C(O)R. g -C(O)NR e R f -SO2-NR e R f , -SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-10 membered cycloalkyl groups, 3-10 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0106] R d They do not exist, or each time they appear, hydrogen and -NR are independently present. e R f , -NRe C(O)OR g 、 -NR e C(O)R g 、 -NR e SO2R g 、 C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, cyano C 1-6 alkyl group, amino C 1-6 alkyl group, C 1-6 alkyl group amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy group C 1-6 1-6 alkoxy group C 1-6 alkoxy group, -C 1-6 alkyl group -R', -C 1-6 alkoxy group -R', -O-R', -NR b [[ID=]43]C(O)-R', 3- to 12-membered cycloalkyl group, 3- to 12-membered cycloalkenyl group, 3- to 14-membered heterocyclic group, 6- to 14-membered aryl group, 5- to 10-membered heteroaryl group, selected therefrom. <(

[0107] R e 、 R f does not exist, or each time it appears, independently hydrogen, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom, C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, cyano C 1-6 alkyl group, amino C 1-6 alkyl group, C 1-6 alkyl group amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 ' alkoxyl group C 1-6 alkyl group, -C 1-6 alkyl group -R', -C(O)-R', -SO2-R', 3- to 12-membered cycloalkyl group, 3- to 12-membered cycloalkenyl group, 3- to 14-membered heterocyclic group, 6- to 14-membered aryl group, 5- to 10-membered heteroaryl group, selected therefrom.

[0108] It should be noted that there may be some inaccuracies in the original text's format and content, especially in the Japanese characters and the lack of clear punctuation in some parts, which may affect the overall understanding and translation accuracy. The above translation is based on the best effort to follow the rules. R g It does not exist, or each time it appears, hydrogen and C are independently present. 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0109] R' is a 3-8 membered cycloalkyl group, a 3-10 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group.

[0110] n is an integer between 0 and 4.

[0111] In the base shown in formulas (b-1) and (b-2)

[0112] [ka]

[0113] This indicates an arbitrary double bond region in the ring structure.

[0114] The condition is that in the base shown in equation (b-1), X 1 and X 3 If C=O is chosen, Cy 2 R as a substituent 2 It does not show a halogen atom,

[0115] In the base shown in formula (a),

[0116] [ka]

[0117] The part does not form a hydrogen atom.

[0118] In another preferred embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, ester, stereoisomer, or tautomer has the structure represented by general formula (II),

[0119] [ka]

[0120] However, W is either hydrogen or C 1-6 Selected from alkyl groups.

[0121] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0122] X 4 , X 5 Each is independently selected from C or N.

[0123] M 1 M 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 , -NRb C(O)R d 、 -SO2-NR b R c 、 -SO2R d 、 -NR b SO2R d 、 C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, cyano C 1-6 alkyl group, amino C 1-6 alkyl group, C 1-6 alkyl group amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 selected from alkoxy groups, or, M 1 and M 2 can form a 3- to 8-membered cycloalkyl group with the atoms to which they are attached; or,

[0124] <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0127] Cy 3 R can be any one or more R 3 Selected from 3-8 membered cycloalkyl groups and 5-10 membered heteroaryl groups to be substituted, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group; X 1 or X 2 is NR b If that is the case, Cy 3 This can be any one or more R 3 It may also be a 6-14 membered aryl group that is substituted.

[0128] Cy 4 R can be any one or more R 4 Selected from 9-10 member heteroaryl groups that are substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', a 3-8 membered cycloalkyl group, a 3-8 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group, or two R 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0129] L is -NR b It is selected from -, -O-, and -S-.

[0130] R a Either they are absent, or each time they appear, they are independently hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0131] R b , R c They are either absent, or each time they appear, they independently consist of hydrogen, a hydroxyl group, and -C(O)R. g -C(O)NR e R f -SO2-NR e R f , -SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, -C 1-6Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-8 membered cycloalkyl groups, 3-8 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0132] R d They do not exist, or each time they appear, hydrogen and -NR are independently present. e R f , -NR e C(O)OR f , -NR e C(O)R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0133] R e , R f It is not present, or each time it appears, it independently contains hydrogen, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0134] R g It does not exist, or each time it appears, hydrogen and C are independently present. 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0135] R' is a 3-8 member cycloalkyl group, a 3-8 member cycloalkenyl group, a 3-14 member heterocyclic group, a 6-14 member aryl group, or a 5-10 member heteroaryl group.

[0136] n is an integer between 0 and 3.

[0137] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0138] Preferably, X 1CR a X 2 is N, and X 3 C=O.

[0139] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0140] Preferably, X 1 CR a X 2 C=O and X 3 C=O.

[0141] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0142] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0143] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0144] [ka]

[0145] This indicates an arbitrary double bond region in the ring structure.

[0146] The condition is, X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2R as a substituent 2 The fact that it does not show a halogen atom.

[0147] In another preferred embodiment, the compound represented by formula (I) or general formula (II) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, has the structure represented by general formula (II),

[0148] [ka]

[0149] However, W is either hydrogen or C 1-6 Selected from alkyl groups.

[0150] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0151] M 1 M 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups, or M 1 and M 2 They can form a 3-8 membered cycloalkyl group with the atoms they bond to; or,

[0152] [ka]

[0153] The portion can be formed from hydrogen atoms.

[0154] Cy 2 R can be any one or more R 2 A 6-14 membered aryl group or a 5-10 membered heteroaryl group is selected to be substituted, R 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0155] Cy 3 R can be any one or more R 3 Selected from 3-8 membered cycloalkyl groups and 5-10 membered heteroaryl groups to be substituted, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group; X 1 or X 2 is NR b If that is the case, Cy 3 This can be any one or more R 3 It may also be a 6-14 membered aryl group that is substituted.

[0156] Cy 4 R can be any one or more R 4 Selected from 9-10 member heteroaryl groups that are substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', a 3-8 membered cycloalkyl group, a 3-8 membered cycloalkenyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-10 membered heteroaryl group, or two R 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0157] L is -NR b It is selected from -, -O-, and -S-.

[0158] R a Each time it appears, it independently represents hydrogen, cyano group, hydroxyl group, halogen atom, carboxyl group, nitro group, and -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 -SO2-NR e R f , -SO2R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C1-6 Alkoxy group C 1-6 Alkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0159] R b , R c Each time it appears, it independently forms a hydrogen atom, a hydroxyl group, and -C(O)R. g -C(O)NR e R f -SO2-NR e R f , -SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-8 membered cycloalkyl groups, 3-8 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0160] R d Each time it appears, hydrogen and -NR appear independently. e R f , -NR e C(O)OR g , -NR e C(O)R g , -NR e SO2R g , C 1-6 Alkyl group, hydroxyl group C 1-6Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkoxy group, -C 1-6 Alkyl alkyl groups -R', -C 1-6 Alkoxy groups -R', -O-R', -NR e Selected from C(O)-R', 3-8 membered cycloalkyl group, 3-8 membered cycloalkenyl group, 3-14 membered heterocyclic group, 6-14 membered aryl group, and 5-10 membered heteroaryl group.

[0161] R e , R f It is not present, or each time it appears, it independently contains hydrogen, hydroxyl group, carboxyl group, cyano group, nitro group, halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0162] R g It does not exist, or each time it appears, hydrogen and C are independently present. 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, -C 1-6 Selected from alkyl groups -R', -C(O)-R', -SO2-R', 3-12 membered cycloalkyl groups, 3-12 membered cycloalkenyl groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups, and 5-10 membered heteroaryl groups.

[0163] n is an integer between 0 and 3.

[0164] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0165] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0166] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0167] Preferably, X 1 CR a X 2 C=O and X 3 C=O.

[0168] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0169] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0170] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0171] [ka]

[0172] This indicates an arbitrary double bond region in the ring structure.

[0173] The condition is, X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0174] In another preferred embodiment, in a compound represented by formula (I) or formula (II) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0175] However, X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0176] X 4 is selected from C or N, X 5 It will be selected from C.

[0177] M 1 M 2Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-8 membered cycloalkyl groups with atoms that bond to them; or

[0178] [ka]

[0179] The portion can be formed from hydrogen atoms.

[0180] Cy 2 R can be any one or more R 2 A phenyl group or a 5-6 member heteroaryl group is selected to be substituted, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0181] Cy 3 R can be any one or more R 3 A 5-6 member heteroaryl group or a 3-6 member cycloalkyl group is selected to be substituted, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. bR c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0182] Cy 4 R can be any one or more R 4 Selected from 9-10 member heteroaryl groups that are substituted, R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0183] L is -NR b It is selected from -, -O-, and -S-.

[0184] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6Selected from alkyl groups.

[0185] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0186] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0187] n is an integer between 0 and 2.

[0188] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0189] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0190] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0191] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0192] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0193] Preferably, X 1 CR aX 2 C=O and X 3 CR a That is the case.

[0194] Preferably, Cy 3 teeth

[0195] [ka]

[0196] Y 2 , Y 3 , Y 6 , Y 7 Each is independently selected from CH or N, and at least one is N.

[0197] In another preferred embodiment, in a compound represented by formula (I) or (II) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0198] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0199] X 4 is selected from C or N, X 5 It will be selected from C.

[0200] Cy 2 R can be any one or more R 2 The substitution is selected from a phenyl group or a 5-6 membered heteroaryl group.

[0201] Cy 3 R can be any one or more R 3 Replaced with

[0202] [ka]

[0203] This indicates.

[0204] Y 2 , Y 3 , Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0205] Cy 4 R can be any one or more R 4 Replaced with

[0206] [ka]

[0207] Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0208] M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0209] [ka]

[0210] The portion can be formed from hydrogen atoms.

[0211] R 2Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0212] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0213] R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C1-6 Alkoxy C 1-6 Alkyl alkyl group, C 1-6 Alkoxy C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0214] L is -NR b It is selected from -, -O-, and -S-.

[0215] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0216] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0217] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0218] n is an integer between 0 and 2.

[0219] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0220] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0221] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0222] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0223] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0224] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0225] In another preferred embodiment, the compound represented by formula (I) or (II) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, has the structure represented by general formula (III),

[0226] [ka]

[0227] However, X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0228] Cy 2 The group is selected from a phenyl group and a 5-6 membered heteroaryl group.

[0229] Y 2 and Y 3 Each element is independently selected from CH or N, and at least one of them is N.

[0230] Cy4 teeth

[0231] [ka]

[0232] Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0233] M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0234] [ka]

[0235] The portion can be formed from hydrogen atoms.

[0236] R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0237] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0238] R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0239] L is -NR b It is selected from -, -O-, and -S-.

[0240] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0241] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0242] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0243] n is an integer between 0 and 2.

[0244] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0245] [ka]

[0246] This indicates an arbitrary double bond region in the ring structure.

[0247] The condition is, X 1 and X 3 C=O and Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0248] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0249] Preferably, X 1 CR a X 2 is N, and X3 C=O.

[0250] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0251] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0252] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0253] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0254] In another preferred embodiment, the compound represented by formula (I) or (II) above, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, has the structure represented by general formula (IV),

[0255] [ka]

[0256] However, X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0257] Cy 2The group is selected from a phenyl group and a 5-6 membered heteroaryl group.

[0258] Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0259] Cy 4 teeth

[0260] [ka]

[0261] Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0262] M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0263] [ka]

[0264] The portion can be formed from hydrogen atoms.

[0265] R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)Rd -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0266] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0267] R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0268] L is -NR b It is selected from -, -O-, and -S-.

[0269] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0270] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0271] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0272] n is an integer between 0 and 2.

[0273] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0274] [ka]

[0275] This indicates an arbitrary double bond region in the ring structure.

[0276] The condition is, X 1 and X 3 C=O and Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0277] Preferably, X1 is N, and X 2 CR a X 3 C=O.

[0278] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0279] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0280] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0281] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0282] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0283] In another preferred embodiment, in a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0284] However, R represents the following group:

[0285] [ka]

[0286] X 1 , X 2 , X 3 Each of them independently performs CR a , C=O, NR b They are selected from among and at least one of them is C=O.

[0287] Cy 2 R can be any one or more R 2 The substitution is selected from a phenyl group or a 5-6 membered heteroaryl group.

[0288] Cy 3 R can be any one or more R 3 Replaced with

[0289] [ka]

[0290] This indicates.

[0291] Y 2 , Y 3 , Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0292] Cy 4 R can be any one or more R 4 Replaced with

[0293] [ka]

[0294] Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0295] M 1 M 2Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0296] [ka]

[0297] The portion can be formed from hydrogen atoms.

[0298] R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0299] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0300] R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0301] L is -NR b It is selected from -, -O-, and -S-.

[0302] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0303] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0304] R d They do not exist, or each time they appear, hydrogen and C are independently present.1-6 Selected from alkyl groups.

[0305] n is an integer between 0 and 2.

[0306] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0307] [ka]

[0308] This indicates an arbitrary double bond region in the ring structure.

[0309] The condition is, X 1 and X 3 C=O and Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0310] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0311] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0312] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0313] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0314] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0315] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0316] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0317] However, X 1 , X 2 Each of them independently performs CR a or NR b Selected from X 3 C=O.

[0318] Cy 2 R can be any one or more R 2 The phenyl group to be substituted is selected.

[0319] Cy 3 R can be any one or more R 3 Replaced with

[0320] [ka]

[0321] This indicates.

[0322] Y 2 and Y 3 Each is independently selected from CH or N, and at least one is N, and Y 6 and Y 7 Each is independently selected from CH or N.

[0323] Cy 4 R can be any one or more R 4 Replaced with

[0324] [ka]

[0325] They are selected from among them.

[0326] M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0327] [ka]

[0328] The portion can be formed from hydrogen atoms.

[0329] R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0330] R 3Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0331] R 4 Each of these is independently hydrogen, a hydroxyl group, a halogen atom, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0332] L is -NR b It is selected from -, -O-, and -S-.

[0333] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0334] R b , R c They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0335] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0336] n is an integer between 0 and 1.

[0337] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 3.

[0338] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0339] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0340] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0341] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0342] However, M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR.b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C 1-6 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0343] [ka]

[0344] The portion can be formed from hydrogen atoms.

[0345] Cy 2 R can be any one or more R 2 The phenyl group and pyridine group to be substituted are selected, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0346] Cy 3 R can be any one or more R 3 Selected from 5-6 member nitrogen-containing heteroaryl groups that are substituted, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups.

[0347] Cy 4 R can be any one or more R4 Replaced with

[0348] [ka]

[0349] Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group or a 5-6 membered heteroaryl group.

[0350] R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0351] L is chosen from -O-.

[0352] R b They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0353] R d They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0354] n is an integer between 0 and 2.

[0355] Preferably, X 1 is N, and X 2 CRa X 3 C=O.

[0356] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0357] Preferably, X 1 C=O and X 2 CR a X 3 C=O.

[0358] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0359] Preferably, X 1 C=O and X 2 CR a X 3 CR a That is the case.

[0360] Preferably, X 1 CR a X 2 C=O and X 3 CR a That is the case.

[0361] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0362] However, W is selected from hydrogen.

[0363] X 1 , X 2 Each of them independently performs CR a or NR b Selected from X 3C=O.

[0364] X 4 It is selected from C or N.

[0365] M 1 M 2 Each of these is independently hydrogen, hydroxyl group, halogen atom, nitro group, and C 1-4 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0366] [ka]

[0367] The portion can be formed from hydrogen atoms.

[0368] Cy 2 R can be any one or more R 2 Replaced with

[0369] [ka]

[0370] Selected from, R 2 These are each independently hydrogen, hydroxyl group, fluorine, chlorine, bromine, and C 1-4 Selected from alkyl groups.

[0371] Cy 3 R can be any one or more R 3 Replaced with

[0372] [ka]

[0373] Selected from, R 3 These are each independently hydrogen, hydroxyl group, fluorine, chlorine, bromine, and C 1-4 Selected from alkyl groups.

[0374] Cy 4 R can be any one or more R 4 Replaced with

[0375] [ka]

[0376] They are selected from among them.

[0377] R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, halogenated C 1-4 Selected from alkoxy groups, 3-14 membered heterocyclic groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0378] L is -O-

[0379] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0380] R b They do not exist, or each time they appear, hydrogen and C are independently present. 1-6 Selected from alkyl groups.

[0381] n is an integer between 0 and 1.

[0382] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0383] Preferably, X 1 CR a X 2 is N, and X3 C=O.

[0384] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0385] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0386] However, W is selected from hydrogen.

[0387] X 1 , X 2 CR a or NR b Selected from X 3 C=O.

[0388] X 4 It will be selected from C.

[0389] M 1 M 2 Each of these is independently a hydrogen atom, a hydroxyl group, and C. 1-4 Selected from alkyl groups, or M 1 and M 2 They can form 3-6 membered cycloalkyl groups with atoms that bond to them; or

[0390] [ka]

[0391] The portion can be formed from hydrogen atoms.

[0392] Cy 2 R can be any one or more R 2 Replaced with

[0393] [ka]

[0394] Selected from, R 2 These are hydrogen, fluorine, chlorine, and C, respectively, independently. 1-4 Selected from alkyl groups.

[0395] Cy 3 R can be any one or more R 3 Replaced with

[0396] [ka]

[0397] Selected from, R 3 These are hydrogen, fluorine, chlorine, and C, respectively, independently. 1-4 Selected from alkyl groups.

[0398] Cy 4 R can be any one or more R 4 Replaced with

[0399] [ka]

[0400] Selected from, R 4 These are, independently, hydrogen, halogen atom, and C. 1-4 Alkyl alkyl group, C 1-4 Selected from alkoxy groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0401] L is -O-

[0402] R a They do not exist, or each time they appear, hydrogen and C are independently present. 1-4 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups.

[0403] R bThey do not exist, or each time they appear, hydrogen and C are independently present. 1-4 Selected from alkyl groups.

[0404] n is an integer between 0 and 1.

[0405] Preferably, X 1 is N, and X 2 CR a X 3 C=O.

[0406] Preferably, X 1 CR a X 2 is N, and X 3 C=O.

[0407] Preferably, X 1 CR a X 2 CR a X 3 C=O.

[0408] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0409] X 1 , X 3 Each of them independently performs CR a , C=O, NR b One is chosen from and both are not simultaneously C=O; X 2 CR a or NR b That is the case.

[0410] In another preferred embodiment, in a compound represented by formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0411] Cy 3 R can be any one or more R 3It is selected from 5-6 member heteroaryl groups that are substituted.

[0412] More specifically, the present invention provides the following technical solutions.

[0413] Embodiment 1. Compounds represented by general formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof:

[0414] [ka]

[0415] However, W is hydrogen or C is optionally substituted with a substituent. 1-6 Selected from alkyl groups.

[0416] R is the group shown in the following general formula (a'), (b'), or (c'):

[0417] [ka]

[0418] In formula (a'), ring A is a 6-10 membered aryl ring, NR b , a 5-6 membered heteroaryl ring or NR having 1-3 heteroatoms selected from O and S b The ring A represents a 5-6 membered heterocycle having 1-4 heteroatoms selected from O and S; preferably, the ring A portion represents 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, pyrazine ring, pyran ring, thiopyran ring, pyrrolidine ring, pyrroline ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, or tetrahydropyran ring.

[0419] Q independently represents a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -NR. b Rc , -C(O)R d -C(O)NR b R c -OC(O)NR b R c , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0420] In equation (a'),

[0421] [ka]

[0422] The portion is bonded by a bonding group.

[0423] [ka]

[0424] It combines with the parts.

[0425] In equation (a'), X 6, X 7 Each of them independently performs CR a R a , C=O and NR b They are selected from among and at least one of them is C=O.

[0426] In equation (b'),

[0427] [ka]

[0428] The portion is bonded by a bonding group.

[0429] [ka]

[0430] It combines with the parts.

[0431] In equation (c'),

[0432] [ka]

[0433] The portion is bonded by a bonding group.

[0434] [ka]

[0435] It combines with the parts.

[0436] X 1 , X 2 , X 3 Each of them independently performs CR a R a , C=O and NR b They are selected from among and at least one of them is C=O.

[0437] X 4 , X5 Each of them independently performs CR a Or selected from N.

[0438] M 1 M 2 Each of these is independently substituted with a hydrogen atom or optionally with a substituent. 1-6 Alkyl group, optionally substituted with substituents C 1-6 Alkoxyl group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Selected from the alkoxyl group -R', or M 1 and M 2 These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0439] [ka]

[0440] The portion can be formed from hydrogen atoms.

[0441] Cy 2 This can be any one or more R 2 A 3-12 member cycloalkyl group substituted for, optionally one or more R 2 A 3-12 membered cycloalkenyl group is substituted, and one or more R groups are optionally added. 2 A 3-14 member heterocyclic group that is substituted, and one or more R groups as arbitrary. 2 A 6-14 membered aryl group is substituted for and optionally one or more R 2 Selected from 5-10 member heteroaryl groups that are substituted, R 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c -OC(O)NR b Rc , -NR b C(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0442] Cy 3 This can be any one or more R 3 A 3-12 member cycloalkyl group substituted for, optionally one or more R 3 A 3-14 membered heterocyclic group is substituted for and one or more R groups are optionally added. 3 Selected from 5-10 member heteroaryl groups that are substituted, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 , -SO2R d , -NR bSO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups; X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 It may also be a 6-14 member aromatic group substituted for it.

[0443] Cy 4 This can be any one or more R 4 A 3-12 member cycloalkyl group substituted for, optionally one or more R 4 A 3-14 member heterocyclic group that is substituted, and one or more R groups as arbitrary. 4 A 5-14 member heteroaryl group is substituted for and optionally one or more R 4 Selected from 6-14 membered aryl groups that are substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2Rd , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups, or two R 4 These atoms can bond with each other to form a 5-14 membered cyclic group.

[0444] L is -NR b -, -O-, -S- and -(CR a R a ) m - is chosen from, and m is chosen from integers 1-3.

[0445] R a Either they are absent, or each time they appear, they are independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0446] R b , R c Each of these is either absent or, each time it appears, is independently substituted with a hydrogen atom, a hydroxyl group, or optionally a substituent. 1-6 Alkyl group, C optionally substituted with a substituent 1-6 Selected from alkyl-R', -C(O)-R', -SO2-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0447] R d They are either absent or, each time they appear, independently exist as a hydrogen atom, a halogen atom, and an amino group (C optionally substituted with a substituent). 1-6 (Alkyl group) 1-2 , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Alkyl group, C optionally substituted with substituents 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6The group is selected from alkoxy groups -R', -O-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0448] R' is independently selected from a 3-12 member cycloalkyl group, a 3-12 member cycloalkenyl group, a 3-14 member heterocyclic group, a 6-14 member aryl group, and a 5-10 member heteroaryl group, each of which can be optionally substituted with a substituent.

[0449] q is an integer between 0 and 4.

[0450] n is an integer between 0 and 4.

[0451] In the phrase "arbitrarily substituted with substituents," the substituents are, independently of each other, a hydroxyl group, a mercapto group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylalkyl group C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 Alkyl(2 amino groups, C) 1-6 Alkylamino group carbonyl group, (C 1-6 Alkyl group) 2 amino group carbonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl group oxy group, C 1-6 Alkyl carbonyl group, amino group, C 1-6 Alkyl sulfonyl amino group, halogenated C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkoxy group, C 1-6Alkyl sulfonyl group, C 1-6 The group is selected from alkylthio groups, 3-12 membered cycloalkyl groups, 6-14 membered aryl groups, 3-12 membered heterocyclic groups, 5-10 membered heteroaryl groups, and oxo groups.

[0452] In the groups shown in formulas (a'), (b'), and (c'):

[0453] [ka]

[0454] This indicates an arbitrary double bond region in the ring structure.

[0455] The conditions are as shown in the bases of formulas (a') and (c'):

[0456] [ka]

[0457] The part does not form a hydrogen atom.

[0458] The condition is that in the base shown in equation (b'), X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0459] Embodiment 2. The compound described in Embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, provided that,

[0460] M 1 M 2 Each of these is independently substituted with a hydrogen atom or optionally with a substituent. 1-6 C is substituted with alkyl groups and optionally with substituents. 2-8 Selected from alkenyl groups, or M 1 and M 2These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0461] [ka]

[0462] The portion can be formed from hydrogen atoms; preferably, M 1 M 2 Each of these C atoms can be independently and arbitrarily substituted with a substituent. 1-6 Selected from alkyl groups, or M 1 and M 2 These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0463] [ka]

[0464] The portion can be formed from hydrogen atoms; preferably, M 1 M 2 Each is independently C 1-6 Selected from alkyl groups, or M 1 and M 2 These can form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups with atoms that bond to them.

[0465] In formula (a'), ring A represents a 6-10 membered aryl ring; preferably, ring A represents a benzene ring or a naphthalene ring.

[0466] Q independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , C which can be optionally substituted with substituents 1-6 C is substituted with alkyl groups and optionally with substituents. 1-6 Selected from alkoxyl groups.

[0467] Cy 2 This can be any one or more R2 A 6-14 membered aryl group is substituted for and optionally one or more R 2 Selected from 5-10 member heteroaryl groups to be substituted, preferably Cy 2 This can be any one or more R 2 The group to be substituted is selected from either a phenyl group or a naphthyl group.

[0468] R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)OR d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups; preferably, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups; preferably, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0469] Cy 3 This can be any one or more R 3 A 3-8 membered cycloalkyl group is substituted for and optionally one or more R 3 Selected from 5-10 member heteroaryl groups to be substituted, X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 It may be a 6-10 member aromatic group substituted with; preferably, Cy 3 This can be any one or more R 3A 3-6 member cycloalkyl group substituted for, optionally one or more R 3 Selected from 5-6 member heteroaryl groups to be substituted, X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 The substituted phenyl or naphthyl group may be Cy 3 This can be any one or more R 3 A pyrrolyl group substituted with, optionally one or more R 3 A pyridyl group substituted for, optionally one or more R 3 A pyrimidyl group substituted with, optionally one or more R 3 A pyridazole group substituted with or optionally one or more R 3 Selected from the pyrazyl groups to be substituted.

[0470] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0471] Cy 4 This can be any one or more R4 A 5-10 membered heterocyclic group that is substituted, and one or more R groups as arbitrary. 4 A 5-10 member heteroaryl group is substituted for and optionally one or more R 4 Selected from 6-10 membered aryl groups that are substituted; preferably Cy 4 This can be any one or more R 4 A 9-10 member heteroaryl group substituted for or one or more R 4 The group to be substituted is selected from either a phenyl group or a naphthyl group.

[0472] R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups, or two R groups 4 These are formed with atoms that bond to them and a 5-6 membered cyclic group; preferably, R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkylalkyl group C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Selected from alkoxyl groups, or two R groups 4 These can form a 5-6 member oxygen-containing cyclic group with atoms that bond to them; preferably, R 4 C is a hydrogen atom, a hydroxyl group, a mercapto group, a halogen atom, and 1-4 Alkyl alkyl groups, C halogenated compounds 1-4Alkyl alkyl group, C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkyl alkyl group, C 1-4 Alkylalkyl group C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkoxyl group, halogenated C 1-4 Selected from alkoxyl groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0473] L is -NR b -, -O-, and -S- are selected.

[0474] R a They are either absent or, each time they appear, independently represent a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups; preferably, R a They are either absent, or each time they appear, they are independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkyl groups, preferably R a They do not exist, or each time they appear, they independently form a hydrogen atom, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxyl groups.

[0475] R b , R c Each of these is either absent or, each time it appears, is independently substituted with a hydrogen atom or optionally a substituent. 1-6 Selected from alkyl groups; preferably, Rb , R c Each of them either does not exist or appears independently of the hydrogen atom and C. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkyl groups; preferably, R b , R c Each of them either does not exist or appears independently of the hydrogen atom and C. 1-6 Selected from alkyl groups.

[0476] R d Either they are absent, or each time they appear, they are independently a hydroxyl group, a halogen atom, an amino group, and a C-amino group (optionally substituted with a substituent). 1-6 (Alkyl group) 1-2 , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups; preferably, R d They are either absent or appear independently as hydroxyl group, amino group, and -amino group (C) each time they appear. 1-6 (Alkyl group) 1-2 , C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups; preferably, R d They are either absent or, each time they appear, independently exist as a hydroxyl group, an amino group, and C. 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group, halogenated C 1-4 Selected from alkoxyl groups.

[0477] R' is selected from optionally substituted 3-8 member cycloalkyl groups, optionally substituted 3-8 member cycloalkenyl groups, optionally substituted 3-10 member heterocyclic groups, optionally substituted 6-10 member aryl groups, and optionally substituted 5-6 member heteroaryl groups; preferably, R' is optionally substituted 3-6 member cycloalkyl groups, optionally substituted 4-7 member heterocyclic groups, optionally substituted 6-10 member aryl groups, and optionally substituted The group is selected from 5-6 membered heteroaryl groups to be substituted; preferably, R' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, oxacycloheptyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, and pyridazyl groups.

[0478] In "arbitrarily substituted with substituents," the substituents are independently hydroxyl groups, mercapto groups, amino groups, carboxyl groups, cyano groups, nitro groups, halogen atoms, and C. 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, C 1-6 Alkylalkyl group C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkoxyl group, C 1-6 Alkylamino group, (C 1-6 Alkyl(2 amino groups, C) 1-6 Alkylamino group carbonyl group, (C 1-6 Alkyl group) 2 amino group carbonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl group oxy group, C 1-6 Alkyl carbonyl group, amino group, C 1-6 Alkyl sulfonyl amino group, halogenated C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Carbonyl group, C1-6 Alkyl sulfonyl group, C 1-6 The substituents are selected from alkylthio groups, 3-8 membered cycloalkyl groups, 6-10 membered aryl groups, 3-8 membered heterocyclic groups, 5-6 membered heteroaryl groups, and oxo groups; preferably, the substituents in "optionally substituted with substituents" are independently hydroxyl groups, mercapto groups, amino groups, carboxyl groups, cyano groups, nitro groups, halogen atoms, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group C 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group, C 1-4 Alkylalkyl group C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkoxyl group, C 1-4 Alkylamino group, (C 1-4 Alkyl(2 amino groups, C) 1-4 Alkylamino group carbonyl group, (C 1-4 Alkyl group) 2 amino group carbonyl group, C 1-4 Alkylcarbonyl group, C 1-4 Alkyl carbonyl group oxy group, C 1-4 Alkyl carbonyl group, amino group, C 1-4 Alkyl sulfonyl amino group, halogenated C 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkoxyl group, C 1-4 Alkyl sulfonyl group, C 1-4 Selected from alkylthio groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, phenyl groups, naphthyl groups, oxacyclopropyl groups, oxacyclobutyl groups, oxacyclopentyl groups, oxacyclohexyl groups, oxacycloheptyl groups, pyrrolyl groups, furyl groups, thienyl groups, oxazolyl groups, isoxazolyl groups, pyrazolyl groups, thiazolyl groups, pyridyl groups, pyrimidyl groups, pyridazyl groups, and oxo groups, n is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, or 4.

[0479] Embodiment 3. A compound described in Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, provided that, X 1 is NR b X 2 CR a R a X 3 C=O. Or X 1 CR a R a X 2 is NR b X 3 C=O. Or X 1 C=O, X 2 CR a R a X 3 C=O. Or X 1 CR a R a X 2 C=O and X 3 C=O. Or X 1 CR a R a X 2 CR a R a X 3 C=O. Or X 1 C=O and X 2 CR a R a X 3 CR a R a It is. Or X 1 CR a R a X 2 C=O and X 3 CR a R a That is the case.

[0480] Embodiment 4. A compound described in any of Embodiments 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, However, X 4 X is selected from N. 5 CR a Selected from. Or X 4 CR a Selected from X 5 CR a Selected from. Or X 4 X is selected from N. 5 It is selected from N. Or X 4 CR a Selected from X 5 It is selected from N.

[0481] Embodiment 5. A compound described in any of Embodiments 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, provided that, X 6 C=O and X 7 CR a R a It is. Or X 6 CR a R a X 7 C=O. Or X 6 C=O and X 7 is NR b It is. Or X 6 is NR b X 7 C=O.

[0482] Embodiment 6. A compound described in any of Embodiments 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, provided that, In the ring of equations (a'), (b'), and (c'), there is only one C=O.

[0483] Embodiment 7. A compound described in any of Embodiments 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, provided that, Cy 3 This can be any one or more R 3 Replaced with

[0484] [ka]

[0485] The base shown is represented in the formula,

[0486] [ka]

[0487] Y indicates a single bond or a double bond. 2 , Y 3 , Y 6 and Y 7 Each of them independently performs CR a R a or NR b Selected from and at least one of them is NR b And preferably, Cy 3 This can be any one or more R 3 Replaced with

[0488] [ka]

[0489] The group shown is Y 2 , Y 3 , Y 6 , Y 7 Each is independently selected from CH or N, and at least one is N.

[0490] R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d-C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0491] Cy 4 This can be any one or more R 4 Replaced with

[0492] [ka]

[0493] The base shown is represented in the formula,

[0494] [ka]

[0495] Y indicates a single bond or a double bond. 4 and Y 5 Each of them independently performs CR a R a or NR b Selected from and at least one is NR b Ring B is a benzene ring, a naphthalene ring, or a 5-6 membered heteroaryl ring, preferably Cy 4 This can be any one or more R 4 Replaced with

[0496] [ka]

[0497] The group shown is Y 4 and Y 5 Each is independently selected from CH or N, and at least one is N, preferably ring B is a benzene ring or NR b It is a 5-6 membered heteroaryl ring containing 1-3 atoms in O and S.

[0498] R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups, or two R groups 4 These are formed with atoms that bond to them and a 5-6 membered cyclic group; preferably, R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydrogen group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkylalkyl group C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Selected from alkoxyl groups, or two R groups 4 These can form a 5-6 member oxygen-containing cyclic group with atoms that bond to them; preferably, R 4C is a hydrogen atom, hydrogen group, mercapto group, halogen atom, C 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkyl alkyl group, C 1-4 Alkylalkyl group C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkoxyl group, halogenated C 1-4 Selected from alkoxyl groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0499] L is -NR b - or -O- is selected.

[0500] Embodiment 8. A compound described in any of Embodiments 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0501] However, R is the group shown in formula (b'), and the six-membered ring in the group shown in formula (b') is shown by one of the following, in the formula

[0502] [ka]

[0503] This indicates a single bond or a double bond.

[0504] [ka]

[0505] X 1 and X 2 The definition is as shown in Embodiment 1-7.

[0506] Embodiment 9. A compound described in any of Embodiments 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof,

[0507] However, Cy 3 This can be any one or more R 3 The following elements are selected to be substituted:

[0508] [ka]

[0509] Preferably, Cy 3 This can be any one or more R 3 The following elements are selected to be substituted:

[0510] [ka]

[0511] And * is connected to N, and · is connected to L, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0512] Cy 4 This can be any one or more R 4 The following elements are selected to be substituted:

[0513] [ka]

[0514] Preferably, Cy 4 This can be any one or more R 4 The following elements are selected to be substituted:

[0515] [ka]

[0516] R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Alkyl alkyl group, C 1-6 Alkylalkyl group C 1-6 Alkoxyl group, C 1-6 Alkoxyl group C 1-6 Selected from alkoxyl groups, or two R groups 4 These can form a 5-6 member oxygen-containing cyclic group with atoms that bond to them; preferably, R 4 C is a hydrogen atom, a hydroxyl group, a mercapto group, a halogen atom, and 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkyl alkyl group, C 1-4 Alkylalkyl group C 1-4 Alkoxyl group, C 1-4 Alkoxyl group C 1-4 Alkoxyl group, halogenated C 1-4 Selected from alkoxyl groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0517] Embodiment 10. A compound described in any of Embodiments 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, having the structure represented by general formula (II),

[0518] [ka]

[0519] However, the definition of each group is as shown in Embodiments 1-9.

[0520] Embodiment 11. A compound described in any of Embodiments 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, having the structure represented by general formula (III),

[0521] [ka]

[0522] However, M 1 M 2 Each is independently C 1-6 Selected from alkyl groups, or M 1 and M 2 These can form 3-6 membered cycloalkyl groups with atoms that bond to them; preferably, M 1 and M 2 These atoms can bond with each other to form a cyclopropyl group.

[0523] X 1 , X 2 , X 3 Each of them independently performs CR a R a , C=O, NR b Selected from and at least one of them is C=O; preferably X 1 , X 2 Each of them independently performs CR a R a and NR b Selected from X 3 This shows that C=O,

[0524] Y 2 and Y 3 Each is independently selected from CH or N, and at least one is N.

[0525] L is -NR b - or -O- is selected.

[0526] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0527] Other bases are as defined in Embodiments 1-9.

[0528] Embodiment 12. A compound described in any of Embodiments 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, having the structure represented by general formula (IV),

[0529] [ka]

[0530] However, M 1 M 2 Each is independently C 1-6 Selected from alkyl groups, or M 1 and M 2 These can form 3-6 membered cycloalkyl groups with atoms that bond to them; preferably, M 1 and M 2 These atoms can bond with each other to form a cyclopropyl group.

[0531] X 1 , X 2 , X 3 Each of them independently performs CR a R a , C=O, NR b Selected from and at least one of them is C=O; preferably X 1 , X 2 Each of them independently performs CR a R a and NR b Selected from X 3 This shows that C=O,

[0532] Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0533] L is -NR b - or -O- is selected.

[0534] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0535] Other bases are as defined in Embodiments 1-9.

[0536] One embodiment of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the compound being as follows:

[0537] [Table 1-1]

[0538] [Table 1-2]

[0539] [Table 1-3]

[0540] [Table 1-4]

[0541] The present invention further provides a drug composition comprising at least one of the compounds represented by any of the above formulas (I), (II), (III), and (IV), a pharmaceutically acceptable salt thereof, an ester, a stereoisomer, or a tautomer.

[0542] The present invention further provides a drug composition comprising a compound represented by any one of the above formulas (I), (II), (III), and (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein the drug composition may optionally contain one or more drug carriers.

[0543] The present invention further provides pharmaceutically acceptable dosage forms comprising a compound represented by any one of the above formulas (I), (II), (III), and (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein the dosage form optionally comprises one or more drug carriers.

[0544] In one embodiment of the present invention, the drug composition or dosage form may further include one or more second therapeutic agents.

[0545] One embodiment of the present invention provides a drug composition comprising a compound represented by any one of the above formulas (I), (II), (III), and (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein the drug composition may optionally contain at least one second therapeutic agent.

[0546] In one embodiment of the present invention, the second therapeutic agent is at least one selected from the following: antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal-based preparations, topoisomerase inhibitors, hormones, immunomodulators, tumor suppressor genes, cancer vaccines, antibodies related to immune checkpoints or tumor immunotherapy, small molecule drugs, and cell therapy agents.

[0547] In one embodiment of the present invention, the drug composition or dosage form can be administered to patients or test subjects in need of prevention and / or treatment by any suitable administration method known in the industry, such as oral, extra-gastrointestinal (including subcutaneous, intramuscular, intravenous, intra-arterial, intradermal, intrasacral and epidural), percutaneous, rectal, nasal, transpulmonary, local (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

[0548] In one embodiment of the present invention, the drug composition or dosage form can be manufactured as a conventional solid preparation, such as tablets, capsules, pills, or granules; it can also be manufactured as an oral liquid preparation, such as an oral solution, oral suspension, or syrup. When prepared as an oral preparation, appropriate fillers, adhesives, disintegrants, lubricants, etc., can be added. For extra-gastrointestinal administration, the drug composition can be prepared as an injectable, sterile powder for injection, or concentrated solution for injection. When prepared as an injectable, it can be produced using the conventional methods of the pharmaceutical industry, and when preparing the injectable, adducts may be omitted or appropriate adducts may be added depending on the properties of the drug. For rectal administration, the drug composition can be prepared as a suppository or the like. For transpulmonary administration, the drug composition can be prepared as an inhalant or spray or the like.

[0549] In one embodiment of the present invention, the use of a compound represented by any of the above formulas (I), (II), (III), or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, drug composition, or dosage form thereof in the preparation of a drug for the treatment and / or prevention of diseases mediated by the abnormal expression of the TAM family kinase receptor and / or its ligand is provided, wherein the diseases mediated by the abnormal expression of the TAM family kinase receptor and / or its ligand include at least one of the following diseases: tumors, tumor immunity, ectopic endometriosis, vascular diseases / injuries, psoriasis, visual impairments / lesions (due to causes such as macular degeneration, diabetes and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis and related diseases.

[0550] In one embodiment of the present invention, a compound represented by any one of the above formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, the above drug composition, or the above dosage form is used for the treatment and / or prevention of a disease mediated by the abnormal expression of the TAM family kinase receptor and / or its ligand, the disease mediated by the abnormal expression of the TAM family kinase receptor and / or its ligand includes at least one of the following diseases: tumors, tumor immunity, ectopic endometriosis, vascular diseases / injuries, psoriasis, visual impairment / lesions (due to causes such as macular degeneration, diabetes and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis and related diseases.

[0551] In one embodiment of the present invention, the use of a compound represented by any of the above formulas (I), (II), (III), or (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, drug composition, or dosage form thereof in the preparation of a drug for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinases / and CSF1R kinase receptors and / or their ligands is provided, wherein the diseases mediated by the abnormal expression of TAM family kinases / and CSF1R kinase receptors and / or their ligands include at least one of the following diseases: tumors, tumor immunity, ectopic endometriosis, vascular diseases / injuries, psoriasis, visual impairments / lesions (due to causes such as macular degeneration, diabetes and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis and related diseases.

[0552] In one embodiment of the present invention, a compound represented by any one of the above formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, the drug composition, or the dosage form thereof is used for the treatment and / or prevention of diseases mediated by the abnormal expression of TAM family kinases / and CSF1R kinase receptors and / or their ligands, the diseases mediated by the abnormal expression of TAM family kinases / and CSF1R kinase receptors and / or their ligands include at least one of the following diseases: tumors, tumor immunity, ectopic endometriosis, vascular diseases / injuries, psoriasis, visual impairments / lesions (due to causes such as macular degeneration, diabetes and premature birth), kidney diseases, rheumatoid arthritis, osteoporosis and related diseases.

[0553] In one embodiment of the present invention, the use of a compound represented by any of the above formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, drug composition, or dosage form thereof, in the preparation of a drug for the treatment and / or prevention of NTRK-induced related diseases, particularly drug-resistant related diseases induced by NTRK mutations, which include, but are not limited to, non-small cell lung cancer, colorectal cancer, secretory-type mammary carcinoma, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid carcinoma, secretory mammary carcinoma, and mammary carcinoma of unknown pathological type.

[0554] In one embodiment of the present invention, a compound represented by any of the above formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, the drug composition, or the dosage form thereof is used for the treatment and / or prevention of NTRK-induced related diseases, particularly drug-resistant related diseases induced by NTRK mutations, which include, but are not limited to, non-small cell lung cancer, colorectal cancer, secretory-type mammary carcinoma, sarcoma, astrocytoma, glioblastoma, Spitzian melanoma, cholangiocarcinoma, papillary thyroid carcinoma, secretory mammary carcinoma, and mammary carcinoma of unknown pathological type.

[0555] In one embodiment of the present invention, a compound represented by any one of the above formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, the drug composition, or the dosage form thereof is used for the treatment and / or prevention of NTRK-induced related diseases, particularly drug-resistant related diseases induced by NTRK mutations.

[0556] In one embodiment of the present invention, the tumors include sarcomas, lymphomas, and cancers, specifically lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, colonic trophoblastoma, melanoma, cell tumor, and sarcoma. [Effects of the Invention]

[0557] The compounds according to the present invention have an inhibitory effect on TAM family kinases. Furthermore, the compounds according to the present invention can target CSF1R kinase and have an inhibitory effect on CSF1R kinase. The compounds according to the present invention can treat and / or prevent diseases mediated by the abnormal expression of TAM family kinase receptors and / or their ligands. Furthermore, the compounds according to the present invention can treat and / or prevent diseases mediated by the abnormal expression of TAM family kinases and CSF1R kinase receptors and / or their ligands. By simultaneously targeting and inhibiting TAM family kinases and CSF1R kinases, the compounds according to the present invention reverse immunosuppression in the tumor microenvironment, suppressing tumor growth, metastasis, and / or the development of drug resistance, thereby achieving tumor immunosuppression and antitumor effects.

[0558] Furthermore, the compounds according to the present invention have very good NTRK mutation targeting activity and have good applicability in patients with acquired drug resistance treated with first-generation NTRK inhibitors, and can treat and / or prevent NTRK-induced related diseases, particularly drug-resistant related diseases caused by NTRK mutations.

[0559] Furthermore, the compounds according to the present invention have a long half-life in the body, excellent metabolic stability, and superior drugability, thus improving the efficacy of the drug, reducing the burden on patients taking medication, and increasing compliance. [Modes for carrying out the invention]

[0560] The embodiments of the present invention will be described in more detail below with reference to specific embodiments, but those skilled in the art will understand that the embodiments described herein are merely illustrative and not limitations on the scope of protection of the present invention. Conversely, the present invention includes all alternative, modified, and equivalent forms within the scope of the present invention as defined by the claims. Unless otherwise specified, each embodiment of the present invention may be combined in any way, and any transformations, variations, or changes in the technical concept resulting therefrom are also included within the scope of the present invention and do not deviate from the scope of the present invention.

[0561] In the description of this invention, unless otherwise clearly defined, or unless the meaning exceeds the understanding of those skilled in the art, hydrocarbon or hydrocarbon derivative groups having three or more carbon atoms (e.g., propyl group, propoxy group, butyl group, butane, butylene, butyrenyl group, hexane, etc.) have the same meaning as if they had "n-" prefixes, even if they do not. For example, unless otherwise specified, a propyl group is understood as an n-propyl group, and a butyl group is understood as an n-butyl group.

[0562] All publications, patent applications, patents, and other references referenced herein are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the meanings that are ordinarily understood by those skilled in the art. In case of any inconsistency, the definitions herein shall prevail.

[0563] In the description of this specification, unless otherwise clearly explained, any circumstances or matters not mentioned shall be regarded as being directly well-known in the art and shall not require any modification. Moreover, any embodiment described in this specification can be freely combined with one or more other embodiments described in this specification, and all technical forms or technical ideas formed thereby shall be regarded as part of the original disclosure or original description of the present invention, and shall not be regarded as new content not disclosed or anticipated in this specification unless those skilled in the art consider that the combination is clearly unreasonable.

[0564] In the present invention, the description of " a-b group" (where a and b are integers greater than or equal to 1 and a < b) indicates that there are a - b carbon atoms in the " 1-4 alkyl group" indicates an alkyl group having 1 to 4 carbon atoms, 1-4 alkoxy group" indicates an alkoxy group having 1 to 4 carbon atoms, 3-10 cycloalkyl group" indicates a cycloalkyl group having 3 to 10 carbon atoms, 1-4 alkoxy group 1-4 alkyl group" indicates a group formed by the combination of an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms.

[0565] In the present invention, "group" and "atomic group" refer to a monovalent atomic group or, if necessary, an atomic group with two or more valencies that matches the chemical value. For example, "cycloalkyl group (also called a cycloalkyl atomic group)" includes a monovalent atomic group obtained by removing one hydrogen atom from it, and also includes an atomic group with two or more valencies obtained by removing two hydrogen atoms from a similar carbon atom or two or more different carbon atoms. When a "cycloalkyl group" is a terminal group, it naturally becomes a monovalent group, and when an alkyl group is a bonding group in the structure, it becomes a group with two or more valencies. In the present invention, a monovalent or divalent or more atomic group generally refers to a monovalent or divalent atomic group, but if necessary, the atomic group may have an even higher chemical value (e.g., trivalent, tetravalent, pentavalent, hexavalent, etc.). Those skilled in the art can determine without doubt the number of valence electrons represented by the "group". The atomic group described in this text as "obtained by removing one hydrogen atom" refers to a monovalent atomic group obtained by removing one hydrogen atom, a divalent atomic group obtained by removing two hydrogen atoms, a trivalent atomic group obtained by removing three hydrogen atoms, a tetravalent atomic group obtained by removing four hydrogen atoms, etc. The number of hydrogen atoms to be removed can be determined based on the chemical valency of the atomic group (e.g., monovalent, divalent, trivalent, tetravalent, etc.).

[0566] The term "halogen atom" as used in this invention refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably, it refers to a fluorine atom, a chlorine atom, and a bromine atom.

[0567] In this invention, "halogenation" refers to the substitution of one or more identical or different halogen atoms at any carbon atom in a substituent. A "halogen atom" is defined as described above.

[0568] The "C" described in the present invention 1-6 An alkyl group refers to a linear or branched alkyl group obtained by removing one or more hydrogen atoms from a paraffin moiety containing 1 to 6 carbon atoms, and is a linear C 1-6 Alkyl and branched chain C 1-6 It contains alkyl groups. In reality, what is known to those skilled in the art is C 1-6 Alkyl group is branched chain (branched chain C 1-6In a situation where an alkyl group has at least three carbon atoms, it has "C 1-6 Examples of alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, and 1-methyl-2-methylpropyl group. 1-4 An "alkyl group" is the example above, which has 1-4 carbon atoms.

[0569] The "hydroxyl group C" described in the present invention 1-6 Alkyl group, cyano group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl group, C 1-6 alkylamino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group C 1-6 "Alkyl group" refers to one or more hydroxyl groups, cyano groups, amino groups, and C 1-6 Alkylamino group, halogen, C 1-6 Each alkoxyl group is independently C 1-6 This indicates a group formed by substituting a hydrogen atom in an alkyl group.

[0570] "C 1-6 "C" containing alkyl group 1-6 "(C) 1-6 (Alkyl group) 2 amino group, "C 1-6 "Alkyl amino group carbonyl group", C 1-6 "alkyl carbonyl group", "C 1-6 "Alkylcarbonyl group oxy group", "C 1-6 "Alkyl sulfonyl amino group", "C 1-6 "alkyl sulfonyl group", "C1-6 Groups such as "alkylthio group" are C 1-6 This refers to groups formed when an alkyl group is bonded to a corresponding group such as -NH-, -CO-O-, -NH-CO-, -CO-, -SO2NH-, -SO2-, or -S-. For example, the above "C 1-6 The groups listed in "alkyl group" can be formed by the bonding of each group with a corresponding group such as -NH-, -CO-O-, -NH-CO-, -CO-, -SO2NH-, -SO2-, and -S-.

[0571] In this invention, "C 2-8 An "alkenyl group" is a linear or branched alkene group obtained by removing one or more hydrogen atoms from an alkene moiety of 2 to 8 carbon atoms having at least one carbon-carbon double bond. Examples include vinyl group, 1-propenyl group, 2-propenyl group, 1-butyrenyl group, 2-butyrenyl group, 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, and 1,4-hexadien-1-yl. Preferably, "C 2-8 It has one carbon-carbon double bond in the alkenyl group.

[0572] In this invention, "C 2-8 An "alkynyl group" is a linear or branched alkyne group obtained by removing one or more hydrogen atoms from an alkyne moiety of 2 to 8 carbon atoms having at least one carbon-carbon triple bond. Examples include ethynyl group, propynyl group, 2-butyne-1-yl, 2-pentin-1-yl, 3-pentin-1-yl, 4-methyl-2-pentin-1-yl, 2-hexyne-1-yl, 2-hexyne-2-yl, 3-hexyne-1-yl, and 3-hexyne-2-yl. Preferably, "C 2-8 It has one carbon-carbon triple bond in the "alkynyl group".

[0573] In this invention, "C 1-6 An "alkoxy group" is defined as "C" as described above. 1-6An alkyl group is a group that is bonded to the parent part by an oxygen atom, that is, "C 1-6 The alkyl-O- group is, for example, a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, t-butoxy group, n-pentyloxy group, neopentyloxy group and n-hexyloxy group. 1-4 An "alkoxy group" is the above example containing 1-4 carbon atoms, i.e., "C 1-4 This indicates an alkyl-O- group.

[0574] In the description of the present invention, "C 1-6 "Halogenated C" containing an alkoxy group 1-6 "alkoxy group", "C 1-6 Alkoxy group C 1-6 "alkoxy group", "C 1-6 Alkylalkyl group C 1-6 A group such as an "alkoxy group" is composed of one or more halogen atoms, C 1-6 Alkoxy group, C 1-6 Each appropriate group, such as an alkyl group, is independently C 1-6 This indicates a group formed by substituting one or more hydrogen atoms in an alkoxy group.

[0575] In this invention, the term "fused ring" refers to a polycyclic structure formed by bonding, spiro, or bridging of two or more cyclic structures. The bonding ring is a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing the same key). The bridging ring is a fused ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spiro ring is a fused ring structure formed by two or more cyclic structures sharing one ring atom.

[0576] The "cycloalkyl group" or "cycloalkyl atom group" (hereinafter commonly referred to as "cycloalkyl group") described in the present invention refers to a monovalent group or (if necessary) a group with two or more valents obtained from a cycloparaffin derivative, wherein the cycloparaffin includes monocyclic cycloparaffins or fused ring cycloparaffins. For example, it is a "3-12 membered cycloalkyl group," which may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-constituting carbon atoms. Unless otherwise specified, a certain membered cycloalkyl group includes any monocyclic or fused ring (including condensation in the form of bonding, spiro, or bridging) that can be formed. A cycloalkyl group can be a 3-12 member monovalent group or (as necessary) a group with two or more members, a 3-10 member monovalent group or (as necessary) a group with two or more members, a 3-8 member monovalent group or (as necessary) a group with two or more members, a 3-6 member monovalent group or (as necessary) a group with two or more members, a 4-6 member monovalent group or (as necessary) a group with two or more members, or a 5-7 member monovalent group or (as necessary) a group with two or more members.

[0577] Specifically, monocyclic cycloalkyl groups (monovalent or divalent or more) include 3-12 membered cycloalkyl groups, 3-10 membered cycloalkyl groups, 3-8 membered cycloalkyl groups, 3-6 membered cycloalkyl groups, 4-6 membered cycloalkyl groups, 5-6 membered cycloalkyl groups, and 5-7 membered cycloalkyl groups. Examples include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, and cycloheptane-1,4-diyl.

[0578] (Monovalent or divalent or more) condensed ring cycloalkyl groups include bonded ring cycloalkyl groups, crosslinked ring cycloalkyl groups, and spiro ring cycloalkyl groups.

[0579] (Monovalent or divalent or more) ring-binding cycloalkyl groups are 6-11 membered ring-binding cycloalkyl groups and 7-10 membered ring-binding cycloalkyl groups. Typical examples include, but are not limited to, monovalent or divalent or more groups 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.

[0580] (Monovalent or divalent or more) crosslinked ring cycloalkyl groups may further be monovalent groups obtained by removing one hydrogen atom from a 6-12 membered crosslinked ring or a 7-11 membered crosslinked ring, or divalent or more groups obtained by removing two or more hydrogen atoms from the same carbon atom or a different carbon atom as needed.

[0581] Examples of the aforementioned bridging rings

[0582] [ka]

[0583] This includes, but is not limited to, these.

[0584] A (monovalent or divalent or more) spirocyclic cycloalkyl group may be a monovalent group obtained by removing one hydrogen atom from a 7-12 membered spiro ring or a 7-11 membered spiro ring, or a divalent or more group obtained by removing two or more hydrogen atoms from a similar or different carbon atom as needed. Examples of spiro rings

[0585] [ka]

[0586] This includes, but is not limited to, these.

[0587] The "cycloalkenyl group" described in this invention refers to a group obtained by having at least one double bond in the cycloalkyl group described above. For example, it is a "3-12 membered cycloalkenyl group," which can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbon atoms. Unless otherwise specified, a certain-membered cycloalkenyl group includes any monocyclic or fused ring (including condensation in the form of bond, spiro, or bridge). The cycloalkenyl group may be a 3-12 membered cycloalkenyl group, a 3-8 membered cycloalkenyl group, a 4-6 membered cycloalkenyl group, a 7-11 membered spirocycloalkenyl group, a 7-11 membered bonded cycloalkenyl group, a 6-11 membered bridged cycloalkenyl, and the like. Examples of cycloalkenyl groups include, but are not limited to, cyclobutyrenyl, cyclopentenyl, cyclopiperenyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cyclohexenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, and 1,5-cyclooctadien-1-yl.

[0588] The "heterocycle" described in the present invention includes non-aromatic cyclic hydrocarbons containing at least one heteroatom selected from O, S, and N (1-5, 1-4, 1-3, 1-2, or 1) as a ring constituent atom within the ring. It may be a heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring constituent atoms. The ring may optionally have at least one double bond. The heterocycle according to the present invention may be a monocyclic system or a fused-ring system (condensed in the form of bonds, spiros, or bridges). Examples of heterocycles include monocyclic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, pentamethylene sulfide, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, and tetrahydroisothiazole; and condensed heterocycles such as dihydroindole, isodihydroindole, benzopyran, benzodioxane, tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, and tetrahydrobenzothiophene. Furthermore, heterocycles obtained by substituting at least one ring-constituting carbon atom in the above 7-12 membered spiro rings, 7-11 membered spiro rings, 6-12 membered bridged rings, and 7-11 membered bridged rings with a heteroatom selected from O, S, and N can be mentioned, preferably substituted with 1 to 4 heteroatoms. Furthermore, the following 6-12 membered linkage groups, 7-10 membered linkage groups, 6-10 membered linkage groups, 6-12 membered saturated linkage groups, 6-12 membered spiroheterocycles, 7-11 membered spiroheterocycles, 6-12 membered saturated spiroheterocycles, 7-11 membered saturated spiroheterocycles, 6-12 membered bridging heterocycles, 7-11 membered bridging heterocycles, 6-12 membered saturated bridging heterocycles, and 7-8 membered saturated bridging heterocycles are examples of the present invention.

[0589] The "heterocyclic group" or "heterocyclic atom group" described in the present invention (hereinafter commonly referred to as "heterocyclic group") refers to a monovalent or divalent or more group obtained by deriving from the above-mentioned "heterocyclic group". Furthermore, the "heterocyclic group" described in the present invention may also be a non-aromatic monovalent or divalent or more cyclic group in which at least one ring-constituting carbon atom of the above-mentioned cycloalkyl group or cycloalkenyl group is substituted with at least one heteroatom selected from O, S, and N, preferably substituted with 1 to 4 heteroatoms. In addition, the heterocyclic group also includes cases in which carbon atoms and sulfur atoms are simultaneously substituted with oxygen and nitrogen, for example, carbon atoms and sulfur atoms are substituted with C(=O), S(=O), S(=O)2, and S(=O)(=N).

[0590] Specifically, a "heterocyclic group" can be a heterocyclic group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming atoms. It may also be a 3-14 membered heterocyclic group, a 3-10 membered heterocyclic group, a 4-10 membered heterocyclic group, a 3-8 membered heterocyclic group, a 4-8 membered heterocyclic group, a 4-6 membered heterocyclic group, a 3-12 membered heterocyclic group, or a 4-12 membered heterocyclic group, and includes monocyclic heterocyclic groups or fused heterocyclic groups.

[0591] Furthermore, "heterocyclic group" refers to monovalent or (as necessary) divalent or more monocyclic heterocyclic groups, monovalent or (as necessary) divalent or more bicyclic heterocyclic group systems, or monovalent or (as necessary) divalent or more polycyclic heterocyclic group systems (also called fused ring systems), and includes saturated and partially saturated heterocyclic groups, but does not include aryl rings. Unless otherwise specified, it includes any monocyclic or fused ring (including condensation in the form of bonds, spiros, and bridges) that can be formed, and is saturated or partially saturated. For example, it could be a "3-14 membered heterocyclic group".

[0592] Monovalent or (as needed) divalent or more monocyclic heterocyclic groups can include 3-14 member heterocyclic groups, 3-12 member heterocyclic groups, 3-10 member heterocyclic groups, 4-10 member heterocyclic groups, 3-8 member heterocyclic groups, 3-8 member heterocyclic groups, 4-8 member heterocyclic groups, 3-6 member heterocyclic groups, 4-6 member heterocyclic groups, 4-7 member heterocyclic groups, 5-7 member heterocyclic groups, 5-6 member heterocyclic groups, 5-6 member heterocyclic groups, 5-6 member oxygen-containing heterocyclic groups, 3-8 member nitrogen-containing heterocyclic groups, 5-6 member nitrogen-containing heterocyclic groups, 5-6 member saturated heterocyclic groups, and the like. Furthermore, these can also be 3-14 member oxygen-containing heterocyclic groups, 3-14 member nitrogen-containing heterocyclic groups, 3-12 member oxygen-containing heterocyclic groups, 3-12 member sulfur-containing heterocyclic groups, 3-12 member sulfone (S(O)2) heterocyclic groups, 3-12 member sulfoxide (S(O)) heterocyclic groups, and so on. Examples of "heterocyclic groups" include azacyclopropyl group, oxacyclopropyl group, thiacyclopropyl group, azacyclobutyl group, oxacyclobutyl group, thiocyclobutyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydrothienyl group, imidazolyl alkyl group, pyrazolyl alkyl group, 1,2-oxazolyl alkyl group, 1,3-oxazolyl alkyl group, 1,2-thiazolyl group, 1,3-thiazolyl group, tetrahydro-2H-pyranyl group, tetrahydro-2H-thiopyranyl group, piperidinyl group, piperazinyl group, morpholyl group, 1,4-dioxacyclohexanyl group, 1,4-oxathiacyclohexanyl group, 4,5-dihydroisoxazolyl group, 4,5-dihydro This includes, but is not limited to, xazolyl groups, 2,5-dihydroxazolyl groups, 2,3-dihydroxazolyl groups, 3,4-dihydro-2H-pyrrolyl groups, 2,3-dihydro-1H-pyrrolyl groups, 2,5-dihydro-1H-imidazolyl groups, 4,5-dihydro-1H-imidazolyl groups, 4,5-dihydro-1H-pyrazolyl groups, 4,5-dihydro-3H-pyrazolyl groups, 4,5-dihydrothiazolyl groups, 2,5-dihydrothiazolyl groups, 2H-pyranyl groups, 4H-pyranyl groups, 2H-thiopyranyl groups, 4H-thiopyranyl groups, 2,3,4,5-tetrahydropyridyl groups, 1,2-isoxazinyl groups, 1,4-isoxazinyl groups, or 6H-1,3-oxazinyl groups.

[0593] The monovalent or (as needed) divalent or more condensed heterocyclic groups include bonded heterocyclic groups, spiroheterocyclic groups, and crosslinked heterocyclic groups, which are saturated, partially saturated, or unsaturated, but are not aromatic. The condensed heterocyclic groups may be heterocyclic groups obtained by condensing the above heterocyclic groups with a 6-14 membered aryl group (e.g., a benzene ring), a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group or a 3-14 membered heteroaryl group, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl group.

[0594] The aforementioned heterocyclic groups are 6-12 membered ring groups, 7-10 membered ring groups, 6-10 membered ring groups, and 6-12 membered saturated ring groups. Representative examples include, but are not limited to, the following: 3-azabicyclo[3.1.0]hexanyl group, 3,6-diazabicyclo[3.2.0]heptanyl group, 3,8-diazabicyclo[4.2.0]octanyl group, 3,7-diazabicyclo[4.2.0]octanyl group, octahydropyrrolo[3,4-c]pyrrolyl group, octahydropyrrolo[3,4-b]pyrrolyl group, octahydropyrrolo[3,4-b][1,4]oxazinyl group, and octahydro-1H -Pyrrolo[3,4-c]pyridyl group, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindole-1-yl, dihydroindole-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl group, octahydrobenzofuranyl group, octahydrocyclopiperileno[c]pyrrole, hexahydrocyclopentadieno[c]furan, 2,2-dioxohexahydrocyclopentadieno[c]thiophene, 2-imino-2oxa-octahydrocyclopenteno[c]thiophene.

[0595] The aforementioned spiroheterocyclic groups are monovalent groups obtained by removing one hydrogen atom from a 6-12 membered spiroheterocyclic, a 7-11 membered spiroheterocyclic, a 6-12 membered saturated spiroheterocyclic, or a 7 membered saturated spiroheterocyclic, or groups with two or more valencies obtained by removing one hydrogen atom from the same carbon atom or different carbon atoms as needed. Examples of spiroheterocyclics include, but are not limited to, the following:

[0596] [ka]

[0597] The aforementioned bridging heterocyclic groups are monovalent groups obtained by removing one hydrogen atom from a 6-12 membered bridging heterocycle, a 7-11 membered bridging heterocycle, a 6-12 membered saturated bridging heterocycle, or a 7-8 membered saturated bridging heterocycle, or groups with two or more valencies obtained by removing one hydrogen atom from the same carbon atom or different carbon atoms as needed. Examples of bridging heterocycles include, but are not limited to, the following:

[0598] [ka]

[0599] The term "aryl ring" as used in this invention refers to an aromatic cyclic hydrocarbon. It is a monovalent group derived from an aromatic cyclic hydrocarbon, or a group with two or more valencies if necessary, and the aromatic cyclic hydrocarbon includes a 6-14 membered aryl ring, a 6-10 membered aryl ring, a 6-8 membered monocyclic aryl ring, and an 8-14 membered fused aryl ring. An example of a 6-8 membered monocyclic aryl group is a phenyl group. An example of an 8-14 membered fused aryl ring is a naphthyl group, a phenantrenyl group, or an anthracenyl group. Examples of divalent groups include a phenylenyl group and a naphthyrenyl group.

[0600] The "aryl group" or "aromatic group" (hereinafter commonly referred to as "aryl group") described in this invention refers to a monovalent group or, optionally, a group containing two or more valent groups, obtained by derivation from aromatic cyclic hydrocarbons. This includes 6-14 membered aryl groups and 6-10 membered aryl groups. Examples of 6-14 membered aryl groups are phenyl, naphthyl, phenantrenyl, and anthracenyl groups. Examples of 6-10 membered aryl groups are phenyl and naphthyl groups. Examples of divalent groups include phenylenyl and naphthyrenyl groups.

[0601] The "heteroaryl ring" described in the present invention refers to an aromatic cyclic hydrocarbon having at least one heteroatom (1-5, 1-4, 1-3, 1-2, or 1) selected from O, S, and N as ring constituent atoms. It is an aromatic cyclic group with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members, preferably having 1-3 heteroatoms. Furthermore, the heteroaryl ring according to the present invention may be a monocyclic system or a fused ring system (condensed in the form of bonds, spiros, or bridges). Specifically, examples include monocyclic heteroaryl rings such as pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, and oxadiazole; further, examples include condensed heteroaryl rings such as isoindole, indazole, indidine, isodihydroindole, quinoline, isoquinoline, cinnoline, 2,3-phthalazinone, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzoisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, thiazolopyridine, imidazothiazole, pyrazinopyridazine, and benzimidazolin.

[0602] The "heteroaryl group" or "heteroaryl atom group" (hereinafter commonly referred to as "heteroaryl group") described in the present invention refers to a monovalent or greater group derived from the above-mentioned "heteroaryl ring". Furthermore, the "heteroaryl group" described in the present invention may also be an aromatic cyclic hydrocarbon group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring constituent atoms, each containing at least one heteroatom selected from O, S, and N. That is, it may be a 5-14 membered heteroaryl group, a 5-10 membered heteroaryl group, or a 5-6 membered heteroaryl group. In a heteroaryl group, 1, 2, 3, 4, or 5 heteroatoms may be present as ring constituent atoms. Furthermore, the heteroaryl group may also include cases where carbon atoms and sulfur atoms are substituted with oxygen and nitrogen, for example, carbon atoms and sulfur atoms may be substituted with C(=O), S(=O), S(=O)2, and S(=O)(=N). Heteroaryl groups include monocyclic heteroaryl groups and fused-ring heteroaryl groups. Unless otherwise specified, a certain-membered heteroaryl group includes any monocyclic, fused-ring, fully aromatic, or partially aromatic group that can be formed. Monocyclic heteroaryl groups are 5-7 membered heteroaryl groups and 5-6 membered heteroaryl groups. Examples include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazini groups.In some embodiments, a condensed heteroaryl group refers to a group formed by the condensation of a monocyclic heteroaryl ring with a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group. The condensed heteroaryl group is an 8-12 membered heteroaryl group or a 9-10 membered heteroaryl group. Examples include benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiadiazolyl, benzothiazolyl, synnolinyl, 5,6-dihydroquinoline-2-yl, 5,6-dihydroisoquinoline-1-yl, and phlopyridyl This includes, but is not limited to, a nyl group, an indazolyl group, an indolyl group, an isoindolyl group, an isoquinolinyl group, a naphthilidinyl group, a prinyl group, a quinolinyl group, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolinyl group, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, a thienopyridyl group, a 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl group, and a 6,7-dihydro[c][1,2,5]oxadiazole-4(5H)onyl group. The heteroaryl group may also be a divalent group derived from the above groups.

[0603] The "5-14 membered cyclic group" described in this invention refers to a group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring constituent atoms, and may be the case when the cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl ring group, or heteroaryl group of this invention has 5-14 ring constituent atoms. Specifically, it may be a 5-10 membered cyclic group or a 5-6 membered cyclic group. Furthermore, the "5-6 membered cyclic group" described in this invention refers to a cyclic structure of 5-6 possible cyclic atoms in the chemical structure, and the cyclic atoms are arbitrarily selected from C, N, O, S, C(=O), S(=O), S(=O)2, and S(=O)(=N). The formed cyclic structure may be monocyclic, polycyclic by condensation, saturated, partially saturated, or aromatic. Examples include, but are not limited to, groups derived from pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolan, pentamethylene sulfide, 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, that is, a cyclic group having at least one oxygen atom and 5 or 6 ring constituent atoms.

[0604] In the present invention, "one or more" refers to the number of substituents, which is the total number of chemically substituted positions of the group being substituted, preferably 1-6, more preferably 1-5, even more preferably 1-3, even more preferably 1-2, and even more preferably 1.

[0605] In the phrase "optionally substituted with substituents" as described in the present invention, the number of substituents is 0 (i.e., not substituted), or 1 to the number of all chemically substituted positions of the substituted group, preferably 1-6, more preferably 1-5, even more preferably 1-4, even more preferably 1-3, and even more preferably 1-2 or 1.

[0606] Specifically, the present invention provides compounds represented by general formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof:

[0607] [ka]

[0608] However, W is hydrogen or C is optionally substituted with a substituent. 1-6 Selected from alkyl groups.

[0609] R is the group shown in the following general formula (a'), (b'), or (c'):

[0610] [ka]

[0611] In formula (a'), ring A is a 6-10 membered aryl ring, NR b , a 5-6 membered heteroaryl ring or NR having 1-3 heteroatoms selected from O and S b It exhibits a 5-6 membered heterocycle having 1-4 heteroatoms selected from O and S.

[0612] Q independently represents a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c -OC(O)NR b R c , -NR bC(O)R d -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0613] In equation (a'),

[0614] [ka]

[0615] The portion is bonded by a bonding group.

[0616] [ka]

[0617] It combines with the parts.

[0618] In equation (a'), X 6 , X 7 Each of them independently performs CR a R a , C=O and NR b They are selected from among and at least one of them is C=O.

[0619] In equation (b'),

[0620] [ka]

[0621] The portion is bonded by a bonding group.

[0622] [ka]

[0623] It combines with the parts.

[0624] In equation (c'),

[0625] [ka]

[0626] The portion is bonded by a bonding group.

[0627] [ka]

[0628] Join with a part; X 1 , X 2 , X 3 Each of them independently performs CR a R a , C=O and NR b They are selected from among and at least one of them is C=O.

[0629] X 4 , X 5 Each of them independently performs CR a Or selected from N.

[0630] M 1 M 2 Each of these is independently substituted with a hydrogen atom or optionally with a substituent. 1-6Alkyl group, optionally substituted with substituents C 1-6 Alkoxyl group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Selected from the alkoxyl group -R', or M 1 and M 2 These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0631] [ka]

[0632] The portion can be formed from hydrogen atoms.

[0633] Cy 2 This can be any one or more R 2 A 3-12 member cycloalkyl group substituted for, optionally one or more R 2 A 3-12 membered cycloalkenyl group is substituted, and one or more R groups are optionally added. 2 A 3-14 member heterocyclic group that is substituted, and one or more R groups as arbitrary. 2 A 6-14 membered aryl group is substituted for and optionally one or more R 2 Selected from 5-10 member heteroaryl groups that are substituted, R 2 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0634] Cy 3 This can be any one or more R 3 A 3-12 member cycloalkyl group substituted for, optionally one or more R 3 A 3-14 membered heterocyclic group is substituted for and one or more R groups are optionally added. 3 Selected from 5-10 member heteroaryl groups that are substituted, R 3 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b Selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups; X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 It may also be a 6-14 member aromatic group substituted for it.

[0635] Cy 4 This can be any one or more R 4 A 3-12 member cycloalkyl group substituted for, optionally one or more R 4 A 3-14 member heterocyclic group that is substituted, and one or more R groups as arbitrary. 4 A 5-14 member heteroaryl group is substituted for and optionally one or more R 4 Selected from 6-14 membered aryl groups that are substituted, R 4 Each of these is independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups, or two R 4 These atoms can bond with each other to form a 5-14 membered cyclic group.

[0636] L is -NR b -, -O-, -S- and -(CR a R a ) m - is chosen from, and m is chosen from integers 1-3.

[0637] R a Either they are absent, or each time they appear, they are independently a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, and -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 -SO2-NR b R c , -SO2R d , -NR b SO2R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 alkoxy group, optionally substituted with substituents C 2-8 Alkenyl group, optionally substituted with substituents C 2-8 Alkynyl group, C optionally substituted with a substituent 1-6Alkyl-R', C is optionally substituted with a substituent. 1-6 Alkoxy groups -R', -O-R', -C(O)-R', -SO2-R', -NR b The group is selected from C(O)-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0638] R b , R c Each of these is either absent or, each time it appears, is independently substituted with a hydrogen atom, a hydroxyl group, or optionally a substituent. 1-6 Alkyl group, C optionally substituted with a substituent 1-6 Selected from alkyl-R', -C(O)-R', -SO2-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0639] R d They are either absent or, each time they appear, independently exist as a hydrogen atom, a halogen atom, and an amino group (C optionally substituted with a substituent). 1-6 (Alkyl group) 1-2 , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Alkyl group, C optionally substituted with substituents 1-6 Alkyl-R', C is optionally substituted with a substituent. 1-6 The group is selected from alkoxy groups -R', -O-R', optionally substituted 3-12 member cycloalkyl groups, optionally substituted 3-12 member cycloalkenyl groups, optionally substituted 3-14 member heterocyclic groups, optionally substituted 6-14 member aryl groups, and optionally substituted 5-10 member heteroaryl groups.

[0640] R' is independently selected from a 3-12 member cycloalkyl group, a 3-12 member cycloalkenyl group, a 3-14 member heterocyclic group, a 6-14 member aryl group, and a 5-10 member heteroaryl group, each of which can be optionally substituted with a substituent.

[0641] q is an integer between 0 and 4.

[0642] n is an integer between 0 and 4.

[0643] In the phrase "arbitrarily substituted with substituents," the substituents are, independently of each other, a hydroxyl group, a mercapto group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylalkyl group C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 Alkyl(2 amino groups, C) 1-6 Alkylamino group carbonyl group, (C 1-6 Alkyl group) 2 amino group carbonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl group oxy group, C 1-6 Alkyl carbonyl group, amino group, C 1-6 Alkyl sulfonyl amino group, halogenated C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkoxy group, C 1-6 Alkyl sulfonyl group, C 1-6 The group is selected from alkylthio groups, 3-12 membered cycloalkyl groups, 6-14 membered aryl groups, 3-12 membered heterocyclic groups, 5-10 membered heteroaryl groups, and oxo groups.

[0644] In the groups shown in formulas (a'), (b'), and (c'):

[0645] [ka]

[0646] This indicates an arbitrary double bond region in the ring structure.

[0647] The conditions are as shown in the bases of formulas (a') and (c'):

[0648] [ka]

[0649] The part does not form a hydrogen atom.

[0650] The condition is that in the base shown in equation (b'), X 1 and X 3 X is chosen from C=O. 4 If is selected from N, Cy 2 R as a substituent 2 The fact that it does not show a halogen atom.

[0651] In another embodiment of the present invention, the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts, esters, stereoisomers, and tautomers are represented by the following formula (II).

[0652] [ka]

[0653] In another embodiment of the present invention, the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts, esters, stereoisomers, and tautomers are represented by the following formula (III).

[0654] [ka]

[0655] Y2 and Y 3 Each is independently selected from CH or N, and at least one is N.

[0656] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0657] In another embodiment of the present invention, the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts, esters, stereoisomers, and tautomers are represented by the following formula (IV).

[0658] [ka]

[0659] Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0660] t 2 , t 3 , t 4 Each of these is independently chosen from integers between 1 and 5.

[0661] One embodiment of the present invention, M 1 M 2 Each of these is independently substituted with a hydrogen atom or optionally with a substituent. 1-6 C is substituted with alkyl groups and optionally with substituents. 2-8 Selected from alkenyl groups, or M 1 and M 2 These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0662] [ka]

[0663] The portion can be formed from hydrogen atoms.

[0664] One embodiment of the present invention, M 1 M 2 Each of these C atoms can be independently and arbitrarily substituted with a substituent. 1-6 Selected from alkyl groups, or M 1 and M 2 These can form 3-8 membered cycloalkyl groups that are optionally substituted with substituents on atoms that bond to them, or

[0665] [ka]

[0666] The portion can be formed from hydrogen atoms.

[0667] One embodiment of the present invention, M 1 M 2 Each is independently C 1-6 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0668] One embodiment of the present invention, X 1 is NR b X 2 CR a R a X 3 C=O.

[0669] One embodiment of the present invention, X 1 CR a R a X 2 is NR b X 3 C=O.

[0670] One embodiment of the present invention, X 1 C=O and X 2 CR a R a X 3C=O.

[0671] One embodiment of the present invention, X 1 CR a R a X 2 C=O and X 3 C=O.

[0672] One embodiment of the present invention, X 1 CR a R a X 2 CR a R a X 3 C=O.

[0673] One embodiment of the present invention, X 1 C=O and X 2 CR a R a X 3 CR a R a That is the case.

[0674] One embodiment of the present invention, X 1 CR a R a X 2 C=O and X 3 CR a R a That is the case.

[0675] One embodiment of the present invention, X 4 X is selected from N. 5 CR a They are selected from among them.

[0676] One embodiment of the present invention, X 4 CR a Selected from X 5 CR a They are selected from among them.

[0677] One embodiment of the present invention, X 4 X is selected from N.5 It is selected from N.

[0678] One embodiment of the present invention, X 4 CR a Selected from X 5 It is selected from N.

[0679] One embodiment of the present invention, X 6 C=O and X 7 CR a R a That is the case.

[0680] One embodiment of the present invention, X 6 CR a R a X 7 C=O.

[0681] One embodiment of the present invention, X 6 C=O and X 7 is NR b That is the case.

[0682] One embodiment of the present invention, X 6 is NR b X 7 C=O.

[0683] In one embodiment of the present invention, in formula (a'), ring A represents a 6-10 membered aryl ring.

[0684] In one embodiment of the present invention, in formula (a'), ring A represents a benzene ring and a naphthalene ring.

[0685] In one embodiment of the present invention, in formula (a'), ring A represents 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, a pyridine ring, a pyridazine ring, a 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.

[0686] In one embodiment of the present invention, in formula (a'), Q is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , C which can be optionally substituted with substituents 1-6 C is substituted with alkyl groups and optionally with substituents. 1-6 Selected from alkoxyl groups.

[0687] One embodiment of the present invention, Cy 2 This can be any one or more R 2 A 6-14 membered aryl group is substituted for and optionally one or more R 2 It is selected from 5-10 member heteroaryl groups that are substituted.

[0688] One embodiment of the present invention, Cy 2 This can be any one or more R 2 The group to be substituted is selected from either a phenyl group or a naphthyl group.

[0689] One embodiment of the present invention, Cy 3 This can be any one or more R 3 A 3-8 membered cycloalkyl group is substituted for and optionally one or more R 3 Selected from 5-10 member heteroaryl groups to be substituted, X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 It may also be a 6-10 member aromatic group that is substituted.

[0690] One embodiment of the present invention, Cy 3 This can be any one or more R 3 A 3-6 member cycloalkyl group substituted for, optionally one or more R 3 Selected from 5-6 member heteroaryl groups to be substituted, X 1 or X 2 is NR b When indicating Cy 3 This can be any one or more R 3 The substituted group may be a phenyl group or a naphthyl group.

[0691] One embodiment of the present invention, Cy 3 This can be any one or more R 3 A pyrrolyl group substituted with, optionally one or more R 3 A pyridine group substituted with, optionally one or more R 3 A pyrimidyl group substituted with, optionally one or more R 3 A pyridazine group substituted with or optionally one or more R 3 It is selected from the pyrazine groups that are substituted.

[0692] One embodiment of the present invention, Cy 3 This can be any one or more R 3 Replaced with

[0693] [ka]

[0694] Selected from the bases shown, in the formula,

[0695] [ka]

[0696] Y indicates a single bond or a double bond. 2 , Y 3 , Y 6 and Y 7 Each of them independently performs CR a R a or NRb Selected from and at least one of them is NR b That is the case.

[0697] One embodiment of the present invention, Cy 3 This can be any one or more R 3 Replaced with

[0698] [ka]

[0699] The group shown is Y 2 , Y 3 , Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N.

[0700] One embodiment of the present invention, Cy 3 This can be any one or more R 3 The following bases are selected to be substituted:

[0701] [ka]

[0702] One embodiment of the present invention, Cy 3 This can be any one or more R 3 The following bases are selected to be substituted:

[0703] [ka]

[0704] *The ends are connected to N, and the · ends are connected to L.

[0705] One embodiment of the present invention, Cy 4 This can be any one or more R 4 A 5-10 membered heterocyclic group that is substituted, and one or more R groups as arbitrary. 4A 5-10 member heteroaryl group is substituted for and optionally one or more R 4 It is selected from 6-10 membered aryl groups that are substituted.

[0706] One embodiment of the present invention, Cy 4 This can be any one or more R 4 A 9-10 heteroaryl group substituted for or one or more R groups. 4 The group to be substituted is selected from either a phenyl group or a naphthyl group.

[0707] One embodiment of the present invention, Cy 4 This can be any one or more R 4 Replaced with

[0708] [ka]

[0709] The base shown is represented in the formula,

[0710] [ka]

[0711] Y indicates a single bond or a double bond. 4 and Y 5 Each of them independently performs CR a R a or NR b Selected from and at least one is NR b Ring B is a benzene ring, a naphthalene ring, or a 5-6 membered heteroaryl ring.

[0712] One embodiment of the present invention, Cy 4 This can be any one or more R 4 Replaced with

[0713] [ka]

[0714] The group shown is Y 4 and Y 5 Each is independently selected from CH or N, and at least one is N.

[0715] In one embodiment of the present invention, ring B is a benzene ring or NR b It is a 5-6 membered heteroaryl ring containing 1-3 atoms selected from O and S.

[0716] One embodiment of the present invention, Cy 4 This can be any one or more R 4 The following bases are selected to be substituted:

[0717] [ka]

[0718] One embodiment of the present invention, Cy 4 This can be any one or more R 4 The following bases are selected to be substituted:

[0719] [ka]

[0720] One embodiment of the present invention, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)OR d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxy groups.

[0721] One embodiment of the present invention, R 2Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups; preferably, R 2 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0722] One embodiment of the present invention, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxy groups.

[0723] One embodiment of the present invention, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkoxy groups; preferably, R 3 Each of these is independently a hydrogen atom, a hydroxyl group, fluorine, chlorine, bromine, and C. 1-4 Selected from alkyl groups.

[0724] One embodiment of the present invention, R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and -NR. b R c , -C(O)Rd -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxy groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered cyclic group.

[0725] One embodiment of the present invention, preferably, R 4 Each of these is independently a hydrogen atom, a hydroxyl group, a halogen atom, and C 1-6 Alkyl group, hydroxyl group C 1-6 Alkyl group, amino group C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkylalkyl group C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Selected from alkoxy groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0726] One embodiment of the present invention, R 4 C is a hydrogen atom, a hydroxyl group, a mercapto group, a halogen atom, and 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 1-4 Alkoxy group C 1-4 Alkyl alkyl group, C 1-4 Alkylalkyl group C 1-4 Alkoxy group, C 1-4 Alkoxy group C 1-4 Alkoxy group, halogenated C 1-4 Selected from alkoxy groups, or two R groups 4 These atoms can bond with each other to form a 5-6 membered oxygen-containing cyclic group.

[0727] One embodiment of the present invention, R a They are either absent or, each time they appear, independently represent a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, and -NR. b R c , -C(O)R d -C(O)NR b R c , -NR b C(O)R d , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups.

[0728] One embodiment of the present invention, R a They are either absent, or each time they appear, they are independently a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Selected from alkyl groups.

[0729] One embodiment of the present invention, R a They do not exist, or each time they appear, they independently form a hydrogen atom, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups.

[0730] One embodiment of the present invention, R b , R c Each of these is either absent or, each time it appears, is independently substituted with a hydrogen atom or optionally a substituent. 1-6 Selected from alkyl groups.

[0731] One embodiment of the present invention, R b , R c Each of them either does not exist or appears independently of the hydrogen atom and C. 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Selected from alkoxy groups.

[0732] One embodiment of the present invention, Rb , R c Each of them either does not exist or appears independently of the hydrogen atom and C. 1-6 Selected from alkyl groups.

[0733] One embodiment of the present invention, R d Either they are absent, or each time they appear, they are independently a hydroxyl group, a halogen atom, an amino group, and a C-amino group (optionally substituted with a substituent). 1-6 (Alkyl group) 1-2 , C which can be optionally substituted with substituents 1-6 Alkyl group, optionally substituted with substituents C 1-6 Selected from alkoxyl groups.

[0734] One embodiment of the present invention, R d They are either absent or appear independently as hydroxyl group, amino group, and -amino group (C) each time they appear. 1-6 (Alkyl group) 1-2 , C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group, halogenated C 1-6 Selected from alkoxyl groups.

[0735] One embodiment of the present invention, R d They are either absent or, each time they appear, independently exist as a hydroxyl group, an amino group, and C. 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkyl alkyl group, C 1-4 Alkoxyl group, halogenated C 1-4 Selected from alkoxyl groups.

[0736] In one embodiment of the present invention, R' is selected from optionally substituted 3-8 membered cycloalkyl groups, optionally substituted 3-8 membered cycloalkenyl groups, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 6-10 membered aryl groups, and optionally substituted 5-6 membered heteroaryl groups.

[0737] In one embodiment of the present invention, R' is selected from optionally substituted 3-6 member cycloalkyl groups, optionally substituted 4-7 member heterocyclic groups, optionally substituted 6-10 member aryl groups, and optionally substituted 5-6 member heteroaryl groups.

[0738] In one embodiment of the present invention, R' is selected from cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, oxacyclopropyl group, oxacyclobutyl group, oxacyclopentyl group, oxacyclohexyl group, oxacycloheptyl group, pyrrolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, pyrazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group, and pyridadinyl group.

[0739] In one embodiment of the present invention, the substituents in "optionally substituted with substituents" are independently selected from the following: hydroxyl group, mercapto group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylalkyl group C 1-6 Alkoxy group, C 1-6 Alkoxy group C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 Alkyl(2 amino groups, C) 1-6 Alkylamino group carbonyl group, (C 1-6 (Alkyl group) 2 amino group, carbonyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl group oxy group, C 1-6 Alkyl carbonyl group, amino group, C 1-6 Alkyl sulfonyl amino group, halogenated C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkoxy group, C 1-6 Alkyl sulfonyl group, C 1-6The group is selected from alkylthio groups, 3-8 membered cycloalkyl groups, 6-10 membered aryl groups, 3-8 membered heterocyclic groups, 5-6 membered heteroaryl groups, and oxo groups.

[0740] In one embodiment of the present invention, the substituents in "optionally substituted with substituents" are independently selected from the following: hydroxyl group, mercapto group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylalkyl group C 1-4 Alkoxy group, C 1-4 Alkoxy group C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 Alkyl(2 amino groups, C) 1-4 Alkylamino group carbonyl group, (C 1-4 Alkyl group) 2 amino group carbonyl group, C 1-4 Alkylcarbonyl group, C 1-4 Alkyl carbonyl group oxy group, C 1-4 Alkyl carbonyl group, amino group, C 1-4 Alkyl sulfonyl amino group, halogenated C 1-4 Alkyl alkyl groups, C halogenated compounds 1-4 Alkoxy group, C 1-4 Alkyl sulfonyl group, C 1-4 Alkylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, phenyl group, naphthyl group, oxacyclopropyl group, oxacyclopropyl group, oxacyclopentyl group, oxacyclohexyl group, oxacycloheptyl group, pyrrolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, pyrazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, and oxo group.

[0741] In one embodiment of the present invention, n is 0, 1, 2, 3, or 4.

[0742] In one embodiment of the present invention, q is 0, 1, 2, 3, or 4.

[0743] In one embodiment of the present invention, L is -NR b -, -O-, and -S- are selected.

[0744] In one embodiment of the present invention, R represents a group shown in formula (b'), and the six-membered ring in the group shown in formula (b') is represented by any of the following, in formula

[0745] [ka]

[0746] This indicates a single bond or a double bond.

[0747] [ka]

[0748] In the present invention, the groups represented by formulas (a'), (b'), and (c')

[0749] [ka]

[0750] The symbol indicates an arbitrary double bond region in a ring structure, and the condition is that it does not collide with the valence of any atom.

[0751] In one embodiment of the present invention, in the compound represented by formula (I) of the present invention, three or more N atoms as ring constituent atoms are not directly bonded.

[0752] In one embodiment of the present invention, in the compound represented by formula (I) of the present invention, two or more carbonyl groups (C=O) in the ring are not directly bonded.

[0753] In one embodiment of the present invention, in the ring of formula (a'), there is only one C=O.

[0754] In one embodiment of the present invention, in the ring of formula (b'), there is only one C=O.

[0755] In one embodiment of the present invention, in the ring of formula (c'), there is only one C=O.

[0756] One embodiment of the present invention, X 1 , X 2 Each of them independently performs CR a R a and NR b Selected from X 3 This indicates C=O.

[0757] One embodiment of the present invention, X 1 or X 2 If C=O, then X 4 is NR b isn't it.

[0758] One embodiment of the present invention, X 4 is NR b isn't it.

[0759] One embodiment of the present invention, X 1 and X 2 At least one of them is NR b X 3 This indicates C=O.

[0760] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester formed by the compound according to the present invention, and more specifically, esters such as formic acid esters, acetate esters, propionic acid esters, butyric acid esters, acrylic acid esters, and ethyl succinate esters of the compound according to the present invention, but is not limited to these.

[0761] The "pharmaceutically acceptable salt" described in this invention refers to an addition salt of a pharmaceutically acceptable acid and base or its solvide. Such pharmaceutically acceptable salts include 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 alkanic acid (e.g., acetic acid, HOOC-(CH2)). n This includes salts of acids such as -COOH (where n is between 0 and 4). Salts of bases include sodium salts, potassium salts, calcium salts, ammonium salts, etc. Those skilled in the art will be familiar with a wide variety of non-toxic, medicinal addition salts.

[0762] The hydrogen atom, fluorine atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom, etc. in this invention further include their respective radioisotopes or stable isotopes.

[0763] The tumors described in the present invention include sarcomas, lymphomas, and cancers, and specifically include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, colonic trophoblastoma, melanoma, cell tumors, and sarcomas.

[0764] The "NTRK-induced related diseases" described in this invention include non-small cell lung cancer, colorectal cancer, similar secretory breast cancer, sarcoma, astrocytoma, glioblastoma, Spitzian melanoma, cholangiocarcinoma, papillary thyroid cancer, secretory breast cancer, and breast cancer of unknown pathological type.

[0765] In this invention, the description "A / and B" refers to A alone or both A and B. For example, "TAM family kinase / and CSF1R kinase" means either "TAM family kinase" alone or both "TAM family kinase" and "CSF1R kinase".

[0766] The "stereoisomers" of the compounds of formulas (I), (II), (III), and (IV) of the present invention refer to enantiomers that occur when asymmetric atoms are present in the compounds of formulas (I), (II), (III), and (IV); cis-trans isomers that occur when carbon-carbon double bonds or cyclic structures are present in the compounds; and all enantiomers, diastereomers, meso or racemic isomers, cis-trans isomers, geometric isomers, epiisomers, and mixtures thereof of the compounds of formulas (I), (II), (III), and (IV) are included in the scope of the present invention. The definition of a compound according to the present invention includes all possible stereoisomers and mixtures thereof, particularly separated optical isomers having specified activity in racemic form. Racemic forms can be separated by physical means, for example, by classification crystallization, separation of diastereomer derivatives, or separation by crystallization or chiral column chromatography. Individual optical isomers can be obtained from racemic forms by conventional methods (e.g., chlorination with optically active acids, adhesion crystallization).

[0767] The "tautomers" of the compounds of formulas (I), (II), (III), and (IV) of the present invention refer to functional group isomers that arise when a certain atom in the compounds of formulas (I), (II), (III), and (IV) rapidly moves between two positions; ketone tautomers that arise when the α-hydrogen of a functional group containing a carbonyl group is located at the α-carbon; and enol tautomers that arise when the α-hydrogen of a functional group containing a carbonyl group is located at the oxygen of the carbonyl group.

[0768] The drug composition of the present invention comprises at least one of the compounds represented by formula (I), formula (II), formula (III), and formula (IV), or their pharmaceutically acceptable salts, esters, stereoisomers, and tautomers.

[0769] The drug composition of the present invention comprises compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, and one or more optionally selected drug carriers.

[0770] The drug composition of the invention can be administered to patients or test subjects in need of prevention and / or treatment by any suitable administration method known in the industry, such as oral, extra-gastrointestinal (including subcutaneous, intramuscular, intravenous, intra-arterial, intradermal, intrasacral and epidural), percutaneous, rectal, nasal, transpulmonary, local (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration.

[0771] The drug composition of the present invention can be prepared in the form of conventional solid formulations such as tablets, capsules, pills, and granules; or it can be prepared in the form of oral liquid formulations such as oral solutions, oral suspensions, and syrups. When prepared as an oral formulation, one or more substances such as appropriate excipients, diluents, sweeteners, solubilizers, lubricants, adhesives, tablet disintegrants, stabilizers, preservatives, or sealing materials may be added. For extra-gastrointestinal administration, the drug composition can be prepared as an injectable, sterile powder for injection, and concentrated solution for injection. When prepared as an injectable, it can be produced using the conventional methods of the pharmaceutical industry, and when preparing the injectable, adducts may be omitted or appropriate adducts may be added depending on the properties of the drug. For rectal administration, the drug composition can be prepared as a suppository or the like. For pulmonary administration, the drug composition can be prepared as an inhalant or spray or the like. In the present invention, suitable solid carriers include, but are not limited to, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, trantogum, acacia gum, sodium alginate, parahydroxybenzoic acid esters, methylcellulose, carboxymethylcellulose, low-melting-point waxes, cocoa butter, and the like. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerides, and mixtures thereof.

[0772] The drug compositions of the present invention are manufactured by commonly known methods. Known methods for manufacturing the drug compositions of the present invention include conventional mixing, granulation, tableting, coating, dissolution, or freeze-drying methods.

[0773] The drug formulation is preferably in unit dose form. In this form, the formulation is divided into unit doses containing an appropriate amount of the active ingredient. The unit dose form can be packaged in packaging that contains discrete amounts, such as packaged tablets, capsules, or powders in small bottles or ampoules.

[0774] The dosage of a drug depends on various factors, including the patient's age, weight, condition, and route of administration. The exact dosage is determined at the discretion of the treating physician. Typical doses of the active compound may be, for example, approximately 0.01 to 100 mg per day, approximately 0.05 to 75 mg / day, approximately 0.1 to 50 mg / day, or approximately 5 to 10 mg / day. The desired dose also depends on the specific compound used, the severity of the disease, the route of administration, the patient's weight and health condition, and the judgment of the treating physician.

[0775] Method for preparing the compound of general formula (I) of the present invention

[0776] The compounds according to the present invention can be prepared by several methods, including standard chemical methods. Unless otherwise specified, previously defined variables continue to have the previously defined meaning. Exemplary conventional synthesis methods are described in the following embodiments, but they can be easily improved to prepare other compounds of the present invention. Those skilled in the art can carry out the following reactions by conventional methods known in the art (e.g., Organic Synthesis 2nd, Michael B. Smith, etc.). The compounds of the present invention are specifically prepared in the Examples section.

[0777] The method for preparing the compound represented by general formula (I) is as follows:

[0778] [ka]

[0779] Add formula (Ia) to the solvent, add the peptide coupling reagent, alkali, and formula (Ib), stir to allow complete reaction, and separate to obtain formula (I). Alternatively,

[0780] Formulas (Ia) and (Ib) are added to an alkali, a coupling reagent is added dropwise, and the mixture is stirred to allow a complete reaction. The mixture is then separated to obtain formula (I).

[0781] However, M 1 M 2 , R, n, W, Cy 3 , L and Cy 4 This is as defined above.

[0782] The solvent is selected from one of the following and mixtures thereof: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ethyl ether, dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, butanol, water.

[0783] The alkali is selected from one of the following and mixtures thereof: methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, methylpyridine, and quinoline.

[0784] The peptide coupling reagent is selected from one of the following and a mixture thereof: 2-(7-azobenzotriazole)-tetramethylurea hexafluoride phosphate (HATU), benzotriazole-N,N,N',N'-tetramethylurea hexafluoride phosphate (HBTU), and 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TBTU).

[0785] The coupling reagent is selected from one of the following: phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, 1-n-propyl phosphoric anhydride, and mixtures thereof.

[0786] The intermediate for the preparation of the compound of general formula (I) has the structure shown in formula (Ia) or formula (Ic) below:

[0787] [ka]

[0788] However, R 1 is C 1-6 It is an alkyl group.

[0789] X 1 , X 2 , X 3 , X 4 , X 5 M 1 M 2 , R, Cy 2 , n and

[0790] [ka]

[0791] This is as defined above.

[0792] Reaction equation

[0793] [ka]

[0794] The compound of formula (I) can be prepared by the reaction of the compound of formula (Ia) with the compound of formula (Ib).

[0795] [ka]

[0796] However, M 1 M 2 , R, n, W, Cy 3 , L and Cy 4 This is as defined above.

[0797] Those skilled in the art can prepare compound (I) from compound (Ia) and compound (Ib) by conventional methods of the art, and below, an exemplary method for preparing compound (I) by reaction of compound (Ia) and compound (Ib) is provided:

[0798] For example, the compound of formula (Ia) is added to a suitable solvent (e.g., tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide), a suitable peptide coupling reagent (preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoride phosphate), and then a suitable alkali (e.g., triethylamine, pyridine, N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine) is added. The mixture is then cooled to a suitable temperature (e.g., 0°C), stirred for a suitable time (e.g., 10-30 minutes), the compound of formula (Ib) is added, and the mixture is stirred at a suitable temperature (e.g., 0°C to room temperature) for a suitable time (e.g., 1-16 hours). The reaction mixture is concentrated under reduced pressure, an appropriate amount of water is added, and the mixture is extracted using a suitable extractant (e.g., ethyl acetate). The extract is concentrated, and the crude product is separated by a conventional purification method (e.g., silica gel column chromatography) to obtain the compound of formula (I).

[0799] Furthermore, for example, the compounds of formula (Ia) and formula (Ib) are added to a suitable alkali (e.g., pyridine), the mixture is cooled to a suitable temperature (e.g., 0°C), a coupling reagent (e.g., phosphorus oxychloride) is added dropwise, the mixture is stirred for a suitable time (e.g., 0.5 to 3 hours) until the reaction is complete, the reaction mixture is concentrated under reduced pressure, an appropriate amount of water is added, the mixture is extracted using a suitable extractant (e.g., ethyl acetate), the extract is concentrated, and the crude product is separated by a normal purification method (e.g., silica gel column chromatography) to obtain the compound of formula (I).

[0800] The compound of formula (Ia) can be prepared from the compound of formula (Ic).

[0801] [ka]

[0802] However, R1 is C 1-6 It is an alkali group, M 1 M 2 R and n are as defined above. Those skilled in the art can prepare the compound of formula (Ia) from the compound of formula (Ic) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ia) from the compound of formula (Ic) is provided:

[0803] For example, the compound of formula (Ic) is dissolved in a suitable solvent (e.g., methanol, ethanolamine, tetrahydrofuran, dioxane, preferably methanol), a suitable alkali (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably lithium hydroxide) is added, the mixture is stirred at a suitable temperature (e.g., room temperature) for a suitable time (e.g., 0.5 to 3 hours), the reaction is completed, the mixture is concentrated under reduced pressure, the pH is adjusted to a suitable range (e.g., 2 to 5) using an aqueous solution of a suitable acid (e.g., hydrochloric acid, citric acid), and the mixture is filtered to obtain the compound of formula (Ia).

[0804] The compound of formula (Ic) can be prepared by the reaction of the compound of formula (Id) with the compound of formula (Ie).

[0805] [ka]

[0806] However, R and R1 are as defined above, LG is a leaving group such as chlorine, bromine, iodine, methanesulfonic acid ester or benzenesulfonic acid ester, or boric acid, boric acid ester, M 1 M 2 And n are as defined above. Those skilled in the art can prepare the compound of formula (Ic) from the compound of formula (Id) and the compound of formula (Ie) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ic) by the reaction of the compound of formula (Id) and the compound of formula (Ie) is provided:

[0807] For example, the compound of formula (Id) and the compound of formula (Ie) (LG is a leaving group) are dissolved in a suitable solvent (e.g., acetonitrile, tetrahydrofuran, N,N-dimethylformamide, preferably N,N-dimethylformamide), a suitable alkali (e.g., sodium carbonate, potassium carbonate, cesium carbonate, preferably potassium carbonate) is added, and the mixture is stirred and reacted at a suitable temperature (e.g., 50°C) for a suitable time (e.g., 10-16 hours). After the reaction is complete, water and a suitable extractant are added, and the crude product is separated by a conventional purification method (e.g., silica gel column chromatography) to obtain the compound of formula (Ic).

[0808] Furthermore, for example, the compound of formula (Id) and the compound of formula (Ie) (LG being boric acid or a boric acid ester) are dissolved in a suitable solvent (e.g., acetonitrile, dichloromethane, chloroform, pyridine, N,N-dimethylformamide, preferably N,N-dimethylformamide), a suitable alkali (e.g., triethylamine, pyridine, etc.) and a suitable catalyst (e.g., copper acetate, copper chloride, etc.) are added, and the mixture is reacted under air or oxygen conditions at a suitable temperature (e.g., from room temperature to 50°C) for a suitable time (e.g., 14 hours). After the reaction is complete, the crude product is obtained by conventional work-up (e.g., extraction, concentration), and the final product is obtained by conventional purification methods (e.g., silica gel column chromatography).

[0809] The compound of formula (Ib) can be prepared by the reaction of the compound of formula (I-b') with W-LG.

[0810] [ka]

[0811] However, Cy 3 , L, Cy 4 W and LG are as defined above. Those skilled in the art can prepare the compound of formula (Ib) from the compound of formula (I-b') by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ib) from the compound of formula (I-b') is provided:

[0812] For example, the compounds of formula (I-b') and formula W-LG are dissolved in a suitable solvent (e.g., acetonitrile, tetrahydrofuran, N,N-dimethylformamide, preferably N,N-dimethylformamide), a suitable alkali (e.g., sodium carbonate, potassium carbonate, cesium carbonate, preferably potassium carbonate) is added, and the mixture is stirred and reacted at a suitable temperature (e.g., 50°C) for a suitable time (e.g., 10-16 hours). After the reaction is complete, water and a suitable extractant are added, and the crude product is separated by a conventional purification method (e.g., silica gel column chromatography) to obtain the compound of formula (Ib).

[0813] The compound of formula (Ib) can be prepared by reacting it with the compound of formula (If).

[0814] [ka]

[0815] However, Cy 3 , L and Cy 4 The above definition is as described above. Those skilled in the art can prepare compound (Ib) from compound (If) by conventional methods of the art, and below, an exemplary method for preparing compound (Ib) from compound (If) is provided:

[0816] For example, the compound of formula (If) and a suitable reducing agent (e.g., iron powder, zinc powder, stannous chloride, sodium dithionite, preferably iron powder) are placed in a suitable solvent (e.g., ethanol, aqueous ammonium chloride solution, acetic acid, a mixture of ethanol and aqueous ammonium chloride solution, etc.) and reacted at a suitable temperature (e.g., 80°C) for a suitable time (e.g., 4 hours). After the reaction is complete, the mixture is filtered, concentrated under reduced pressure, extracted using a suitable extractant (e.g., dichloromethane), and concentrated under reduced pressure to obtain the product.

[0817] The compound of formula (If) can be prepared by the reaction of the compound of formula (Ig) and the compound of formula (Ih).

[0818] [ka]

[0819] However, L, Cy 4 Cy 3 And LG are as defined above. Those skilled in the art can prepare the compound of formula (If) from the compound of formula (Ig) and the compound of formula (Ih) by ordinary methods of the art, and below, an exemplary method for preparing the compound of formula (If) from the compound of formula (Ig) and the compound of formula (Ih) is provided:

[0820] For example, the compound of formula (Ig) and the compound of formula (Ih) are placed in a suitable solvent (e.g., tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide), a suitable alkali (e.g., potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, preferably potassium carbonate) is added, and the mixture is stirred at a suitable temperature (e.g., room temperature to 80°C) for a suitable time (e.g., 14 hours). After the reaction is complete, the crude product is obtained by a conventional work-up method (e.g., filtration, extraction, etc.), and the product is separated by a conventional purification method (e.g., silica gel column chromatography).

[0821] In several implementations, the compound of formula (Ib) can be prepared by the following reaction.

[0822] [ka]

[0823] However, LG, Cy 3 , L, Cy 4 And W are as defined above. Those skilled in the art can prepare the compound of formula (Ib) from the compound of formula (Il) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ib) from the compound of formula (Il) is provided:

[0824] For example, the compound of formula (Il) and the compound of formula (Ik) are placed in a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, preferably xylene), heated to a suitable temperature (e.g., 140°C), and stirred for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (Ii) is obtained by a normal workup method (e.g., filtration, extraction, etc.).

[0825] The compound of formula (Ii) and the compound of formula (Ij) are placed in a suitable solvent (e.g., ethanol, water, etc.), heated to a suitable temperature (e.g., 90°C), and after the reaction is complete, the compound of formula (Ib) is obtained by a standard workup method (e.g., concentration, extraction, filtration, etc.).

[0826] Specifically, if R is the group shown in general formula (b), the compound of formula (Ic) can be prepared by the following reaction.

[0827] [ka]

[0828] In several implementations, the compound of formula (Ic) can be prepared by the following reaction.

[0829] [ka]

[0830] However, X 1 , X 2 , X 5 , X 4 Each is independently selected from C, CH, or CH2, and X 3 C=O, and R 2 is an alkoxyl group or a double-substituted amino group, Cy 2 , R 1 M 1 M 2 And n are as defined above. Those skilled in the art can prepare the compound of formula (Ic) from the compound of formula (Im) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ic) from the compound of formula (Im) is provided:

[0831] For example, the compound of formula (Im) is placed in a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, preferably toluene), a suitable reagent (e.g., N,N-dimethylformamide dimethylal, trimethyl orthoformate, triethyl orthoformate, preferably N,N-dimethylformamide dimethylal) is added, and the mixture is heated to a suitable temperature (e.g., 100°C) and stirred for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (In) is obtained by a normal work-up method (e.g., filtration, extraction, concentration, etc.).

[0832] The compounds of formula (In) and formula (Io) are placed in a suitable solvent (e.g., ethanol, isopropanol, toluene, etc.), heated to a suitable temperature (e.g., 100°C), and reacted for a suitable time (e.g., 3 hours). After the reaction is complete, the compound of formula (Ic) is obtained by a standard purification method (e.g., silica gel column chromatography).

[0833] In several other implementations, the compound of formula (Ic) can be prepared by the following reaction.

[0834] [ka]

[0835] However, X 1 , X 5 , X 4 Each is independently selected from C, CH, or CH2, and X 3 C=O and Cy 2 , R 1 M 1 M 2 And n are as defined above. Those skilled in the art can prepare the compound of formula (Ic) from the compound of formula (Ip) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Ic) from the compound of formula (Ip) is provided:

[0836] For example, the compound of formula (Ip) and the compound of formula (Iq) are placed in a suitable solvent (e.g., dichloromethane, chloroform, 1,2-dichloroethane, preferably dichloromethane), the temperature is lowered to a suitable temperature (e.g., 0°C), a suitable alkali (e.g., potassium carbonate, sodium carbonate, sodium hydroxide, preferably potassium carbonate) is added, the temperature is slowly raised to room temperature, and the reaction is allowed to proceed for a suitable time (e.g., 3 to 15 hours). After the reaction is complete, the compound of formula (Ir) is obtained by a conventional purification method (e.g., silica gel column chromatography).

[0837] The compound of formula (Ir) is placed in a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, preferably toluene), and a suitable reagent (e.g., N,N-dimethylformamide dimethylal, trimethyl orthoformate, triethyl orthoformate, preferably N,N-dimethylformamide dimethylal) is added. The mixture is heated to a suitable temperature (e.g., 110°C) and stirred for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (Ic) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., silica gel column chromatography).

[0838] In several other implementations, the compound of formula (Ic) can be prepared by the following reaction equation.

[0839] [ka]

[0840] However, X 2 , X 5 , X 4 Each is independently selected from C, CH, or CH2, and X 3 C=O and Cy 2 , R 1 M 1 M 2 And n are as defined above. Those skilled in the art can prepare the compound of formula (Ic) from the compound of formula (Is) by ordinary methods of the art, and below, an exemplary method for preparing the compound of formula (Ic) from the compound of formula (Is) is provided:

[0841] For example, the compound of formula (Is) and the compound of formula (It) are placed in a suitable solvent (e.g., methanol, ethanol, isopropanol, preferably ethanol) and reacted at a suitable temperature (e.g., 80°C) for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (Iu) is obtained by a conventional purification method (e.g., silica gel column chromatography).

[0842] The compound of formula (Iu) is placed in a suitable solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, preferably 2-methyltetrahydrofuran), cooled to a suitable temperature (e.g., 0°C), a suitable alkali (e.g., sodium hydroxide, sodium butanol, potassium butanol, sodium ethanol, preferably sodium butanol) is added, and then the temperature is raised to a suitable temperature (e.g., room temperature) and stirred for a suitable time (e.g., 15 hours). After the reaction is complete, the reaction mixture is adjusted to a suitable pH value (e.g., 5-6), and the compound of formula (Iv) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., silica gel column chromatography).

[0843] The compound of formula (Iv) is placed in a suitable solvent (e.g., acetonitrile), a suitable oxidizing agent (e.g., copper chloride) is added, and the mixture is heated to a suitable temperature (e.g., 80°C) and reacted for a suitable time (e.g., 2-4 hours). After the reaction is complete, the compound of formula (Ic) is obtained by conventional workup methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., silica gel column chromatography).

[0844] Here, the compound of formula (It) can be prepared by the following reaction:

[0845] [ka]

[0846] However, X 2 , X 5 Each is selected from CH or CH2, and PG is a protecting group (e.g., t-butyloxycarbonyl group, benzyloxycarbonyl group, acetyl group, methoxybenzyl, etc.), R 1 M 1 M 2And n are as defined above, and n ≥ 1. Those skilled in the art can prepare the compound of formula (It) from the compound of formula (Iw) by ordinary methods of the art, and below, an exemplary method for preparing the compound of formula (It) from the compound of formula (Iw) is provided:

[0847] For example, the compound of formula (Iw) and the compound of formula (Ix) are placed in a suitable solvent (e.g., dichloromethane, methanol, ethanol, etc., preferably dichloromethane), a suitable acid (e.g., acetic acid) and a dehydrating agent (e.g., magnesium sulfate) are added, and a suitable reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) is added, and the mixture is reacted at a suitable temperature (e.g., room temperature) for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (Iy) is obtained by a normal work-up method (e.g., filtration, extraction, concentration, etc.).

[0848] The compound of formula (Iy) and the compound of formula (Iz) are placed in a suitable solvent (e.g., ethanol) and reacted at a suitable temperature (e.g., 80°C) for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (I-a1) is obtained by conventional workup methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., silica gel column chromatography).

[0849] The compound of formula (I-a1) is treated with an appropriate deprotection method (e.g., acid, alkali, hydrogenation, oxidation, etc.), and the compound of formula (It) is obtained by a normal post-treatment method (e.g., filtration, extraction, concentration, etc.) and a purification method (e.g., recrystallization, silica gel column chromatography, etc.).

[0850] In several other implementations, the compound of formula (I-a1) can be prepared by the following reaction:

[0851] [ka]

[0852] However, X 2 , X 5Each is independently selected from CH or CH2, PG is a protecting group (e.g., t-butyloxycarbonyl group, benzyloxycarbonyl group, acetyl group, methoxybenzyl group, etc.), LG is a leaving group (e.g., benzenesulfonic acid ester, methanesulfonic acid ester, etc.), R1, M 1 M 2 And n are as defined above. Those skilled in the art can prepare the compound of formula (I-a1) from the compound of formula (Io) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (I-a1) from the compound of formula (Io) is provided:

[0853] For example, the compound of formula (Io) is dissolved in a suitable solvent (e.g., ethanol), the compound of formula (Iz) is added at a suitable temperature (e.g., 0°C to room temperature), and the reaction is allowed to proceed for a suitable time (2 to 15 hours). After the reaction is complete, the compound of formula (I-a2) is obtained by conventional workup methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).

[0854] The compound of formula (I-a2) is placed in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), a suitable alkali (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, etc.) is added, the temperature is lowered to a suitable temperature (e.g., -5°C), the compound of formula (I-a3) is added, and the temperature is raised to room temperature and the reaction is carried out for a suitable time (e.g., 14 hours). After the reaction is complete, the compound of formula (I-a1) is obtained by a standard workup method (e.g., filtration, extraction, concentration, etc.) and a purification method (e.g., recrystallization, silica gel column chromatography, etc.).

[0855] If R is the group shown in general formula (b),

[0856] [ka]

[0857] However, X 1 , X 4 , X5 Each is independently selected from C, CH, or CH2, and X 2 is N, and X 3 C=O and Cy 2 The above definition applies. Compounds of formula (Id) can be prepared by the following reaction:

[0858] [ka]

[0859] However, LG is a leaving group (e.g., chlorine), PG is a protecting group (preferably a t-butyloxycarbonyl group), and R 1 The above definition is as described above. Those skilled in the art can prepare the compound of formula (Id) from the compound of formula (I-d3) by conventional methods of the art, and below, an exemplary method for preparing the compound of formula (Id) from the compound of formula (I-d3) is provided:

[0860] For example, the compound of formula (I-d3) is dissolved in a suitable solvent (e.g., ethyl acetate), the temperature is lowered to a suitable temperature (e.g., 0°C), the compound of formula (I-d4) is added, and the temperature is raised to room temperature and the reaction is carried out for a suitable time (e.g., 15 hours). After the reaction is complete, the mixture is quenched by adding a suitable alkali (e.g., potassium carbonate), and the compound of formula (I-d5) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).

[0861] The compound of formula (I-d5) is dissolved in a suitable solvent (e.g., methyl tert-butyl ether), the temperature is lowered to a suitable temperature (e.g., 0°C), a suitable reducing agent (e.g., triphenylphosphine, tri-n-butylphosphine, preferably tri-n-butylphosphine) is added, and the temperature is raised to room temperature and the reaction is carried out for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (I-d6) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).

[0862] The compound of formula (I-d6) is dissolved in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, etc.), the temperature is lowered to a suitable temperature (e.g., 0°C), a suitable alkali (e.g., triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine) and a suitable protecting group reagent (e.g., di-tert-butyl dicarbonate) are added, and the temperature is raised to room temperature and the reaction is allowed to proceed for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (I-d7) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).

[0863] The compound of formula (I-d7) is placed in a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, preferably toluene), and a suitable reagent (e.g., N,N-dimethylformamide dimethylal, trimethyl orthoformate, triethyl orthoformate, preferably N,N-dimethylformamide dimethylal) is added. The mixture is heated to a suitable temperature (e.g., 60°C) and stirred for a suitable time (e.g., 15 hours). After the reaction is complete, the compound of formula (Id) is obtained by conventional work-up methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).

[0864] In the synthesis of compounds according to the present invention, the reaction solvent can be a solvent commonly used in this field, and includes, but is not limited to, ethers, paraffins, halogenated paraffins, aromatics, and alcohols. Specifically, examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, aromatics (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, ethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), water, and mixed solvents thereof.

[0865] In the synthesis of the compounds according to the present invention, the alkalis used are alkalis commonly used in this field, and include organic bases and inorganic bases. Examples of organic bases include methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, methylpyridine, and quinoline; examples of inorganic bases include alkali metal hydrides, carbonates, and bicarbonates (e.g., lithium, sodium, potassium, cesium); alkaline earth metal hydrides, carbonates, and bicarbonates (magnesium, calcium, strontium, barium); and sodium butanol, potassium butanol, and sodium ethanol.

[0866] In the synthesis of compounds according to the present invention, the acids used are commonly used acids in this field and include organic acids and inorganic acids. 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, ascorbic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid; examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and hydroiodic acid.

[0867] In the synthesis of the compounds according to the present invention, the reducing agents used are reducing agents commonly used in this field, and include, but are not limited to, triphenylphosphine, tri-n-butylphosphine, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, iron powder, zinc powder, stannous chloride, sodium dithionite, and hydrogen.

[0868] In the synthesis of the compounds according to the present invention, the oxidizing agents used are commonly used in this field and include, but are not limited to, copper chloride, manganese dioxide, permanganate, dichromate, peracetic acid, and perbenzoic acid.

[0869] In the synthesis of the compounds according to the present invention, the catalyst used is a catalyst commonly used in this field, and includes, but is not limited to, copper acetate, copper chloride, palladium carbon, iron chloride, palladium acetate, and [1,1'-bis(diphenylphosphine group)ferrocene]dipalladium chloride. [Examples]

[0870] The following embodiments and experimental examples will provide a better understanding of the present invention. Furthermore, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and do not limit the scope of protection of the present invention.

[0871] Unless otherwise specified in the examples, the reaction conditions should be carried out under normal conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available, standard products.

[0872] In this invention, unless otherwise specified, (i) temperature is expressed in degrees Celsius (°C), and unless otherwise specified, the operation is carried out at room temperature; (ii) the progress of the reaction is followed up by thin-layer chromatography (TLC) or LC-MS; (iii) the final product has a clear proton nuclear magnetic resonance spectrum. 1 It has 1H-NMR (H-NMR) data and mass spectrometry (MS) data. The abbreviations and English descriptions used in this invention have the following meanings: DAST: N,N-diethylaminosulfur trifluoride DCM: Dichloromethane -Boc:t-butoxycarbonyl group TEA: Triethylamine TBSCl:t-butyldimethylchlorosilane TBS-:t-butyldimethylsilyl group DMSO: Dimethyl sulfoxide NaHMDS: Hexamethyldisilazane sodium TBAF: Tetrabutylammonium fluoride MsCl: Methanesulfonyl chloride TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium Concentrated hydrochloric acid (HCl) NBS: N-bromosuccinimide AIBN: Azobisisobutyronitrile THF: Tetrahydrofuran TMSCN: Trimethylsilylcyanide CPBA: m-chloroperbenzoic acid TMSI: Trimethylsilylimidazole BHT: Dibutylhydroxytoluene Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium dichloride EA: Ethyl acetate EtOH: Ethanol MTBE: Methyl t-butyl ether PE: Petroleum ether HATU: 2-(7-azobenzotriazole)-tetramethylurea hexafluoride phosphate regurgitation: reflux pyridine: pyridine Toluene: Toluene PBu3: Tributylphosphine 1,4-dioxane: 1,4-dioxane DMF-DMA: N,N-dimethylformamide dimethylacetal DIPEA / DIEA: N,N-diisopropylethylamine DEC: Dichloroethane Pd(dppf)Cl 2· CH2Cl2:[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex DMAP: 4-dimethylaminopyridine rt: room temperature

[0873] Example 1: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-formamide (Compound 14)

[0874] [ka]

[0875] Step 1: Synthesis of 2-(4-fluorophenyl)acetyl chloride

[0876] [ka]

[0877] 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) are dissolved in dichloromethane (250.0 mL), the mixture is heated to 60°C under N2 protection, refluxed for 3 hours, and the reaction is indicated as complete by TLC. The reaction mixture is then concentrated under reduced pressure, an appropriate amount of dichloromethane is added, and the mixture is concentrated again. This process is repeated twice to obtain a yellow oily substance.

[0878] Step 2: Synthesis of 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0879] [ka]

[0880] 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) are dissolved in dichloromethane (250.0 mL), the mixture is cooled to 0°C under N2 protection, the crude 2-(4-fluorophenyl)acetyl chloride obtained in the previous step is diluted with dichloromethane (100.0 mL), and slowly added dropwise to the reaction mixture. After addition, the mixture is heated to room temperature, and after 3 hours, the reaction is detected as complete by TLC. The reaction mixture is washed three times with 1 mol / L hydrochloric acid until the pH of the aqueous phase is 3-4, then washed twice with saturated sodium chloride aqueous solution, dried, and concentrated under reduced pressure to obtain a yellow oily substance.

[0881] Step 3: Synthesis of ethyl 4-(4-fluorophenyl)-3-oxobutyrate

[0882] [ka]

[0883] 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione is dissolved in ethanol (250.0 mL), heated to 100°C, refluxed for 3 hours, and indicated as not completely reacted by TLC. Concentrated hydrochloric acid (10.0 mL) is added, and the mixture is reacted for 2 hours. After that, the mixture is indicated as completely reacted by TLC. The reaction mixture is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (PE:EA = 75:1~10:1) to obtain a yellow oily substance (35.0 g, three-step yield: 48.1%).

[0884] Step 4: Synthesis of 5-(dimethylamino)-2-((dimethylamino)methylene)-4-(4-fluorophenyl)-3-oxopentane-4-ethyl phosphate

[0885] [ka]

[0886] Ethyl 4-(4-fluorophenyl)-3-oxobutyrate (2.0 g, 8.92 mmol, 1.0 eq) is dissolved in toluene (20.0 mL), DMF-DMA (3.188 g, 26.76 mmol, 3.0 eq) is added, and the mixture is heated to 100°C and reacted overnight. The reaction is then marked as complete by TLC. The reaction mixture is concentrated under reduced pressure to obtain the product (2.5 g crude product).

[0887] Step 5: Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate ethyl

[0888] [ka]

[0889] 5-(dimethylamino)-2-((dimethylamino)methylene)-4-(4-fluorophenyl)-3-oxopentane-4-enoate ethyl (3.5 g crude product) is dissolved in ethanol (20.0 mL), isopropylamine (791.0 mg, 13.38 mmol, 1.5 eq) is added, and the mixture is heated to 100 °C and reacted for 3 hours. The reaction is indicated as complete by TLC. The reaction mixture is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (PE:EA = 50:1~2:1) to obtain the product (1.0 g, two-step yield: 50%).

[0890] Step 6: Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid

[0891] [ka]

[0892] 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate ethyl (1.0 g, 3.297 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10.0 mL), 1 mol / L aqueous lithium hydroxide solution (5.0 mL) is added, and the mixture is stirred at room temperature for 0.5 hours. The reaction is indicated as complete by TLC. The mixture is concentrated under reduced pressure, the pH is adjusted to 4-5, a large amount of solid precipitates, which is then filtered by suction, and the filtered cake is dried to obtain a white solid product (700.0 mg, yield: 70%).

[0893] Step 7: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-formamide

[0894] [ka]

[0895] 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) were dissolved in N,N-dimethylformamine (2.5 mL), the mixture was cooled to 0°C, HATU (518.0 mg, 1.362 mmol, 1.5 eq) was added under N2 protection, and the mixture was stirred for 0.5 hours. 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-amine (270.0 mg, 0.908 mmol, 1.0 eq) was added, the mixture was slowly heated to room temperature, and after 1 hour, the reaction was indicated as complete by TLC. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed twice with saturated sodium bicarbonate aqueous solution, then washed four times with water, dried, and concentrated under reduced pressure. The crude product was first dissolved in tetrahydrofuran by silica gel column chromatography (DCM:MeOH = 150:1~30:1), 1 mol / L hydrochloric acid was added to adjust the pH to 7~8, the mixture was stirred for 0.5 hours, filtered by suction, the filtered cake was washed with water, and dried to obtain the product (313.0 mg, yield: 62.0%). 1H 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 FN4O5 molecular weight:554.58 LC-MS(Pos,m / z)=555.35 [M+H] + .

[0896] Example 2: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-1-isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-formamide (Compound 1)

[0897] [ka]

[0898] Step 1: Synthesis of 1-isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-carboxylate ethyl

[0899] [ka]

[0900] 4-Oxo-5-paratoluyl-1,4-dihydropyridine-3-carboxylate ethyl (2.00 g, 7.77 mmol, 1.0 eq), isopropyl bromine (1.15 g, 9.33 mmol, 1.2 eq), and K2CO3 (3.22 g, 23.32 mmol, 3.0 eq) were added to DMF (20 mL), stirred, and reacted overnight at 50°C. After detecting completion of the reaction by TLC, the mixture was filtered, the filtrate was washed with dichloromethane, the filtrate was concentrated under reduced pressure, the crude product was dissolved in ethyl acetate (20 mL), washed sequentially with distilled water (10 mL x 4) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1~1:4) to obtain the product (1.60 g, yield: 68.8%).

[0901] Step 2: Synthesis of 1-isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-carboxylic acid

[0902] [ka]

[0903] 1-Isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-carboxylate ethyl (1.60 g, 5.34 mmol, 1.0 eq) is dissolved in methanol (20 mL), and an aqueous solution of lithium hydroxide monohydrate (1.01 g, 24.05 mmol, 4.5 eq) (10 mL) is added. The mixture is stirred at room temperature and allowed to react for 1 hour. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure until a solid precipitate forms. Water is added and the mixture is stirred until the solid dissolves. The pH is adjusted to 3-4 with concentrated hydrochloric acid in an ice bath, and the mixture is stirred for 30 minutes. The mixture is filtered, the filtrate is dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to obtain the product (1.00 g, yield: 69.0%).

[0904] Step 3: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-1-isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-formamide

[0905] [ka]

[0906] Dissolve 1-isopropyl-4-oxo-5-paratoluyl-1,4-dihydropyridine-3-carboxylic acid (200.0 mg, 0.74 mmol, 1.2 eq) in DMF (2 mL), add HATU (350.4 mg, 0.62 mmol, 1.5 eq) and DIPEA (238.2 mg, 1.84 mmol, 3.0 eq), stir for 10 minutes, then add 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine (182.6 mg, 0.62 mmol, 1.0 eq), stir at room temperature and react for 1 hour. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure, and the crude product is dissolved in ethyl acetate (10 mL). The mixture is then washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), water (5 mL x 4), and saturated brine (5 mL). The mixture is dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure. The crude product is purified by thin-layer chromatography (eluent: ethyl acetate) to obtain the final product (216 mg, yield: 53.2%). 1 HNMR (400MHz, 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 N4O5 molecular weight: 550.61 LC-MS(Pos, m / z)= 551.38[M+H] + .

[0907] Example 3: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 15)

[0908] [ka]

[0909] Step 1: Synthesis of 6,7-dimethoxy-4-((6-nitropyridine-3-yl)oxy)quinoline

[0910] [ka]

[0911] 6,7-Dimethoxyquinoline-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 K2CO3 (20.20 g, 146.11 mmol, 2.0 eq) were added to DMF (120 mL), and the mixture was stirred at 80°C under nitrogen protection and allowed to react overnight. After detecting completion of the reaction by TLC, the mixture was filtered, the filtrate was washed with dichloromethane, the filtrate was concentrated under reduced pressure, and dichloromethane (50 mL) was added to dissolve the filtrate. The mixture was then washed sequentially with distilled water (20 mL x 4) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:9~EA) to obtain the product (4.70 g, yield: 19.6%).

[0912] Step 2: Synthesis of 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-amine

[0913] [ka]

[0914] 6,7-Dimethoxy-4-((6-nitropyridine-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 NH4Cl (9.22 g, 172.32 mmol, 12.0 eq) were added to a mixed solvent of ethanol (100 mL) and water (40 mL), and the mixture was stirred at 80°C and reacted for 4 hours. After detecting completion of the reaction by TLC, the mixture was filtered while still hot, the filtrate was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The aqueous phase was extracted with dichloromethane (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain the product (4.07 g, yield: 95.3%).

[0915] Step 3: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide

[0916] [ka]

[0917] Dissolve 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-dimethoxyquinoline-4-yl)oxy)pyridine-2-amine (192.4 mg, 0.65 mmol, 1.2 eq) in anhydrous pyridine (2 mL), stir for 10 minutes, and slowly add POCl3 dropwise until the solid is dissolved. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate (10 mL), and washed sequentially with 1 mol / L hydrochloric acid (5 mL), saturated sodium bicarbonate aqueous solution (5 mL), water (5 mL x 2), and saturated brine (5 mL). The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the final product (151 mg, yield: 50.4%). 1 H NMR (400MHz, DMSO-d6) 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 FN5O5 molecular weight: 555.57 LC-MS(Pos, m / z)= 556.33[M+H] + .

[0918] Example 4: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 16)

[0919] [ka]

[0920] Step 1: Synthesis of 2-(4-fluorophenyl)acetyl chloride

[0921] [ka]

[0922] 2-(4-fluorophenyl)acetic acid (100.0 g, 0.649 mol, 1.0 eq) was dissolved in dichloromethane (200 mL), thionyl chloride (193.0 g, 1.62 mol, 2.5 eq) was added, and the mixture was stirred at 50°C for 2 hours. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain the product (116.0 g crude product).

[0923] Step 2: Synthesis of ethyl 2-diazo-4-(4-fluorophenyl)-3-oxobutyrate

[0924] [ka]

[0925] 2-(4-fluorophenyl)acetyl chloride (116.0 g crude product) was dissolved in ethyl acetate (50 mL), and 2-diazoethyl acetate (153.3 g, 1344 mmol) was added in an ice bath. The mixture was gradually heated to room temperature and stirred overnight. After detecting completion of the reaction by TLC, saturated potassium carbonate aqueous solution (100 mL) was added dropwise in an ice bath, stirred for 20 minutes, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 60:1) to obtain the final product (60.3 g, 2-step yield: 37.1%).

[0926] Step 3: Synthesis of ethyl 4-(4-fluorophenyl)-2-hydrazono-3-oxobutyrate

[0927] [ka]

[0928] Ethyl 2-diazo-4-(4-fluorophenyl)-3-oxobutyrate (57.1 g, 228 mmol, 1.0 eq) is dissolved in methyl t-butyl ether (270.0 mL), and tributylphosphine (55.4 g, 273 mmol, 1.2 eq) is added in an ice bath. The mixture is gradually heated to room temperature and stirred overnight. After detecting completion of the reaction by TLC, ethyl acetate (150 mL) and water (200 mL) are added, and the mixture is separated. The organic phase is washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to obtain the product (125.3 g crude product).

[0929] Step 4: Synthesis of 2-(1-ethoxy-4-(4-fluorophenyl)-1,3-dioxobutane-2-ylidene)hydrazino-1-carboxylate t-butyl ester

[0930] [ka]

[0931] Ethyl 4-(4-fluorophenyl)-2-hydrazono-3-oxobutyrate (93.0 g crude product) is dissolved in tetrahydrofuran (150 mL), cooled to 0°C in an ice bath, triethylamine (37.2 g, 368 mmol) and di-t-butyl dicarbonate (96.5 g, 442.0 mmol) are added, and DMAP (13.4 g, 110.0 mmol) is added in several batches. The mixture is gradually heated to room temperature and stirred overnight. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure, ethyl acetate (300 mL) and water (500 mL) are added, liquid-liquid is separated, the organic phase is dried over anhydrous sodium sulfate, concentrated to dryness, and the filtrate is concentrated under reduced pressure to obtain the product (52.0 g crude product).

[0932] Step 5: Synthesis of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate

[0933] [ka]

[0934] 2-(1-ethoxy-4-(4-fluorophenyl)-1,3-dioxobutane-2-ylidene)hydrazino-1-carboxylate t-butyl ester (52.0 g crude product) is dissolved in toluene (100 mL), N,N-dimethylformamide dimethyl acetal (35.1 g, 338 mmol, 2.0 eq) is added, and the mixture is stirred overnight at 60°C. After detecting completion of the reaction by LC-MS, the system is cooled to room temperature, filtered by suction, and the filtration cake is dried to obtain the product (22.1 g, three-step yield: 49.8%).

[0935] Step 6: Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl

[0936] [ka]

[0937] 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 isopropyl bromide (6.18 g, 50.3 mmol, 1.5 eq) were added, and the mixture was stirred overnight at 50°C under nitrogen protection. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, ethyl acetate (150 mL) and water (200 mL) were added, liquid-liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified with (petroleum ether:ethyl acetate = 10:1~3:1) to obtain the product (8.49 g, yield: 84.0%).

[0938] Step 7: Synthesis of 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

[0939] [ka]

[0940] 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl (7.47 g, 24.0 mmol, 1.0 eq) was dissolved in methanol (30.0 mL), and an aqueous solution of lithium hydroxide monohydrate (3.08 g, 73.0 mmol, 3.0 eq) (15.0 mL) was added. The mixture was stirred at room temperature and allowed to react for 0.5 hours. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, the pH was adjusted to approximately 4 with hydrochloric acid (1 mol / L, 4.0 mL), the mixture was stirred for 20 minutes, and the mixture was filtered by suction. The filtered cake was dried to obtain the product (6.29 g, yield: 94.8%).

[0941] Step 8: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide

[0942] [ka]

[0943] 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (2.0 g, 7.23 mmol, 1.0 eq) and 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-amine (2.15 g, 7.23 mmol, 1.0 eq) were added to pyridine (8 mL), phosphorus oxychloride (0.5 mL) was added dropwise, and the mixture was stirred for 30 minutes. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, water (50 mL) and ethyl acetate (100 mL x 2) were added, 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 obtain the product (2.1 g, yield: 51.2%). 1H NMR (400 MHz, DMSO-d6) 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 FN6O5 molecular weight: 556.55 LC-MS(Pos, m / z)=557.38[M+H] + .

[0944] Example 5: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-formamide (Compound 20)

[0945] [ka]

[0946] Step 1: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-formamide

[0947] [ka]

[0948] 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-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-amine (487.31 mg, 1.63 mmol, 1.0 eq) were added to pyridine (18 mL), phosphorus oxychloride (0.2 mL) was slowly added dropwise in an ice bath, and the mixture was slowly heated to room temperature and reacted for 3 hours. After detecting completion of the reaction by TLC, ethyl acetate (10 mL) and water (20 mL) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1~10:1) to obtain the product (200.0 mg, yield: 22.1%). 1 HNMR(400MHz, DMSO-d6) 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 FN5O5 molecular weight: 555.57 LC-MS(Pos, m / z)=556.3[M+H] + .

[0949] Example 6: Synthesis of N-(6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-yl)-1-isopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridazine-3-formamide (Compound 29)

[0950] [ka]

[0951] Step 1: Synthesis of 6,7-dimethoxy-4-((5-nitropyridine-2-yl)oxy)quinoline

[0952] [ka]

[0953] 6,7-Dimethoxyquinoline-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 K2CO3 (6.73 g, 48.73 mmol, 2.0 eq) were added to DMF (50 mL) and reacted overnight with stirring at 40°C under nitrogen protection. After detecting completion of the reaction by TLC, the mixture was filtered, the filtrate was washed with dichloromethane, the filtrate was concentrated under reduced pressure, the crude product was dissolved in dichloromethane (20 mL) and methanol (20 mL), dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 80:1~30:1) to obtain the product (0.60 g, yield: 7.52%).

[0954] Step 2: Synthesis of 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-amine

[0955] [ka]

[0956] 6,7-Dimethoxy-4-((6-nitropyridine-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 NH4Cl (717.8 mg, 13.42 mmol, 12.0 eq) were added to a mixed solvent of ethanol (10 mL) and water (5 mL), and the mixture was stirred at 80°C and reacted for 4 hours. After detecting completion of the reaction by TLC, Celite was added and the mixture was filtered while still hot. The filtrate was washed with ethanol, and the filtrate was concentrated under reduced pressure. Dichloromethane (5 mL x 3) was added for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain the product (188.0 mg, yield: 56.6%).

[0957] Step 3: Synthesis of N-(6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-yl)-1-isopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridazine-3-formamide

[0958] [ka]

[0959] Dissolve 1-isopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridazine-3-carboxylic acid (184.6 mg, 0.66 mmol, 1.1 eq) in DMF (2 mL), add HATU (346.4 mg, 0.91 mmol, 1.5 eq) and DIPEA (235.4 mg, 1.82 mmol, 3.0 eq), stir for 10 minutes, add 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-amine (180.6 mg, 0.61 mmol, 1.0 eq), stir at room temperature and react for 1 hour. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure, the crude product is dissolved in ethyl acetate (10 mL), and washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), water (5 mL x 4), and saturated brine (5 mL). The mixture is dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure. The crude product is purified by thin-layer chromatography (DCM:MeOH = 15:1) to obtain the final product (230 mg, yield: 67.9%). 1 H NMR (400MHz, DMSO-d6) 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 FN5O5 molecular weight: 555.57 LC-MS(Pos, m / z)= 556.28[M+H] + .

[0960] Example 7: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-1-cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-formamide (Compound 30)

[0961] [ka]

[0962] Step 1: Synthesis of 5-(dimethylamino)-2-((dimethylamino)methylene)-4-parafluorophenyl-3-oxopentane-4-ethyl phosphate

[0963] [ka]

[0964] 4-Parafluorophenyl-3-oxobutyrate ethyl (5.00 g, 22.30 mmol, 1.0 eq) and DMF-DMA (15.94 g, 133.79 mmol, 6 eq) are added to toluene (50 mL) and stirred at 100°C and reacted overnight. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure to obtain a crude product, which is used in the next step without purification.

[0965] Step 2: Synthesis of 1-cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-carboxylate ethyl

[0966] [ka]

[0967] The crude product of 5-(dimethylamino)-2-((dimethylamino)methylene)-4-parafluorophenyl-3-oxopentane-4-enoate ethyl obtained in the previous step and cyclopropylamine (1.91 g, 33.45 mmol, 1.5 eq) are added to EtOH (30 mL) and stirred at 80°C and reacted overnight. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure, the crude product is dissolved in ethyl acetate (20 mL), washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered by suction, the filtrate is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the product (2.67 g, two-step yield: 39.7%).

[0968] Step 3: Synthesis of 1-cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-carboxylic acid

[0969] [ka]

[0970] 1-Cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-carboxylate ethyl (2.67 g, 8.86 mmol, 1.0 eq) is dissolved in methanol (40 mL), and an aqueous solution of lithium hydroxide monohydrate (1.67 g, 39.87 mmol, 4.5 eq) (20 mL) is added. The mixture is stirred at room temperature for 1 hour to allow the reaction to proceed. After detecting completion of the reaction by TLC, the mixture is concentrated under reduced pressure, water is added and stirred until the solid is completely dissolved, the pH is adjusted to 3-4 with concentrated hydrochloric acid in an ice bath, and the mixture is stirred for 30 minutes. The solid is filtered, dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to obtain the product (1.25 g, yield: 51.6%).

[0971] Step 4: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-1-cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-formamide

[0972] [ka]

[0973] Dissolve 1-cyclopropyl-4-oxo-5-parafluorophenyl-1,4-dihydropyridine-3-carboxylic acid (150.0 mg, 0.55 mmol, 1.1 eq) in DMF (1.5 mL), add HATU (285.0 mg, 0.75 mmol, 1.5 eq) and DIPEA (193.0 mg, 1.50 mmol, 3.0 eq), stir for 10 minutes, add 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-amine (148.0 mg, 0.50 mmol, 1.0 eq), and stir at room temperature for 1 hour to allow the reaction to proceed. After detecting completion of the reaction by TLC, the product was concentrated under reduced pressure, the crude product was dissolved in ethyl acetate (10 mL), and washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), water (5 mL x 4), and saturated saline solution (5 mL). The product was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 15:1) to obtain the final product (140.0 mg, yield: 50.7%). 1 H NMR (400 MHz, DMSO-d6) 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 FN4O5 molecular weight: 552.56 LC-MS (Pos, m / z)=553.25[M+H] + .

[0974] Example 8: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-formamide (Compound 32)

[0975] [ka]

[0976] Step 1: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-formamide

[0977] [ka]

[0978] 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-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-amine (247.8 mg, 0.83 mmol, 1.0 eq) were added to pyridine (4 mL), phosphorus oxychloride (0.3 mL) was added dropwise, and the mixture was stirred for 30 minutes. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, ethyl acetate (20 mL) and water (15 mL) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain the final product (110.0 mg, yield: 23.9%). 1H NMR (400 MHz, DMSO-d6) 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, 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). 2H), 1.08-1.09 (m, 2H). Molecular formula:C 30 H 24 N5O5S Molecular weight:553.55 LC-MS(Pos, m / z)=554.26[M+H] + .

[0979] Example 9: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 31)

[0980] [ka]

[0981] Step 1: Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl

[0982] [ka]

[0983] 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl (2.0 g, 7.627 mmol, 1.0 eq), cyclopropylboric 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) are dissolved in DMF (20.0 mL), reacted overnight with oxygen at 50°C, and the reaction is indicated as complete by TLC. The solution was concentrated under reduced pressure, extracted with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by thin-layer chromatography (DCM:MeOH=40:1) to obtain the final product (38.0 mg, yield: 1.65%).

[0984] Step 2: Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

[0985] [ka]

[0986] 1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl (38.0 mg, 0.126 mmol, 1.0 eq) is dissolved in tetrahydrofuran (1.0 mL), and lithium hydroxide aqueous solution (1 mol / L) is added. The mixture is reacted at room temperature for 1 hour and indicated as completely reacted by TLC. The reaction mixture is concentrated under reduced pressure, and water (15.0 mL) and ethyl acetate (6.0 mL x 2) are added for extraction. The organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the product (59.0 mg crude product).

[0987] Step 3: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide

[0988] [ka]

[0989] 1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (59.0 mg crude product) and N,N-diisopropylethylamine (48.7 mg, 0.377 mmol, 3.0 eq) are dissolved in DMF (1.0 mL), cooled to 0°C, and HATU (71.7 mg, 0.188 mmol, 1.5 eq) is added under nitrogen protection. The mixture is stirred at 0°C for 0.5 hours, and 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-2-amine (37.0 mg, 0.126 mmol, 1.0 eq) is added. The mixture is reacted at room temperature for 3 hours and indicated as completely reacted by TLC. The reaction mixture was added to water (20.0 mL), and ethyl acetate (10.0 mL x 2) was added for extraction. The organic phase was then washed sequentially with saturated sodium carbonate aqueous solution (3.0 mL), saturated ammonium chloride aqueous solution (3.0 mL), and saturated sodium chloride solution (3.0 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain the final product (40.0 mg, two-step yield: 57.5%). 1 H NMR (400 MHz, DMSO-d6) 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 FN5O5 molecular weight:553.55 LC-MS(Pos, m / z)=554.32 [M+H]+ .

[0990] Example 10: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 33)

[0991] [ka]

[0992] Step 1: Synthesis of 1-cyclopropyl-N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide

[0993] [ka]

[0994] 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-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-amine (217.5 mg, 0.729 mmol, 1.0 eq) were dissolved in pyridine (4.0 mL), the mixture was cooled to 0°C, phosphorus oxychloride (0.2 mL) was added dropwise under nitrogen protection, and the mixture was reacted at room temperature for 0.5 hours. Complete reaction was indicated by TLC. The reaction mixture was added to water (20.0 mL), the pH was adjusted to 6-7, ethyl acetate (10.0 mL x 2) was added for extraction, the organic phase was washed with 2 mol / L hydrochloric acid solution (2.0 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1-20:1) to obtain the final product (200.0 mg, yield: 49.5%). 1H NMR (400 MHz, DMSO-d6) 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 FN6O5 molecular weight: 554.54 LC-MS(Pos, m / z)=554.66 [M+H] + .

[0995] Example 11: Synthesis of N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-5-parafluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 34)

[0996] [ka]

[0997] Step 1: Synthesis of 6,7-dimethoxy-4-((5-nitropyrimidine-2-yl)oxy)quinoline

[0998] [ka]

[0999] 6,7-Dimethoxyquinoline-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 to DMF (60 mL) and reacted overnight at room temperature with nitrogen protection and stirring. After detecting completion of the reaction by TLC, saturated NH4Cl aqueous solution (30 mL) was added, and the mixture was concentrated under reduced pressure. Saturated saline solution (30 mL) and dichloromethane (20 mL x 3) were added for extraction, and the organic phase was combined. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and 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 obtain the product (1.70 g, yield: 27.5%).

[1000] Step 2: Synthesis of 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-amine

[1001] [ka]

[1002] 6,7-Dimethoxy-4-((5-nitropyrimidine-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 NH4Cl (3.32 g, 62.14 mmol, 12.0 eq) were added to a mixed solvent of ethanol (30 mL) and water (15 mL) and reacted by stirring at 80°C for 2 hours. After detecting completion of the reaction by TLC, the mixture was filtered while still hot, the filtrate was washed with dichloromethane, concentrated under reduced pressure, extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain the product (0.93 g, yield: 60.2%).

[1003] Step 3: Synthesis of N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-5-parafluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-formamide

[1004] [ka]

[1005] Dissolve 5-parafluorophenyl-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (947.4 mg, 3.43 mmol, 1.1 eq) in DMF (12 mL), and while cooling in an ice bath, sequentially add DIPEA (1208.8 mg, 9.35 mmol, 3.0 eq) and HATU (1778.2 mg, 4.68 mmol, 1.5 eq), stir for 10 minutes, then add 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-amine (930.0 mg, 3.12 mmol, 1.0 eq), raise the temperature to room temperature, stir, and allow to react overnight. After detecting completion of the reaction by TLC, the solvent was removed under reduced pressure, ethyl acetate (20 mL) was added to dissolve the mixture, and the mixture was washed sequentially with saturated sodium bicarbonate aqueous solution (10 mL), saturated ammonium chloride aqueous solution (10 mL), distilled water (10 mL x 4), and saturated saline solution (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (developing agent DCM:MeOH = 15:1) to obtain the final product (1410.0 mg, yield: 81.3%). 1 HNMR (400 MHz, DMSO-d6) 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:C29 H 25 FN6O5 molecular weight: 556.55 LC-MS(Pos, m / z)= 557.31[M+H] + .

[1006] Example 12: Synthesis of the intermediate 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl

[1007] [ka]

[1008] Step 1: Synthesis of 1-cyclopropylurea

[1009] [ka]

[1010] Cyclopropylamine (10.0 g, 0.175 mol) and potassium cyanate (16.8 g, 0.21 mol) are added to water (60 mL) and refluxed at 100°C for 30 minutes. The mixture is concentrated under reduced pressure, isopropanol is added, and the mixture is heated to 85°C for 30 minutes. The mixture is filtered, the filtered cake is washed with isopropanol, and the filtrate is concentrated under reduced pressure to obtain the product (6.0 g, yield: 34.3%).

[1011] Step 2: Synthesis of 1-cyclopropyl-1-nitrosourea

[1012] [ka]

[1013] 1-Cyclopropylurea (6.0 g, 60 mmol) and sodium nitrosodium (8.7 g, 126 mmol) were added to water (42 mL), cooled to 0°C in an ice bath, concentrated hydrochloric acid (13.44 mL) was slowly added dropwise, and the mixture was reacted at 0°C for 1 hour. The reaction was detected as complete by TLC. The product was filtered to obtain the product (3.5 g, yield: 45.2%).

[1014] Step 3: Synthesis of ethyl 2-(2-cyclopropylhydrazono)-4-(4-fluorophenyl)-3-oxobutyrate

[1015] [ka]

[1016] 1-Cyclopropyl-1-nitrosourea (3.33 g, 25.8 mmol) and ethyl 4-(4-fluorophenyl)-3-oxobutyrate (4.82 g, 21.5 mmol) were added to dichloromethane (33.3 mL), cooled to 0°C in an ice bath, potassium carbonate (8.92 g, 77.3 mmol) was added, and the mixture was slowly heated to room temperature and reacted for 3 hours. The reaction was then marked as complete by TLC. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 15:1 to 1:1) to obtain the final product (1.5 g, yield: 19.92%).

[1017] Step 4: Synthesis of 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-4-(4-fluorophenyl)-3-oxopentane-4-enoate ethyl

[1018] [ka]

[1019] 2-(2-cyclopropylhydrazono)-4-(4-fluorophenyl)-3-oxobutyrate ethyl (1.5 g, 5.13 mmol) and DMF-DMA (917.8 mg, 7.7 mmol) are added to toluene (10 mL), heated to 110 °C, refluxed overnight, and the reaction is indicated as complete by TLC. The product is concentrated under reduced pressure to obtain the product (1.8 g crude product).

[1020] Step 5: Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl

[1021] [ka]

[1022] 2-(2-cyclopropylhydrazono)-5-(dimethylamino)-4-(4-fluorophenyl)-3-oxopentane-4-enoate ethyl (1.8 g crude product) is added to ethanol (15 mL), heated to 80°C, and allowed to react overnight. After indicating that the reaction is complete by TLC, the product is concentrated under reduced pressure to obtain the final product (1.56 g crude product).

[1023] Example 13: Synthesis of 1-cyclopropyl-N-(6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 36)

[1024] [ka]

[1025] Step 1: Synthesis of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

[1026] [ka]

[1027] 1-Cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate ethyl (1.17 g, 3.87 mmol, 1.0 eq) was added to methanol (10 mL) and stirred until dissolved. Then, an aqueous solution of lithium hydroxide monohydrate (487.0 mg, 11.6 mmol, 3.0 eq) (4 mL) was added and stirred at room temperature for 2 hours. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, the pH was adjusted to 3-4 with 2 mol / L hydrochloric acid (5 mL), and the mixture was extracted with DCM (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (903.5 mg, yield: 85%).

[1028] Step 2: Synthesis of 1-cyclopropyl-N-(6-((6,7-dimethylquinoline-4-yl)oxy)pyridine-3-yl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-formamide

[1029] [ka]

[1030] 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-dimethoxyquinoline-4-yl)oxy)pyridine-3-amine (274.2 mg, 0.92 mmol, 1.1 eq) were added to pyridine (4 mL), phosphorus oxychloride (0.1 mL) was added dropwise, and the mixture was stirred for 5 minutes. After detecting completion of the reaction by TLC, the mixture was concentrated under reduced pressure, ethyl acetate (50 mL) and water (70 mL) were added, and the mixture was separated. The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the product (122.0 mg, two-step yield: 26.5%). 1H NMR (400 MHz, DMSO-d6) 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 FN5O5 molecular weight: 553.55 LC-MS(Pos, m / z)=553.80[M+H] + .

[1031] Example 14: Synthesis of 1-cyclopropyl-N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-5-parafluorophenyl-4-oxo-1,4-dihydropyridazine-3-formamide (Compound 37)

[1032] [ka]

[1033] Step 1: Synthesis of 1-cyclopropyl-N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-5-parafluorophenyl-4-oxo-1,4-dihydropyridazine-3-formamide

[1034] [ka]

[1035] Dissolve 1-cyclopropyl-5-parafluorophenyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (190.0 mg, 0.69 mmol, 1.0 eq) in DMF (3 mL), and while cooling in an ice bath, sequentially add DIPEA (211.5 mg, 2.08 mmol, 3.0 eq) and HATU (395.1 mg, 1.04 mmol, 1.5 eq), stir for 10 minutes, then add 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-amine (207.0 mg, 0.69 mmol, 1.0 eq), raise the temperature to room temperature, stir, and react overnight. After detecting completion of the reaction by TLC, the solvent is removed under reduced pressure, ethyl acetate (10 mL) is added to dissolve the solid, and the mixture is washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), distilled water (5 mL x 4), and saturated brine (5 mL). The mixture is dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure. The crude product is purified by thin-layer chromatography (developing agent DCM:MeOH = 15:1) to obtain the final product (90.0 mg, yield: 23.4%). 1 HNMR (400 MHz, DMSO-d6) 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 FN6O5 molecular weight: 554.54 LC-MS(Pos, m / z)= 554.79[M+H] + .

[1036] Example 15: Synthesis of N-(6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-yl)-6-parafluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide (Compound 38)

[1037] [ka]

[1038] Step 1: Synthesis of N-(6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-yl)-6-parafluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide

[1039] [ka]

[1040] Dissolve 6-parafluorophenyl-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (150.0 mg, 0.54 mmol, 1.0 eq) in DMF (3 mL), and while cooling in an ice bath, sequentially add DIPEA (164.8 mg, 1.63 mmol, 3.0 eq) and HATU (309.7 mg, 0.81 mmol, 1.5 eq), stir for 10 minutes, then add 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyridine-3-amine (177.6 mg, 0.59 mmol, 1.1 eq), raise the temperature to room temperature, stir, and react overnight. After detecting completion of the reaction by TLC, the solvent was removed under reduced pressure, ethyl acetate (10 mL) was added to dissolve the mixture, and the solution was washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), distilled water (5 mL x 4), and saturated saline solution (5 mL). The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 15:1) to obtain the final product (205.0 mg, yield: 68.0%). 1HNMR(400MHz, DMSO-d6) 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 FN5O5 molecular weight: 555.57 LC-MS(Pos, m / z)= 556.26[M+H] + .

[1041] Example 16: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide (Compound 39)

[1042] [ka]

[1043] Step 1: Synthesis of N-(5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide

[1044] [ka]

[1045] 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) and stirred until dissolved. Then 5-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-2-amine (118.7 mg, 0.39 mmol, 1.1 eq) and phosphorus oxychloride (0.2 mL) were added and stirred at room temperature for 10 minutes. After detecting completion of the reaction by TLC, water (40 mL) and ethyl acetate (60 mL) were added to the system, liquid-liquid-liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=15:1) to obtain the product (123.0 mg, yield: 61.1%). 1 HNMR(400 MHz, DMSO-d6) 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 FN6O5 molecular weight:556.55 LC-MS(Pos,m / z)=557.24[M+H] + .

[1046] Example 17: Synthesis of N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide (Compound 40)

[1047] [ka]

[1048] Step 1: Synthesis of N-(2-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-yl)-6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-formamide

[1049] [ka]

[1050] Dissolve 6-(4-fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (101.9 mg, 0.37 mmol, 1.1 eq) in DMF (3 mL), and while cooling in an ice bath, sequentially add DIPEA (101.8 mg, 1.01 mmol, 3.0 eq) and HATU (191.3 mg, 0.50 mmol, 1.5 eq), stir for 10 minutes, then add 6-((6,7-dimethoxyquinoline-4-yl)oxy)pyrimidine-5-amine (100.0 mg, 0.34 mmol, 1.0 eq), raise the temperature to room temperature, stir, and react overnight. After detecting completion of the reaction by TLC, the solvent was removed under reduced pressure, ethyl acetate (10 mL) was added to dissolve the mixture, and the mixture was washed sequentially with saturated sodium bicarbonate aqueous solution (5 mL), saturated ammonium chloride aqueous solution (5 mL), distilled water (5 mL x 4), and saturated brine (5 mL). The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 15:1) to obtain the final product (90.0 mg, yield: 48.2%). 1 HNMR (400 MHz, DMSO-d6) 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 H25 Molecular weight of FN6O5: 556.55 LC-MS (Pos, m / z) = 557.23 [M+H] + .

[1051] Example 18: Synthesis of Intermediate 6-(4-Fluorophenyl)-2-isopropyl-5-oxo-2,5-dihydropyridazine-4-carboxylic Acid

[1052]

Chemical Structure

[1053] Step 1: Synthesis of t-Butyl 2-Isopropylhydrazine-1-carboxylate

[1054]

Chemical Structure

[1055] Add t-butyl hydrazinecarboxylate (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) to dichloromethane (100 mL). React overnight at room temperature. After detecting the completion of the reaction by TLC, filter and concentrate the filtrate under reduced pressure to obtain the product (25 g, yield: 95.6%).

[1056] Step 2: Synthesis...

Claims

1. Compounds represented by general formula (I), or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof: 【Chemistry 1】 However, W is either hydrogen or C 1-6 Selected from alkyl groups. R is the group shown in the following general formula (b): 【Chemistry 2】 In equation (b), 【Transformation 3】 The portion is bonded by an M 1 and M 2 It bonds with a base. X 1 , X 2 Each of them independently performs CR a , selected from N, and X 3 C=O. X 4 、 and X 5 are each independently C. M 1 M 2 These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form 3-8 membered cycloalkyl groups. Cy 2 R can be any one or more R 2 Selected from the phenyl groups to be substituted, R 2 These are, independently, hydrogen, halogen atom, and C. 1-6 Selected from alkyl groups. Cy 3 R can be any one or more R 3 Replaced with 【Chemistry 4】 Selected from, Y 2 , Y 3 , Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N, R 3 These are, independently, hydrogen, halogen atom, and C. 1-6 Selected from alkyl groups. Cy 4 one or more R 4 Replaced with 【Transformation 5】 Selected from, Y 4 and Y 5 R is independently selected from CH or N, and at least one is N, ring B is a phenyl group, and R 4 These are, independently, hydrogen, halogen atom, and C. 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups. L is chosen from -O-. R a These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups. n is an integer between 0 and 2. In the base shown in formula (b) 【Transformation 6】 This indicates that in the ring structure, the bonds between X1 and X4, and between X2 and X5 are double bonds, while all other bonds between atoms constituting the ring are single bonds.

2. A compound according to claim 1 having the structure shown in the following general formula (II), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, 【Transformation 7】 M 1 M 2 These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form 3-6 membered cycloalkyl groups. Other symbols are as defined in Claim 1.

3. A compound according to claim 1 having the structure shown in general formula (III), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, 【Transformation 8】 However, X 1 , X 2 Each of them independently performs CR a , selected from N, and X 3 C=O. Cy 2 It is selected from the phenyl group. Y 2 and Y 3 Each is independently selected from CH or N, and at least one is N. Cy 4 teeth 【Chemistry 9】 Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group. M 1 M 2 These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form a cyclopropyl group. R 2 These are, independently, hydrogen, halogen atom, and C. 1-6 Selected from alkyl groups. R 3 Each is independently selected from hydrogen. R 4 These are hydrogen and C, respectively, independently. 1-6 Selected from alkoxy groups. L is chosen from -O-. R a Each of these is independently selected from hydrogen. n is an integer between 0 and 2. t 2 t4 is independently chosen from integers between 1 and 5, and t3 is chosen from integers between 1 and 3. 【Chemistry 10】 This indicates that in the ring structure, the bonds between X1 and X4, and between X2 and X5 are double bonds, while all other bonds between atoms constituting the ring are single bonds.

4. A compound according to claim 1 having the structure shown in general formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 11】 However, X 1 , X 2 Each of them independently performs CR a , selected from N, and X 3 C=O. Cy 2 It is selected from the phenyl group. Y 6 and Y 7 Each is independently selected from CH or N, and at least one is N. Cy 4 teeth 【Chemistry 12】 Selected from, Y 4 and Y 5 The elements are independently selected from CH or N, and at least one is N, and ring B is a phenyl group. M 1 M 2 These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form a cyclopropyl group. R 2 These are, independently, hydrogen, halogen atom, and C. 1-6 Selected from alkyl groups. R 3 Each is independently selected from hydrogen. R 4 These are hydrogen and C, respectively, independently. 1-6 Selected from alkoxy groups. L is chosen from -O-. R a Each of these is independently selected from hydrogen. n is an integer between 0 and 2. t 2 t4 is independently chosen from integers between 1 and 5, and t3 is chosen from integers between 1 and 3. 【Chemistry 13】 This indicates that in the ring structure, the bonds between X1 and X4, and between X2 and X5 are double bonds, while all other bonds between atoms constituting the ring are single bonds.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, However, W is selected from hydrogen. X 1 , X 2 Each of them independently performs CR a Or selected from N, X 3 C=O. X 4 C is C. M 1 and M 2 are each independently selected from hydrogen, C 1-4 alkyl groups, or M 1 and M 2 can form a 3- to 6-member cycloalkyl group with the atoms to which they are attached. Cy 2 R can be any one or more R 2 Replaced with 【Chemistry 14】 selected from, R 2 are each independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl groups. Cy 3 R can be any one or more R 3 Replaced with 【Chemistry 15】 Selected from, R 3 Each is independently selected from hydrogen. Cy 4 one or more R 4 Replaced with 【Chemistry 16】 They are selected from among them. R 4 These are hydrogen and C, respectively, independently. 1-4 Selected from alkoxy groups. L is -O- R a Each of these is independently selected from hydrogen. n is an integer between 0 and 1.

6. The compound described in claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, However, W is selected from hydrogen. X 1 , X 2 CR a Or selected from N, X 3 C=O. X 4 It will be selected from C. M 1 M 2 These are hydrogen and C, respectively, independently. 1-4 Selected from alkyl groups, or M 1 and M 2 These atoms can bond with each other to form 3-6 membered cycloalkyl groups. Cy 2 R can be any one or more R 2 Replaced with 【Chemistry 17】 Selected from, R 2 These are hydrogen, fluorine, chlorine, and C, respectively, independently. 1-4 Selected from alkyl groups. Cy 3 R can be any one or more R 3 Replaced with [Chemistry 18] Selected from, R 3 Each is independently selected from hydrogen. Cy 4 one or more R 4 Replaced with 【Chemistry 19】 Selected from, R 4 These are hydrogen and C, respectively, independently. 1-4 Selected from alkoxy groups. L is -O- R a Each of these is independently selected from hydrogen. n is an integer between 0 and 1.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, X 1 is N, and X 2 CR a X 3 Is C=O, or X 1 CR a X 2 is N, and X 3 Is C=O, or X 1 CR a X 2 CR a X 3 C=O.

8. A compound according to claim 1, which is selected from the structures shown below, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】

9. A drug composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

10. The drug composition according to claim 9, further comprising one or more second therapeutic agents, wherein the second therapeutic agent is an antimetabolite, a growth factor inhibitor, a mitotic inhibitor, an antitumor hormone, an alkylating agent, a metal, a topoisomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, an immune checkpoint, or an antibody or small molecule drug related to tumor immunotherapy.

11. The use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a drug composition according to claim 9, in the preparation of a drug for the treatment or prevention of a signaling pathway disorder-related disorder due to abnormal expression of a TAM family kinase receptor or its ligand, wherein the signaling pathway disorder-related disorder due to abnormal expression of a TAM family kinase receptor or its ligand includes tumors, ectopic endometriosis, vascular disease or injury, psoriasis, visual impairment or lesions, kidney disease, rheumatoid arthritis, and osteoporosis.

12. The use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a drug composition according to claim 9, in the preparation of a drug for the treatment or prevention of a signaling pathway disorder-related disorder due to abnormal expression of a TAM family kinase receptor or CSF1R kinase receptor or its ligand, wherein the signaling pathway disorder-related disorder due to abnormal expression of a TAM family kinase or CSF1R kinase receptor or its ligand includes tumors, ectopic endometriosis, vascular disease / injury, psoriasis, visual impairment / lesion, kidney disease, rheumatoid arthritis, and osteoporosis.

13. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a drug composition according to claim 9, in the preparation of a drug for the treatment or prevention of NTRK-related diseases.

14. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a drug composition according to claim 9, in the preparation of a drug for the treatment or prevention of drug-resistant diseases associated with NTRK mutations.

15. A method for preparing a compound represented by general formula (I), wherein, 【Chemistry 25】 Add formula (Ia) to the solvent, add a peptide coupling reagent, alkali, and formula (Ib) and react to obtain the compound shown in formula (I); or, Formulas (Ia) and (Ib) are added to an alkali, a coupling reagent is added dropwise, and the reaction is carried out to obtain the compound shown in formula (I). However, M 1 M 2 , R, n, W, Cy 3 , L and Cy 4 This is as defined in claims 1-7.

16. The method according to claim 15, The solvent is selected from one of the following and mixtures thereof: N,N-dimethylformamine, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ethyl ether, dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, butanol, water. The alkali is selected from one of the following and mixtures thereof: methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, methylpyridine, and quinoline. The peptide coupling reagent is selected from one of the following and a mixture thereof: 2-(7-azobenzotriazole)-tetramethylurea hexafluoride phosphate (HATU), benzotriazole-N,N,N',N'-tetramethylurea hexafluoride phosphate (HBTU), and 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TBTU). The coupling reagent is selected from one of the following: phosphorus oxychloride, dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, isobutyl chloroformate, and 1-n-propyl phosphoric anhydride, or a mixture thereof.

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