Nitrogen-containing heteroaryl derivative, preparation method therefor, and use thereof in medicine

Abstract

The present disclosure relates to a nitrogen-containing heteroaryl derivative, a preparation method therefor, and a use thereof in medicine. Specifically, the present disclosure relates to a nitrogen-containing heteroaryl derivative represented by general formula (IA), a preparation method therefor, a pharmaceutical composition containing the derivative, and a use as a therapeutic agent, in particular, a use as an FGFR2 inhibitor and a use in the preparation of a drug for treating and / or preventing FGFR2-mediated tumors.

Description

Nitrogen-containing heteroaryl derivatives, preparation methods thereof and their applications in medicine

[0001] This application claims the Chinese patent application filed with the China Patent Office on November 17, 2023, with application number 202311547369.X and invention name “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and their use in medicine”, the Chinese patent application filed with the China Patent Office on December 4, 2023, with application number 202311649562.4 and invention name “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and their use in medicine”, and the Chinese patent application filed with the China Patent Office on January 26, 2024, with application number 202410117469.7 and invention name “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and their use in medicine”. The present invention relates to a Chinese patent application entitled “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and applications in medicine”, a Chinese patent application filed with the Patent Office of China on May 11, 2024, with application number 202410586553.3 and invention name “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and applications in medicine”, and a Chinese patent application filed with the Patent Office of China on November 11, 2024, with application number 202411606541.9 and invention name “Nitrogen-containing heteroaryl derivatives, preparation methods thereof and applications in medicine”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to the field of medicine and relates to a nitrogen-containing heteroaryl derivative, a method for preparing the same, and its use in medicine. Specifically, the present disclosure relates to a nitrogen-containing heteroaryl derivative represented by general formula (IA), a method for preparing the same, a pharmaceutical composition containing the same, and its use as a therapeutic agent, particularly as an FGFR2 inhibitor and in the preparation of a medicament for treating and / or preventing tumors. Background Art

[0003] Fibroblast growth factor receptors (FGFRs) belong to the receptor protein tyrosine kinase (RTK) family. The FGFR family mainly includes four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. After binding to their ligands, fibroblast growth factors (FGFs), they undergo dimerization and autophosphorylation, thereby activating numerous downstream signaling pathways, including RAS / MAPK, PI3K / AKT, JAK / STAT, PKC, JNK, and SRC. Through these signaling pathways, the FGFR family regulates key physiological processes in the body, such as cell survival, proliferation, migration, differentiation, and metabolism (Pacini L, et al. Cell. 2021).

[0004] FGFR family members undergo mutations in 5-10% of tumor patients, including gene amplification (CNA), gene fusion, and gene mutation. FGFR1 / 2 / 3 gene fusion mutations have been shown to be drivers of specific tumors and are closely associated with tumor development and progression (Xue WJ, et al. Future Med Chem. 2018). Currently, four FGFR small molecule inhibitors have been approved for marketing: pan-FGFR1-4 inhibitors (Erdafitinib, Futibatinib) and pan-FGFR1-3 inhibitors (Pemigatinib, Infigratinib). These pan-FGFR inhibitors are primarily approved for the clinical treatment of patients with urothelial carcinoma harboring FGFR2 or FGFR3 gene fusion mutations, and cholangiocarcinoma harboring FGFR2 gene fusion mutations. According to clinical trial data, the overall response rate (ORR) of pan-FGFR inhibitors in the targeted patient population is 23-43%, and the median duration of response (mDOR) is 5-9 months; however, pan-FGFR inhibitors are highly toxic. In clinical trials, about 50% of patients need to interrupt medication or reduce their dosage. The most common toxicity, hyperphosphatemia, comes from the inhibition of FGFR1 by pan-FGFR inhibitors. Mechanistically, inhibiting the signal transduction of the FGF23 / FGFR1 signaling pathway in the proximal renal tubules will inhibit the renal reabsorption of phosphate by regulating the sodium-dependent phosphate transport protein, thereby increasing the phosphate concentration in the blood (Kommalapati A, et al. Cancers (Basel). 2021). 60-77% of clinical cancer patients taking pan-FGFR inhibitors experience hyperphosphatemia. Although statistically, most cases are grade 1-2, this is the result of dose interruptions or reductions, as well as the concomitant use of numerous hyperphosphatemia-controlling medications. Patients must continuously monitor changes in blood phosphate levels during medication use. The development of FGFR2 or FGFR3 selective inhibitors is expected to significantly reduce the incidence of hyperphosphatemia, reducing the burden on patients and improving their quality of life. Further increasing the tolerated dose to achieve better therapeutic outcomes will greatly enhance their clinical development significance.

[0005] FGFR2 or FGFR3 gene fusion variants have been clinically demonstrated to be drivers of cholangiocarcinoma (10-20% carry FGFR2 fusions) and urothelial carcinoma (6% carry FGFR3 fusions) that harbor these biomarkers. Currently, pan-FGFR inhibitors are primarily approved for these two indications. However, other FGFR2 or FGFR3 gene mutations also warrant attention. For example, FGFR2 mutations are found in 12%, 4%, and 4% of patients with endometrial cancer, non-small cell lung cancer, and gastric cancer, respectively. Furthermore, 5-10% of gastric cancer patients harbor FGFR2 gene amplification variants (Xue WJ, et al. Future Med Chem. 2018). Exploration of pan-FGFR inhibitors in this area has not yet been successful. Whether selective FGFR2 inhibitors can improve efficacy and benefit patients with tumors harboring FGFR2 mutations and amplifications also warrants further investigation.

[0006] RELAY currently holds the only patent (WO2020231990A1) for a selective FGFR2 inhibitor. In 2020, RELAY's small molecule FGFR2 inhibitor, RLY4008, entered Phase I clinical trials. Currently, no FGFR2 selective inhibitors have been approved for marketing, and significant unmet medical needs remain for patients with this condition. Summary of the Invention

[0007] The object of the present disclosure is to provide a compound represented by general formula (IA), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof;

[0008] in:

[0009] Ring A is selected from

[0010] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NRn7 R n8 and Among them, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is independently optionally selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0011] Ring C is selected from 5- to 10-membered heteroaryl, 7- to 14-membered aryl, 5- to 14-membered heterocyclyl, and 5- to 14-membered cycloalkyl;

[0012] x 1 CR x1 or N;

[0013] x 2 CR x2 or N;

[0014] x 3 CR x3 or N;

[0015] x 4 CR x4 or N;

[0016] x 5 CR x5 or N;

[0017] x 6 CR x6 or N;

[0018] x 7 CR x7 or N;

[0019] x 8 CR x8 or N;

[0020] Ring B is selected from 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0021] L and L 3 The same or different, and each independently selected from a chemical bond, -O-, -NR n7 -、-(CR a Rb ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0022] R is selected from hydrogen atoms, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0023] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogen, cyano, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, halogen, amino, hydroxy, hydroxy 1-6 The alkyl group is substituted by one or more substituents;

[0024] Each R 4 are the same or different and are each independently selected from deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)Rc 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0025] R x 、R x1 、R x2 、R x3 、R x4 、R x5 、R x6 、R x7 and R x8 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0026] G 1 Selected from O, S, N, CR g1 and NR 8b ;

[0027] G 2 C or N;

[0028] G 3 C or N;

[0029] G 4 C or N;

[0030] G 5 C or N;

[0031] G 6 Selected from O, S, N, CR g6 and NR 8b ;

[0032] G 7 Selected from O, S, N, CR g7 and NR 8b ;

[0033] R 7 is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、C 1-6 Alkoxy and halogenated C 1-6 Alkoxy, wherein the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0034] R 8 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0035] or R 7 and R 8 The atoms to which it is attached together form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms, and is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkyl cyano, C 1-6 Alkylamino, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0036] L 1 and L 2 are the same or different and are each independently selected from a chemical bond, -C(R a )=C(R b )-、-C(R a )=N-、-N=C(Rb )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0037] Indicates that when x 6 CR x6 When L 1 and R x6 The connected keys, and L 1 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from deuterium, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C1-6 Alkyl cyano, -OR c and hydroxy C 1-6 One or more substituents in the alkyl group; provided that, n5 The nitrogen atom connected to R x6 The ring atoms between the connected carbon atoms are not -CH2- and -CH2CH2-;

[0038] H 1 Selected from O, S(O) p , N, CR h1 and NR 8b ;

[0039] H 2 、H 3 and H 4 are the same or different and are each independently C or N;

[0040] R 9 O or NR r ;

[0041] J is selected from -NR n1 R n2 、C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyl cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0042] Optionally, when J is -NR n1 R n2 When R n2 and H 1 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c, hydroxy C 1-6 The alkyl group is substituted by one or more substituents, and when x 5 、x 6 、x 7 and x 8 When both are CH, Not for

[0043] Y is N or CR 7b ;

[0044] G is N or CR g ;

[0045] Indicates x 5 The bonds connecting the rings;

[0046] represents the bond connected to ring C;

[0047] Indicates that when x 6 CR x6 When L 2 and R x6 The connected keys, and L 2 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0048] R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0049] R 7c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0050] R 8a Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -OR c , halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkyl cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0051] R 8b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0052] R g1 、R g6 、R g7 、R g and R h1 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, -ORc 、C 2-6 Alkenyl, C 2- 6-Alkynyl, halo-C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0053] Optionally, J and H 1 , or R 7a With R 8b , or R 7b With R g , or R 7c With R g Each independently forms a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0054] R a and R b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0055] R c are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0056] R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2- 6-alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, -NR n7 R n8 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0057] R 5 、R r 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0058] or R n1 and R n2 、R n3 and R n4 、R n5 and R n6 、R n7 and R n8 、R n7a and R n8a Together with the nitrogen atoms to which they are attached, they each form a 3- to 8-membered heterocyclic group;

[0059] Optionally, R n6 with x 6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O)p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0060] n is 0, 1, 2, 3 or 4;

[0061] m is 0, 1, 2, 3 or 4;

[0062] p is 0, 1, or 2;

[0063] q is 0, 1, 2, 3, or 4;

[0064] The proviso is that the general formula (IA) is not the following compounds, whose CAS numbers are 2924721-14-0, 2920599-68-2, 2920601-26-7, 2924721-16-2, 2939840-00-1, 2939840-08-9, 2920599-66-0, 2939839-78-6 and 2939840-05-6, respectively.

[0065] The object of the present disclosure is to provide a compound represented by general formula (IA), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof;

[0066] in:

[0067] Ring A is selected from

[0068] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c、-S(O) p R c 、-S(O) p NR n7 R n8 and Among them, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is independently optionally selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0069] Ring C is selected from 5- to 10-membered heteroaryl, 7- to 14-membered aryl, 5- to 14-membered heterocyclyl, and 5- to 14-membered cycloalkyl;

[0070] x 1 CR x1 or N;

[0071] x 2 CR x2 or N;

[0072] x 3 CR x3 or N;

[0073] x 4 CR x4 or N;

[0074] x 5 CR x5 or N;

[0075] x 6 CR x6 or N;

[0076] x 7 CR x7 or N;

[0077] x 8 CR x8 or N;

[0078] Ring B is selected from 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0079] L and L 3The same or different, and each independently selected from a chemical bond, -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0080] R is selected from hydrogen atoms, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a Rn8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0081] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogen, cyano, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, halogen, amino, hydroxy, hydroxy 1-6 The alkyl group is substituted by one or more substituents;

[0082] Each R 4 are the same or different and are each independently selected from deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0083] R x 、R x1 、R x2 、R x3 、R x4 、R x5 、R x6 、R x7 and R x8 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8, 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0084] G 1 Selected from O, S, N, CR g1 and NR 8b ;

[0085] G 2 C or N;

[0086] G 3 C or N;

[0087] G 4 C or N;

[0088] G 5 C or N;

[0089] G 6 Selected from O, S, N, CR g6 and NR 8b ;

[0090] G 7 Selected from O, S, N, CR g7 and NR 8b ;

[0091] R 7 is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NRn7 R n8 、C 1-6 Alkoxy and halogenated C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0092] R 8 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0093] or R 7 and R 8 The atoms to which it is attached together form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms, and is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkyl cyano, C 1-6 Alkylamino, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0094] L 1 and L 2are the same or different and are each independently selected from a chemical bond, -C(R a )=C(R b )-、-C(R a )=N-、-N=C(R b )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0095] Indicates that when x 6 CR x6 When L 1 and R x6 The connected keys, and L 1 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from deuterium, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 One or more substituents in the alkyl group; provided that, n5 The nitrogen atom connected to R x6 The ring atoms between the connected carbon atoms are not -CH2- and -CH2CH2-;

[0096] H 1 Selected from O, S(O) p , N, CR h1 and NR 8b ;

[0097] H 2 、H 3 and H 4 are the same or different and are each independently C or N;

[0098] R is O or NR r ;

[0099] J is selected from -NR n1 R n2 、C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyl cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0100] Optionally, when J is -NR n1 R n2 When R n2 and H 1 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NRn7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents, and when x 5 、x 6 、x 7 and x 8 When both are CH, Not for

[0101] Y is N or CR 7b ;

[0102] G is N or CR g ;

[0103] Indicates x 5 The bonds connecting the rings;

[0104] Indicates x 1 The bonds connecting the rings;

[0105] Indicates that when x 6 CR x6 When L 2 and R x6 The connected keys, and L 2 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0106] R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 Rn8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0107] R 7c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0108] R 8a Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -OR c , halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkyl cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0109] R 8b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0110] R g1 、Rg6 、R g7 、R g and R h1 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2- 6-Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0111] Optionally, J and H 1 、R 7a With R 8b , or R 7b With R g , or R 7c With R g Each independently forms a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0112] R a and R b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0113] Rc are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0114] R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2- 6-alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, -NR n7 R n8 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0115] R 5 、R r 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0116] or R n1 and R n2 、R n3 and R n4 、R n5 and R n6 、R n7 and R n8 、R n7a and R n8a Together with the nitrogen atoms to which they are attached, they each form a 3- to 8-membered heterocyclic group;

[0117] Optionally, R n6 with x 6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0118] n is 0, 1, 2, 3 or 4;

[0119] m is 0, 1, 2, 3 or 4;

[0120] p is 0, 1, or 2;

[0121] q is 0, 1, 2, 3 or 4; provided that the general formula (IA) is not the following compounds, the CAS numbers of the following compounds are 2924721-14-0, 2920599-68-2, 2920601-26-7, 2924721-16-2, 2939840-00-1, 2939840-08-9, 2920599-66-0, 2939839-78-6 and 2939840-05-6, respectively.

[0122] In another aspect, the present disclosure provides a compound represented by general formula (IA), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof;

[0123] in:

[0124] Ring A is selected from

[0125] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)Rc 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 and Among them, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is independently optionally selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0126] Ring C is selected from 5- to 10-membered heteroaryl, 7- to 14-membered aryl, 5- to 14-membered heterocyclyl, and 5- to 14-membered cycloalkyl;

[0127] x 1 CR x1 or N;

[0128] x 2 CR x2 or N;

[0129] x 3 CR x3 or N;

[0130] x 4 CR x4 or N;

[0131] x 5 CR x5 or N;

[0132] x 6 CR x6 or N;

[0133] x 7 CR x7 or N;

[0134] x 8 CR x8 or N;

[0135] Ring B is selected from 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0136] L and L 3 The same or different, and each independently selected from a chemical bond, -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0137] R is selected from hydrogen atoms, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0138] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0139] Each R 4 The same or different, and each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0140] R x 、R x1 、R x2 、R x3 、R x4 、R x5 、R x6 、R x7 and R x8 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0141] G 1 Selected from O, S, N, CR g1 and NR 8b ;

[0142] G 2 C or N;

[0143] G 3 C or N;

[0144] G 4 C or N;

[0145] G 5 C or N;

[0146] G 6 Selected from O, S, N, CR g6 and NR 8b ;

[0147] G 7 Selected from O, S, N, CR g7 and NR 8b ;

[0148] R 7 is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、C 1-6 Alkoxy and halogenated C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NRn7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0149] R 8 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0150] or R 7 and R 8 The atoms to which it is attached together form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms, and is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkyl cyano, C 1-6 Alkylamino, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0151] L 1 and L 2 are the same or different and are each independently selected from a chemical bond, -C(R a )=C(R b )-、-C(R a )=N-、-N=C(R b )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a Rb )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0152] Indicates that when x 6 CR x6 When L 1 and R x6 The connected keys, and L 1 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 One or more substituents in the alkyl group; provided that, n5 The nitrogen atom connected to R x6 The ring atoms between the connected carbon atoms are not -CH2- and -CH2CH2-;

[0153] H 1 Selected from O, S(O) p , N, CRh1 and NR 8b ;

[0154] H 2 、H 3 and H 4 are the same or different and are each independently C or N;

[0155] R is O or NR r ;

[0156] J is selected from -NR n1 R n2 、C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyl cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0157] Optionally, when J is -NR n1 R n2 When R n2 and H 1 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents, and when x 5 、x 6 、x 7 and x 8 When both are CH, Not for

[0158] Y is N or CR 7b ;

[0159] G is N or CRg ;

[0160] Indicates x 5 The bonds connecting the rings;

[0161] Indicates x 1 The bonds connecting the rings;

[0162] Indicates that when x 6 CR x6 When L 2 and R x6 The connected keys, and L 2 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0163] R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0164] R 7c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0165] R 8a Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -OR c , halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkyl cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0166] R 8b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0167] R g1 、R g6 、R g7 、R g and R h1 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2- 6-Alkynyl, halo-C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0168] Optionally, J and H 1 、R 7a With R 8b , or R 7b With R g , or R 7c With R g Each independently forms a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0169] R a and R b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0170] R c are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0171] R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2- 6-alkenyl, halogenated C 2-6Alkynyl, halogen, cyano, -NR n7 R n8 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0172] R 5 、R r 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0173] or R n1 and R n2 、R n3 and R n4 、R n5 and R n6 、R n7 and R n8 、R n7a and R n8a Together with the nitrogen atoms to which they are attached, they each form a 3- to 8-membered heterocyclic group;

[0174] Optionally, R n6 with x 6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0175] n is 0, 1, 2, 3 or 4;

[0176] m is 0, 1, 2, 3 or 4;

[0177] p is 0, 1, or 2;

[0178] q is 0, 1, 2, 3 or 4; provided that the general formula (IA) is not the following compounds, the CAS numbers of the following compounds are 2924721-14-0, 2920599-68-2, 2920601-26-7, 2924721-16-2, 2939840-00-1, 2939840-08-9, 2920599-66-0, 2939839-78-6 and 2939840-05-6, respectively.

[0179] In some embodiments of the present disclosure, the compound represented by general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, is a compound represented by general formula (I), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt:

[0180] in:

[0181] L is selected from -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NRn7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0182] x 1 to x 8 , Ring A, Ring B, R 1 、R 2 、R 3 、R 4 、R 5 and n are as defined in formula (IA).

[0183] The object of the present disclosure is to provide a compound represented by general formula (I), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof;

[0184] in:

[0185] Ring A is selected from

[0186] x 1 CR x1 or N;

[0187] x 2 CR x2 or N;

[0188] x 3 CR x3 or N;

[0189] x 4 CR x4 or N;

[0190] x 5 CR x5 or N;

[0191] x 6 CR x6 or N;

[0192] x 7 CR x7 or N;

[0193] x 8 CR x8 or N;

[0194] Ring B is selected from 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0195] L is selected from -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0196] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6Alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0197] Each R 4 The same or different, and each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0198] R x1 、R x2 、R x3 、R x4 、R x5 、R x6 、Rx7 and R x8 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclic group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0199] G 1 Selected from O, S, N, CR g1 and NR 8b ;

[0200] G 2 C or N;

[0201] G 3 C or N;

[0202] G 4 C or N;

[0203] G 5 C or N;

[0204] G 6 Selected from O, S, N, CR g6 and NR 8b ;

[0205] G 7 Selected from O, S, N, CR g7 and NR 8b ;

[0206] R 7 is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、C 1-6 Alkoxy and halogenated C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0207] R 8 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0208] or R 7 and R 8 The atoms to which it is attached together form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O)p and N ring atoms, and is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkyl cyano, C 1-6 Alkylamino, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0209] L 1 and L 2 are the same or different and are each independently selected from a chemical bond, -C(R a )=C(R b )-、-C(R a )=N-、-N=C(R b )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0210] Indicates that when x 6 CR x6 When L 1 and R x6 The connected keys, and L 1 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 One or more substituents in the alkyl group; provided that, n5 The nitrogen atom connected to R x6 The ring atoms between the connected carbon atoms are not -CH2- and -CH2CH2-;

[0211] H 1 Selected from O, S(O) p , N, CR h1 and NR 8b ;

[0212] H 2 、H 3 and H 4 are the same or different and are each independently C or N;

[0213] R is O or NR r ;

[0214] J is selected from -NR n1 R n2 、C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyl cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0215] Optionally, when J is -NR n1 R n2 When R n2 and H 1 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c , hydroxy C 1-6 The alkyl group is substituted by one or more substituents, and when x 5 、x 6 、x 7 and x 8 When both are CH, Not for

[0216] H is N or CR 7b ;

[0217] G is N or CR g ;

[0218] Indicates x 5 The bonds connecting the rings;

[0219] Indicates x 1 The bonds connecting the rings;

[0220] Indicates that when x 6 CR x6 When L 2 and R x6 The connected keys, and L 2 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0221] R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0222] R 7c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 、C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0223] R 8a Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -OR c , halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkyl cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0224] R 8b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0225] R g1 、R g6 、R g7 、R g and R h1 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, -OR c 、C 2-6 Alkenyl, C 2- 6-Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 、C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0226] Optionally, J and H 1 、R 7a With R 8b , or R 7b With R g , or R 7c With R g Each independently forms a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0227] R a and Rb are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0228] R c are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0229] R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2- 6-alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, -NR n7 R n8 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0230] R 5 、R r 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0231] or Rn1 and R n2 、R n3 and R n4 、R n5 and R n6 、R n7 and R n8 、R n7a and R n8a Together with the nitrogen atoms to which they are attached, they each form a 3- to 8-membered heterocyclic group;

[0232] Optionally, R n6 with x 6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a 、C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents;

[0233] n is 0, 1, 2, 3 or 4;

[0234] m is 0, 1, 2, 3 or 4;

[0235] p is 0, 1 or 2; provided that the general formula (I) is not the following compounds, the CAS numbers of the following compounds are 2924721-14-0, 2920599-68-2, 2920601-26-7, 2924721-16-2, 2939840-00-1, 2939840-08-9, 2920599-66-0, 2939839-78-6 and 2939840-05-6 respectively.

[0236] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt is not the structure corresponding to the following CAS number, wherein the structure corresponding to the CAS number is as follows:

[0237] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 5 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, preferably a hydrogen atom or C 1-6 The alkyl group is more preferably a hydrogen atom.

[0238] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, is a compound represented by the general formula (IC), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt,

[0239] Where: x 1 to x 8 、R c 、R L 、R 1 、R 2 、R 3 、R 6 and n are as defined in formula (I) or formula (IA).

[0240] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R L Selected from C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, -C(O)NR n7 R n8 and R n7 、R n8 , Ring B, L, R 4 and n are as defined in formula (I) or formula (IA).

[0241] In some embodiments of the present disclosure, the compound represented by formula (I), formula (IC) or formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative or its pharmaceutically acceptable salt, wherein R L Selected from C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and Ring B, L, R 4 and n are as defined in formula (I) or formula (IA).

[0242] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R L is methoxy or -OCHF2.

[0243] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R L for

[0244] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L is selected from -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O- and -C(O)-, R n7 、R a 、R b and m are as defined in formula (I) or formula (IA); preferably, L is -O-.

[0245] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L is -C(O) or -C(O)NH.

[0246] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein G 2 N, G 3 , G 4 , G 5 Both C, G 1 C or N; or G 3 N, G 2 , G4 , G 5 Both C, G 1 C or N; or G 2 , G 3 , G 4 , G 5 Both C, G 1 Selected from O, N, CR g1 and NR 8b , R g1 and R 8b As defined in formula (I) or formula (IA).

[0247] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein G 6 Selected from O, N, CR g6 and NR 8b , G 7 Selected from O, N, CR g7 and NR 8b , G 4 , G 5 Both C, R g6 、R g7 and R 8b As defined in formula (I) or formula (IA).

[0248] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein for R g1 , G 6 and G 7 As defined in formula (I) or formula (IA); preferably, Selected from R g1 As defined in formula (I) or formula (IA); more preferably, Selected from

[0249] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein ring C is selected from a 5- to 6-membered monocyclic heteroaryl, a phenyl group, a 6- to 14-membered fused heteroaryl group, a 7- to 14-membered fused aryl group, a 3- to 10-membered heterocyclic group, and a 3- to 10-membered cycloalkyl group.

[0250] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein ring C is selected from a 5- to 6-membered monocyclic heteroaryl, a phenyl group, and a 6- to 14-membered fused heteroaryl group.

[0251] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein ring C is a 6- to 14-membered fused heteroaryl group.

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L 3 Chemical bond or -NR n7 -, R n7 As defined in general formula (IA).

[0253] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L 3 is a chemical bond or -NR n7 -, R n7 A hydrogen atom or C 1-6 alkyl.

[0254] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R is R 5 A hydrogen atom or C 1-6 Alkyl, R 1 、R 2 and R 3 As defined in general formula (IA).

[0255] On the other hand, the present disclosure provides a compound represented by general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,

[0256] in:

[0257] L 4 Selected from chemical bonds, -C(R a )=C(R b )-、-C(Ra )=N-、-N=C(R b )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -;

[0258] x 1 to x 5 、x 7 、x 8 , Ring B, R c 、R 1 、R 2 、R 3 、R 4 、R 6 、n、R a 、R b 、R n7 , m, and p are as defined in the general formula (IA) or the general formula (I).

[0259] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, is a compound represented by general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt:

[0260] in:

[0261] x 1 to x 8 , Ring B, R 1 、R 2 、R 3 、R 4 , G 6 , G 7 、R 6 、R 7 、R 8 、R 8a 、R 8b 、R g 、R c 、R 7a 、R 7c 、H 1 、H 2 、H 3 , G, Y, L 1 、L 2 , J and n are as defined in formula (I) or formula (IA).

[0262] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (IA), general formula (IC), general formula (IC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIC), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0263] in:

[0264] Ring B is selected from 6-membered heteroaryl;

[0265] x 1 to x 8 、R1 、R 2 、R 3 、R 4 、R 6 and n are as defined in formula (I) or formula (IA).

[0266] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (IA), general formula (IC), general formula (IC-1), general formula (IIC), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0267] in:

[0268] x 1 to x 8 、R 1 、R 2 and R 3 As defined in formula (I) or formula (IA).

[0269] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (IA), general formula (IC), general formula (IC-1), general formula (IIC), general formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIC-2), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0270] in:

[0271] x 1 to x 5 、x 7 to x 8 、R 1 、R 2 and R 3 As defined in formula (I) or formula (IA).

[0272] In some embodiments of the present disclosure, the compound represented by the general formula (IH), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, is a compound represented by the general formula (IIH), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt:

[0273] in:

[0274] Ring B is selected from 6-membered heteroaryl;

[0275] L 4 As defined in formula (IH);

[0276] x 1 to x 5 、x 8 、R x7 、R 1 、R 2 、R 3 、R 4 and n are as defined in formula (I) or formula (IA).

[0277] In some embodiments of the present disclosure, the compound represented by general formula (IH), general formula (IIH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0278] in:

[0279] L 4 As defined in formula (IH);

[0280] x 1 to x 5 、x 8 、R x7 、R 1 、R 2 and R 3 As defined in formula (I) or formula (IA).

[0281] In some embodiments of the present disclosure, the compound represented by the general formula (IH), the general formula (IIH), the general formula (IIH-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L 4 is selected from O, -CH2- and -CH2CH2-.

[0282] In some embodiments of the present disclosure, the compound represented by the general formula (IH), the general formula (IIH), the general formula (IIH-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein L 4 Selected from -OCH2-.

[0283] In some embodiments of the present disclosure, wherein L 1 Selected from -OCH2-, -C(O)CH2-, -C(O)NH-, -CH2C(O)-, -CH=CH-, -CH=N-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CF2CH2- and -CH2CF2-; and / or L 4 is selected from -OCH2-, -NHCH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH2-, -CF2CH2- and -CH2CF2-; preferably, L 1 Selected from -OCH2-; and / or L 4 Selected from -OCH2-.

[0284] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 CR x1 , x 2 CR x2 , x 3 CR x3 , x 4 CR x4 ; R x1 、R x2 、R x3 、R x4 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, -CN and C 1-6 Alkoxy.

[0285] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 CR x1 , x 2 CR x2 , x 3 CR x3 , x 4 CR x4 ; R x1 、R x2 、R x3 、R x4 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; preferably, x 1 、x 2 、x 3 and x 4 All are CH.

[0286] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 N or CR x1 ; R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 1 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3.

[0287] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 N or CR x1 ; R x1 is a hydrogen atom or a halogen; preferably, x 1 is selected from N, CH and CF.

[0288] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 2 N or CR x2 ; R x2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 2 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3.

[0289] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 2 N or CR x2 , R x2 is a hydrogen atom or a halogen; preferably, x 2 is selected from N, CH and CF.

[0290] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 3 is CH; and / or, x 4 For CH.

[0291] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 3 is N.

[0292] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 4 is N.

[0293] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 Selected from N, CH and CF, x 2 Selected from N, CH and CF, x 3 is N or CH, x 4 is N or CH.

[0294] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 N or CR x1 , x 2 N or CR x2 , x 3 CRx3 , x 4 CR x4 ; R x1 、R x2 、R x3 、R x4 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 1 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 2 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 3 is N or CH, x 4 is N or CH.

[0295] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 N or CR x1 , x 2 N or CR x2 , x 3 CR x3 , x 4 CR x4 ; R x1 、R x2 、R x3 、R x4 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 1 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 2 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 3 is N or CH, x 4 is N or CH; more preferably, x 1 、x 2 、x 3 and x4 All are CH.

[0296] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 Selected from CH, x 2 Selected from C-CH3, x 3 is CH, x 4 For CH.

[0297] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 N or CR x1 , x 2 N or CR x2 , x 3 N or CR x3 , x 4 N or CR x4 ; R x1 、R x2 、R x3 、R x4 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 1 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 2 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 3is N or CH, x 4 is N or CH; more preferably, x 1 、x 2 、x 3 and x 4 All are CH.

[0298] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R x3 and R x4 are all hydrogen atoms; and / or R x1 and R x2 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, R x3 and R x4 are all hydrogen atoms; and / or R x1 and R x2 are the same or different and are each independently selected from a hydrogen atom, F, and a methyl group.

[0299] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 1 For CH.

[0300] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 2 For CH.

[0301] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 2 It is C-CH3.

[0302] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), and Formula (IIC), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 6 A hydrogen atom.

[0303] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IIC), Formula (IIC-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 5 CR x5 , x 6 CR x6 , x 7 CR x7 , x 8 CR x8 ; R x5 、R x6 、R x7 、R x8 As defined in formula (I) or formula (IA); preferably, x 5 CR x5 , x 6 CR x6 , x 7 CR x7 , x 8 CR x8 ; R x5 、R x6 、R x7 、R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 More preferably, x 5 -CH, x 6 -CH, x 7 -CH, x 8 is -CF.

[0304] In some embodiments of the present disclosure, the compound represented by the general formula (IGH-1), general formula (IG-1), general formula (IJ-1), general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein x 5 CR x5 , x 7 CR x7 ;x 8 CR x8 ; R x5 、R x7 、R x8 As defined in formula (I) or formula (IA); preferably, x 5 CRx5 , x 7 CR x7 ;x 8 CR x8 ; R x5 、R x7 、R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 More preferably, x 5 is CH; x 7 CR x7 ;x 8 CR x8 ; R x7 、R x8 are the same or different and are each independently a hydrogen atom or a halogen; further preferably, x 5 is CH; x 7 CR x7 ;x 8 CR x8 ; R x7 、R x8 are the same or different and are each independently a hydrogen atom or F; most preferably, x 5 is CH; x 7 is CH; x 8 is CH or CF.

[0305] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IGH-1), Formula (IH-1), Formula (IG-1), Formula (IJ-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R x5 A hydrogen atom.

[0306] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IIC), Formula (IIC-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R x6 A hydrogen atom.

[0307] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IIC), formula (IIC-1), and formula (IIC-2), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkoxy; preferably, R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from a hydrogen atom or a halogen; more preferably, R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from a hydrogen atom or F.

[0308] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IIC), Formula (IIC-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 5 N or CR x5 , x 6 N or CR x6 , x7 CR x7 ;x 8 N or CR x8 ; R x5 、R x6 、R x7 、R x8 As defined in formula (I) or formula (IA); preferably, x 5 CR x5 , x 6 N or CR x6 , x 7 CR x7 ;x 8 CR x8 ; R x5 、R x6 、R x7 、R x8 As defined in any one of formula (I) or formula (IA); more preferably, x 5 CR x5 , x 6 N, x 7 CR x7 ;x 8 CR x8 ; R x5 、R x7 、R x8 As defined in any one of Formula (I) or Formula (IA).

[0309] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IIC), Formula (IIC-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 5 CR x5 , x 6 N or CR x6 , x 7 CR x7 ;x 8 CR x8 ; R x5 、R x6 、R x7 、R x8 are the same or different and are independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 5 CR x5 , x6 N, x 7 CR x7 ;x 8 CR x8 ; R x5 、R x7 、R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 More preferably, x 5 is CH, x 6 N, x 7 is CH or CF; x 8 For CH.

[0310] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 5 N or CR x5 , R x5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 5 N or CR x5 , R x5 is a hydrogen atom or a halogen; more preferably, x 5 is N or CH; most preferably, x 5 For CH.

[0311] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 5 CR x5, R x5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 5 CR x5 , R x5 is a hydrogen atom or a halogen.

[0312] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IIC), Formula (IIC-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 6 N or CR x6 , R x6 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 6 N or CR x6 , R x6 is a hydrogen atom or a halogen; more preferably, x 6 is N or CH; most preferably, x 6 is N.

[0313] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), and Formula (IIC-2), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 7 N or CR x7 , R x7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 7 N or CR x7 , R x7 is a hydrogen atom or a halogen; more preferably, x 7 is selected from N, CH and CF; most preferably, x 7 is CH or CF.

[0314] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), and Formula (IIC-2), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 7 CR x7 , R x7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 7 CR x7 , R x7 is a hydrogen atom or a halogen; more preferably, x 7 CR x7 , R x7 is a hydrogen atom or F.

[0315] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), and Formula (IIC-2), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 7 Selected from C-OCH3.

[0316] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 8 N or CRx8 , R x8 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 8 N or CR x8 , R x8 is a hydrogen atom or a halogen; more preferably, x 8 is selected from N, CH and CF.

[0317] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIC-2), Formula (IIH), Formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein x 8 CR x8 , R x8 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, x 8 CR x8 , R x8 is a hydrogen atom or a halogen.

[0318] In some embodiments of the present disclosure, the compound represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IIC), formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from

[0319] In some embodiments of the present disclosure, the compound represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IIC), formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from

[0320] In some embodiments of the present disclosure, the compound represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IIC), formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from

[0321] In some embodiments of the present disclosure, the compound represented by the general formula (IGH-1), general formula (IH-1), general formula (IG-1), general formula (IJ-1), general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein for

[0322] In some embodiments of the present disclosure, the compound represented by the general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein ring C is selected from x 1 、x 2 、x 3 and x 4 As defined in general formula (IA).

[0323] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IH), formula (IIC), formula (IIC-1), formula (IIC-2), formula (IIH), and formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein Selected from

[0324] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IM-1), formula (IN-1), formula (IC), formula (IH), formula (IIC), formula (IIC-1), formula (IIC-2), formula (IIH), and formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein Selected from

[0325] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (IA), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, is a compound represented by general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2) or general formula (IN-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt:

[0326] in:

[0327] R x8 、Rx7 , Ring B, R 1 、R 2 、R 3 、R 4 , G 6 , G 7 、R 7 、R 8 、R 8a 、R 8b 、R g 、R c 、R 7a 、R 7c 、H 1 、H 2 、H 3 , G, Y, L 1 、L 2 , J and n are as defined in formula (I) or formula (IA).

[0328] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2) , a compound represented by general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 10-membered heteroaryl group or a 6- to 10-membered aromatic group, preferably a 5- to 6-membered heteroaryl group or a phenyl group, further preferably a 6-membered heteroaryl group, and more preferably a pyrimidinyl group.

[0329] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2) , a compound represented by general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5- to 10-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a 6- to 10-membered aryl group.

[0330] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2), general formula (IG-2) , a compound represented by general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5- to 10-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, and a 6- to 10-membered aryl group, preferably a 5- to 6-membered heteroaryl group or a phenyl group, more preferably a 6-membered heteroaryl group, and most preferably a pyrimidinyl group or a pyridinyl group.

[0331] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2) , a compound represented by formula (ID-2), formula (IE-2), formula (IG-2), formula (IGH-2), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IM-2), formula (IN-2), formula (IC), formula (IH), formula (IIC), formula (IIH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is

[0332] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IA-2), Formula (IBF-2), Formula (IC-2), Formula (ID-2), Formula (IE-2), Formula (IG-2), Formula (IGH-2), Formula (IH-2), Formula (IJ-2), Formula (IK-2), Formula (IM-2), Formula (IN-2), Formula (IC), Formula (IH), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein Ring B is selected from

[0333] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2 ), a compound represented by general formula (ID-2), general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein for

[0334] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IA-2), Formula (IBF-2), Formula (IC-2), Formula (ID-2), Formula (IE-2), Formula (IG-2), Formula (IGH-2), Formula (IH-2), Formula (IJ-2), Formula (IK-2), Formula (IM-2), Formula (IN-2), Formula (IC), Formula (IH), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein Selected from

[0335] In some embodiments of the present disclosure, the compounds represented by Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IM-1), Formula (IN-1), Formula (IA-2), Formula (IBF-2), Formula (IC-2), Formula (ID-2), Formula (IE-2), Formula (IG-2), Formula (IGH-2), Formula (IH-2), Formula (IJ-2), Formula (IK-2), Formula (IM-2), Formula (IN-2), Formula (IC), Formula (IH), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein Selected from

[0336] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, halogen, cyano, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 Alkyl; preferably, R 1 Selected from hydrogen atoms, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 Alkyl; More preferably, R 1is selected from hydrogen atoms, methyl groups, F, -CH2OCH3, -OCH3 and -CH2OH; most preferably, R 1 Selected from methyl.

[0337] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 Alkyl; preferably, R 1 Selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 Alkyl; More preferably, R 1 is selected from hydrogen atom, methyl, -CD3, F, -CH2OCH3, -OCH3, -CH2CH2OH and -CH2OH; most preferably, R 1 Selected from methyl.

[0338] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogenated C 1-6 alkyl, C optionally substituted by a 3- to 6-membered heterocyclic group 1-6 Alkyl, hydroxy C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 wherein the 3 to 6 membered heterocyclic group is optionally substituted by one or more halogens; preferably, R 2 Selected from hydrogen atom, -CH3, -CH2F, -CH2OH, -CH2OCH3, Most preferably, R 2 Selected from hydrogen atoms.

[0339] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R 2 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogen and cyano; preferably, R 1 and R 2 All are hydrogen atoms.

[0340] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and cyano; preferably, R 3 C 1-6 alkyl.

[0341] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl, R 2A hydrogen atom.

[0342] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 selected from hydrogen atoms, methyl groups and F; and / or R 2 A hydrogen atom.

[0343] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom or C 1-6 Alkyl; preferably, R 3 A hydrogen atom.

[0344] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by -NR n7a R n8a Replaced by R n7a and R n8a The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 3 for

[0345] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (I A compound represented by the general formula (E-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), or general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and cyano, the C 1-6 The alkyl group is optionally replaced by -NRn7a R n8a Replaced by R n7a and R n8a The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 3 Selected from hydrogen atoms, C 1-6 Alkyl and More preferably, R 3 A hydrogen atom.

[0346] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2 ), a compound represented by general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 4 C 1-6 alkyl or halogen, or n is 0; preferably, n is 1, and R 4 C 1-6 alkyl, or n is 0; more preferably, n is 1, and R 4 It is a methyl group.

[0347] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2 ), a compound represented by general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IM-2), general formula (IN-2), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 4 Selected from C 1-6 Alkyl, deuterated C 1-6 alkyl, halogen and 3 to 6 membered cycloalkyl, or n is 0; preferably, n is 1, and R 4 Selected from C 1-6 Alkyl, deuterated C 1-6 alkyl and 3 to 6 membered cycloalkyl, or n is 0; more preferably, n is 1, and R 4 Selected from methyl, isopropyl, -CD3 and cyclopropyl.

[0348] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (IA), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IA-3), general formula (IBF-3), general formula (IC-3), general formula (ID-3), general formula (IE-3), general formula (IG-3), general formula (IGH-3), general formula (IH-3), general formula (IJ-3), general formula (IK-3), general formula (IM-3), or general formula (IN-3), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0349] in:

[0350] G 6 , G 7 、R 7 、R 8 、R x8 、R x7 、R 8a 、R8b 、R c 、R g 、R 7a 、R 7c 、H 1 、H 2 、H 3 , G, Y, L 1 、L 2 and J are as defined in formula (I) or formula (IA-1).

[0351] In some embodiments of the present disclosure, the general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1), general formula (IN-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (I M-2), general formula (IN-2), general formula (IA-3), general formula (IBF-3), general formula (IC-3), general formula (ID-3), general formula (IE-3), general formula (IG-3), general formula (IGH-3), general formula (IH-3), general formula (IJ-3), general formula (IK-3), general formula (IM-3), general formula (IN-3), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIC-2), general formula (IIH), a compound represented by general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R x7 and R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; preferably, R x7 and R x8 are the same or different and are each independently a hydrogen atom or a halogen; more preferably, R x7 and R x8 are the same or different and are each independently a hydrogen atom or F; most preferably, R x7 is a hydrogen atom, R x8 is a hydrogen atom or F.

[0352] In some embodiments of the present disclosure, the compound represented by formula (IC-1), formula (IC), formula (IH), formula (IIC), formula (IIC-1), formula (IIC-2), formula (IIH), formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R x7 and R x8 are the same or different and are each independently a hydrogen atom or a halogen; preferably, R x7 and R x8 are the same or different and are each independently a hydrogen atom or F.

[0353] In some embodiments of the present disclosure, the compounds represented by formula (IIC-2), formula (IH-1), formula (IH-2), formula (IH-3), formula (IH), formula (IIH), formula (IIH-1), or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, wherein R x7 is a hydrogen atom or F; and / or R x8 A hydrogen atom.

[0354] In some embodiments of the present disclosure, the compound represented by the general formula (IBF-2) or the general formula (IBF-3), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from As defined in formula (I) or formula (IA).

[0355] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (IA), general formula (IE-1), (IE-2), general formula (IE-3), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from As defined in formula (I) or formula (IA).

[0356] In some embodiments of the present disclosure, the above-mentioned R 7 In the general formula, R 7 Selected from C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 2-6 Alkynyl, -C(O)NH2, -NHC(O)NH2, 3 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl; preferably, R7 Selected from ethynyl, -C(O)NH2, -NHC(O)NH2, -OCH3, -CH2OH, -CH2OCH3,

[0357] In some embodiments of the present disclosure, the above-mentioned R 7c In the general formula, R 7c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl and -NR n7 R n8 ; R n7 and R n8 As defined in formula (I) or formula (IA); preferably, R 7c Selected from a hydrogen atom and a cyano group.

[0358] In some embodiments of the present disclosure, the above-mentioned R 7a and R 7b In the general formula, R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NH2, -NHC(O)NH2, 3 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl; preferably, R 7a and R 7b is the same or different at each occurrence and is independently selected from a hydrogen atom and a cyano group.

[0359] In some embodiments of the present disclosure, the above-mentioned In the general formula, for R 8b and J are as defined in formula (I) or formula (IA).

[0360] In some embodiments of the present disclosure, the above-mentioned In the general formula, Selected from R 8b 、R n1 and R n2 As defined in formula (I) or formula (IA); preferably, Selected from As defined in formula (I) or formula (IA).

[0361] In some embodiments of the present disclosure, the above-mentioned R c and R 8In the general formula, R c and R 8 is the same or different at each occurrence and is independently C 1-6 Alkyl, more preferably methyl.

[0362] In some embodiments of the present disclosure, the above-mentioned R c and R 8 In the general formula, R c and R 8 are the same or different at each occurrence and are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy C 1-6 alkyl.

[0363] In some embodiments of the present disclosure, the above-mentioned R 8 In the general formula, R 8 are the same or different at each occurrence and are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and hydroxy C 1-6 alkyl.

[0364] In some embodiments of the present disclosure, the above-mentioned R c In the general formula, R c is the same or different at each occurrence and is independently C 1-6 Alkyl or deuterated C 1-6 The alkyl group is preferably a methyl group or a deuterated methyl group.

[0365] In some embodiments of the present disclosure, the above-mentioned R 8 In the general formula, R 8 is the same or different at each occurrence and is independently selected from methyl, methoxy, -CH2OH and -(CH2CH2)OH.

[0366] In some embodiments of the present disclosure, the above-mentioned R 8 In the general formula, R 8 is the same or different at each occurrence and is independently -OCD3.

[0367] In some embodiments of the present disclosure, the above-mentioned R 8a In the general formula, R 8a is the same or different at each occurrence and is independently C 1-6 Alkoxy; preferably, R 8a It is -OCH3.

[0368] In some embodiments of the present disclosure, the above-mentioned R 8b In the general formula, R8b is the same or different at each occurrence and is independently C 1-6 Alkyl or C 1-6 Alkoxy; more preferably, R 8b is the same or different at each occurrence and is each independently -CH3 or -OCH3.

[0369] In some embodiments of the present disclosure, wherein R 8 are the same or different at each occurrence and are independently selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and hydroxy C 1-6 alkyl.

[0370] In some embodiments of the present disclosure, wherein R 8 is the same or different at each occurrence and is independently selected from methyl, -CD3, methoxy, -OCD3, -CH2OH and -(CH2CH2)OH.

[0371] In some embodiments of the present disclosure, wherein R c is the same or different at each occurrence and is independently C 1-6 Alkyl, 3 to 6 membered cycloalkyl or deuterated C 1-6 The alkyl group is preferably a methyl group, an isopropyl group, a cyclopropyl group or a deuterated methyl group, and more preferably a methyl group or -CD3.

[0372] In some embodiments of the present disclosure, wherein R 8a are the same or different at each occurrence and are independently selected from C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3 to 6-membered cycloalkyloxy; preferably, R 8a are the same or different at each occurrence and are independently selected from methoxy, -OCD3,

[0373] and / or R 8b is the same or different at each occurrence and is independently C 1-6 Alkyl or C 1-6 Alkoxy.

[0374] In some embodiments of the present disclosure, in the above general formula containing J, wherein J is a halogenated C 1-6 Alkyl or -NR n1 R n2 ; R n1 and R n2 As defined in formula (I) or formula (IA); preferably, J is -CHF2, -NH2 and -NH(CH3).

[0375] In some embodiments of the present disclosure, the above-mentioned L 1 In the general formula, L 1 Selected from -OCH2-, -C(O)CH2-, -C(O)NH-, -CH2C(O)-, -CH=CH-, -CH=N-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CF2CH2- and -CH2CF2-.

[0376] In some embodiments of the present disclosure, the above-mentioned L 1 In the general formula, L 1 It is -OCH2-.

[0377] In some embodiments of the present disclosure, the above-mentioned L 2 In the general formula, L 2 Selected from -OCH2-, -NHCH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH2-, -CF2CH2- and -CH2CF2-.

[0378] In some embodiments of the present disclosure, the compound represented by the general formula (IGH-2) or the general formula (IGH-3), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from As defined in formula (I) or formula (IA).

[0379] In some embodiments of the present disclosure, the compound represented by the general formula (IH-2) or the general formula (IH-3), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein Selected from As defined in formula (I) or formula (IA).

[0380] In some embodiments of the present disclosure, the compound represented by the general formula (IH-2) or the general formula (IH-3), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein for

[0381] In some embodiments of the present disclosure, the compound represented by the general formula (IH-2) or the general formula (IH-3), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein Selected from

[0382] In some embodiments of the present disclosure, the compound represented by the general formula (IH-2) or the general formula (IH-3), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein Selected from

[0383] In some embodiments of the present disclosure, the compound represented by the general formula (IJ-2) or the general formula (IJ-3), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein Selected from As defined in formula (I) or formula (IA).

[0384] In some embodiments of the present disclosure, the above-mentioned In the general formula, Selected from R g1 As defined in formula (I) or formula (IA); more preferably, Selected from As defined in formula (I) or formula (IA).

[0385] In some embodiments of the present disclosure, ring C is selected from

[0386] In some embodiments of the present disclosure, ring C is selected from

[0387] In some embodiments of the present disclosure, q is 0 or R x Selected from hydrogen atoms, halogens and C 1-6 alkyl, and q is 1 or 2.

[0388] In some embodiments of the present disclosure, Selected from

[0389] In some embodiments of the present disclosure, Selected from

[0390] In some embodiments of the present disclosure, Selected from

[0391] In some embodiments of the present disclosure, Indicates x 5 The rings are connected by a bond; the x 5 The ring refers to the structural unit

[0392] In some embodiments of the present disclosure, Indicates x 1 The rings are connected by a bond; the x 1 The ring refers to the structural unit

[0393] In some embodiments of the present disclosure, represents a bond to ring C.

[0394] In some embodiments of the present disclosure, the above-mentioned R a and R b In the general formula, R a and R b are the same or different at each occurrence and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0395] In some embodiments of the present disclosure, the above-mentioned R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a In the general formula, R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl and hydroxy C 1-6 alkyl.

[0396] In some embodiments of the present disclosure, the above-mentioned R g1 、R g6 、R g7 、R g and R h1 In the general formula, Rg1 、R g6 、R g7 、R g and R h1 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl and hydroxy C 1-6 Alkyl, preferably C 1-6 alkyl.

[0397] In some embodiments of the present disclosure, the compound represented by the general formula (IC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R c Selected from C 1-6 alkyl, ring B is selected from 5- to 6-membered heteroaryl or phenyl, R x8 Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 1 and R 2 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogen and cyano, R 3 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and cyano, n is 1, and R 4 C 1-6 Alkyl, or n is 0.

[0398] In some embodiments of the present disclosure, the compound represented by the general formula (IC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R c Selected from C 1-6 alkyl, ring B is selected from 5- to 6-membered heteroaryl or phenyl, R x8 is selected from hydrogen atom, halogen, R 1 C 1-6 Alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, n is 1, and R 4 C 1-6 Alkyl, or n is 0.

[0399] In some embodiments of the present disclosure, the compound represented by the general formula (IC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R c Selected from C 1-6 alkyl, ring B is selected from 6-membered heteroaryl, R x8 is selected from hydrogen atom, halogen, R 1 C 1-6 Alkyl, R2 is a hydrogen atom, R 3 is methyl, n is 1, and R 4 C 1-6 Alkyl, or n is 0.

[0400] In some embodiments of the present disclosure, the compound represented by the general formula (IC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R c C 1-6 Alkyl, Ring B is a 6-membered heteroaryl, R x8 is a hydrogen atom or a halogen, R 1 Selected from C 1-6 Alkyl, hydrogen and halogen, R 2 is a hydrogen atom, R 3 is a hydrogen atom, n is 1, and R 4 C 1-6 Alkyl, or n is 0.

[0401] In some embodiments of the present disclosure, the compound represented by the general formula (IC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R c is methyl, ring B is pyrimidinyl or pyridinyl, R x8 is a hydrogen atom or F, R 1 is a methyl group or a hydrogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, n is 1, and R 4 is methyl, or n is 0.

[0402] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 C 1-6 Alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 N or CR x1 ; R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; x 2 N or CR x2 ; R x2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; x 3 is CH; x 4is CH; x 5 CR x5 ;x 6 N or CR x6 ;x 7 CR x7 ;x 8 CR x8 ; R x5 、R x6 、R x7 、R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl.

[0403] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 is methyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 CR x1 ; R x1 is a hydrogen atom or a halogen; x 2 CR x2 ; R x2 A hydrogen atom or C 1-6 Alkyl; x 3 is CH; x 4 is CH; x 5 CR x5 , R x5 is a hydrogen atom or a halogen; x 6 is N; x 7 CR x7 , R x7 is a hydrogen atom or a halogen; x 8 CR x8 , R x8 is a hydrogen atom or a halogen.

[0404] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 is methyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 CR x1 ; R x1 is a hydrogen atom; x 2 CR x2 ; R x2 is a hydrogen atom or a methyl group; x 3 is CH; x4 is CH; x 5 CR x5 , R x5 is a hydrogen atom or F; x 6 is N; x 7 CR x7 , R x7 is a hydrogen atom or F; x 8 CR x8 , R x8 is a hydrogen atom or F.

[0405] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 C 1-6 Alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 N or CR x1 ; R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; x 2 N or CR x2 ; R x2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; x 3 is CH; x 4 is CH; x 5 CR x5 ;x 7 CR x7 ;x 8 CR x8 ; R x5 、R x7 、R x8 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl.

[0406] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 is methyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 CR x1 ; R x1 is a hydrogen atom or a halogen; x 2 CRx2 ; R x2 A hydrogen atom or C 1-6 Alkyl; x 3 is CH; x 4 is CH; x 5 CR x5 , R x5 is a hydrogen atom; x 7 CR x7 , R x7 is a hydrogen atom or a halogen; x 8 CR x8 , R x8 is a hydrogen atom or a halogen.

[0407] In some embodiments of the present disclosure, the compound represented by the general formula (IIC-2), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 is methyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, x 1 CR x1 ; R x1 is a hydrogen atom; x 2 CR x2 ; R x2 is a hydrogen atom or a methyl group; x 3 is CH; x 4 is CH; x 5 CR x5 , R x5 is a hydrogen atom; x 7 CR x7 , R x7 is a hydrogen atom or F; x 8 CR x8 , R x8 A hydrogen atom.

[0408] In some embodiments of the present disclosure, the compound represented by the general formula (IIH-1), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 1 C 1-6 Alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, L 4 is O; x 1 CR x1 ; R x1 is a hydrogen atom or a halogen; x 2 CR x2 ; R x2 is a hydrogen atom or a halogen; x 3is CH; x 4 is CH; x 5 N or CR x5 , R x5 is a hydrogen atom or a halogen; R x7 is a hydrogen atom or a halogen; x 8 CR x8 , R x8 is a hydrogen atom or a halogen.

[0409] The present disclosure also provides the following compounds, or stereoisomers, or prodrugs, or nitrogen oxides, or solvates, or isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein typical compounds of the present disclosure include but are not limited to any one of the structures in Table A below, or stereoisomers, or prodrugs, or nitrogen oxides, or solvates, or isotopic derivatives, or pharmaceutically acceptable salts thereof:

[0410] Table A

[0411] On the other hand, the present disclosure also provides the following compounds, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof:

[0412] Another aspect of the present disclosure relates to a pharmaceutical composition comprising the pharmaceutical composition of the present disclosure, comprising: a pharmaceutical composition ... Compounds of Formula (IA-3), General Formula (IBF-3), General Formula (IC-3), General Formula (ID-3), General Formula (IE-3), General Formula (IG-3), General Formula (IGH-3), General Formula (IH-3), General Formula (IJ-3), General Formula (IK-3), General Formula (IM-1), General Formula (IN-1), General Formula (IC), General Formula (IH), General Formula (IIC), General Formula (IIC-1), General Formula (IIH), General Formula (IIH-1) and Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0413] The present disclosure further relates to formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IGH-2), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula (IC-3), formula (ID-3), formula (IE-3), formula (IG-3), formula ( Use of the compounds shown in Formula (IGH-3), Formula (IH-3), Formula (IJ-3), Formula (IK-3), Formula (IM-1), Formula (IN-1), Formula (IC), Formula (IH), Formula (IIC), Formula (IIC-1), Formula (IIH), Formula (IIH-1) and Table A, or their stereoisomers, or their prodrugs, or their nitrogen oxides, or their solvates, or their isotopic derivatives, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them in the preparation of a medicament for inhibiting FGFR2, preferably in the preparation of a medicament for selectively inhibiting FGFR2, more preferably in the preparation of a medicament for selectively inhibiting FGFR2 relative to one or more of FGFR1, FGFR3 or FGFR4.

[0414] The present disclosure further relates to formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IGH-2), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula (I Use of the compounds shown in Table A, or their stereoisomers, or their prodrugs, or their nitrogen oxides, or their solvates, or their isotopic derivatives, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same, in the preparation of medicaments for treating and / or preventing FGFR2-mediated tumors.

[0415] The present disclosure also relates to a method for inhibiting FGFR2, preferably a method for selectively inhibiting FGFR2, more preferably a method for selectively inhibiting FGFR2 relative to one or more of FGFR1, FGFR3 or FGFR4, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IG-2), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IG-2), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IG-2), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IG-2), formula ( (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IA-3), general formula (IBF-3), general formula (IC-3), general formula (ID-3), general formula (IE-3), general formula (IG-3), general formula (IGH-3), general formula (IH-3), general formula (IJ-3), general formula (IK-3), general formula (IM-1), general formula (IN-1), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIH), general formula (IIH-1) and compounds shown in Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0416] The present disclosure also relates to a method for treating and / or preventing FGFR2-mediated tumors, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), Compounds represented by formula (IK-2), formula (IA-3), formula (IBF-3), formula (IC-3), formula (ID-3), formula (IE-3), formula (IG-3), formula (IGH-3), formula (IH-3), formula (IJ-3), formula (IK-3), formula (IM-1), formula (IN-1), formula (IC), formula (IH), formula (IIC), formula (IIC-1), formula (IIH), formula (IIH-1), and Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

[0417] The present disclosure further relates to a general formula (I), general formula (IA), general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IA-2), general formula (IBF-2), general formula (IC-2), general formula (ID-2), general formula (IE-2), general formula (IG-2), general formula (IGH-2), general formula (IH-2), general formula (IJ-2), general formula (IK-2), general formula (IA-3), general formula (IA-4 ...IA-5), general formula (IA-6), general formula (IA-7), general formula (IA-8), general formula (IA-9), general formula (IA-10), general formula (IA-11), general formula (IA-12), general formula (IA-13), general formula (IA-14), general formula (IA-15), general formula (IA-16), general formula (IA-17), general formula (IA-18), general formula (IA-19), general formula (I (IBF-3), general formula (IC-3), general formula (ID-3), general formula (IE-3), general formula (IG-3), general formula (IGH-3), general formula (IH-3), general formula (IJ-3), general formula (IK-3), general formula (IM-1), general formula (IN-1), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIH), general formula (IIH-1) and compounds shown in Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as drugs.

[0418] The present disclosure further relates to formula (IA), formula (I), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IGH-2), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula (IC-3), formula (ID-3), formula (IE-3 ...3), formula (I G-3), general formula (IGH-3), general formula (IH-3), general formula (IJ-3), general formula (IK-3), general formula (IM-1), general formula (IN-1), general formula (IC), general formula (IH), general formula (IIC), general formula (IIC-1), general formula (IIH), general formula (IIH-1) and compounds shown in Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as FGFR2 inhibitors, wherein the FGFR2 inhibitor is preferably a FGFR2 selective inhibitor, more preferably a FGFR2 selective inhibitor relative to one or more of FGFR1, FGFR3 or FGFR4.

[0419] The present disclosure further relates to formula (I), formula (IA), formula (IA-1), formula (IBF-1), formula (IC-1), formula (ID-1), formula (IE-1), formula (IG-1), formula (IGH-1), formula (IH-1), formula (IJ-1), formula (IK-1), formula (IA-2), formula (IBF-2), formula (IC-2), formula (ID-2), formula (IE-2), formula (IG-2), formula (IGH-2), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula (IBF-4), formula (IC-5), formula (ID-6), formula (IE-7), formula (IG-1), formula (IGH-1), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula (IBF-4), formula (IC-5), formula (ID-6), formula (IE-7), formula (IG-1), formula (IGH-1), formula (IH-2), formula (IJ-2), formula (IK-2), formula (IA-3), formula (IBF-3), formula ( Compounds represented by Formula (IC-3), General Formula (ID-3), General Formula (IE-3), General Formula (IG-3), General Formula (IGH-3), General Formula (IH-3), General Formula (IJ-3), General Formula (IK-3), General Formula (IM-1), General Formula (IN-1), General Formula (IC), General Formula (IH), General Formula (IIC), General Formula (IIC-1), General Formula (IIH), General Formula (IIH-1) and Table A, or stereoisomers thereof, or prodrugs thereof, or nitrogen oxides thereof, or solvates thereof, or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for treating and / or preventing FGFR2-mediated tumors.

[0420] Preferably, the tumor as described above in the present disclosure is cancer; the cancer is preferably selected from bile duct cancer (such as intrahepatic bile duct cancer), breast cancer, gastric cancer and endometrial cancer.

[0421] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be in the form of a tablet, capsule, cachet, bottled solution, powder, granules, lozenge, suppository, reconstituted powder, or liquid formulation.

[0422] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0423] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation. Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0424] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0425] Terminology

[0426] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0427] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0428] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Alkyl, "C 1-6 Alkyl", "C 1-4 Alkyl", "C 1-3 "Alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0429] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom, wherein alkyl is as defined above. 1-6 Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl groups are as defined above.

[0430] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group, wherein the definition of alkyl is as described above. The "hydroxyalkyl" described in the present disclosure includes "hydroxy C 1-6 Alkyl", "Hydroxy C 1-4 alkyl"; specific examples include but are not limited to -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0431] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "-O-(alkyl)", wherein alkyl is as defined above. 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-4"alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C 1-6 Alkoxy, more preferably C 1-4 Alkoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0432] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by replacing one or more hydrogen atoms in an alkoxy group with halogen atoms, wherein the definition of alkoxy is as described above. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-4 Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc.

[0433] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched alkene (or an alkyl group containing at least one carbon-carbon double bond, wherein the definition of alkyl is as described above) by removing a hydrogen atom, including "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available connection point. The substituent is preferably selected from one or more of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0434] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (or an alkyl group containing at least one carbon-carbon triple bond, wherein alkyl is as defined above) by removing a hydrogen atom, including "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3"Alkynyl", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, CH≡CHCH2-, CH≡CC≡C-, etc. Alkynyl may be substituted or unsubstituted. When substituted, it may be substituted at any available connection point, and the substituent is preferably selected from one or more of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0435] Unless otherwise specified, the term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatoms), wherein the heteroatoms are generally selected from N, O, S, and P, and the oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein); the number of atoms in the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1 to 3 heteroatoms and / or heteroatoms, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, each ring optionally substituted by an R group, where R is a group defined herein.

[0436] Unless otherwise specified, the term "ring" refers to saturated, partially saturated or unsaturated monocycles and polycycles, and "polycycles" include spirocycles, condensed rings or bridged rings. The group derived from the ring by removing hydrogen atoms is called a "cyclic group", which includes a monovalent ring, a divalent ring (commonly referred to as a subring), a trivalent ring, a tetravalent ring, etc., and the specific valence depends on the number of substituents connected to the ring. The description of "cyclic group" in this disclosure no longer specifically distinguishes the valence of the ring. Representative "cyclic groups" include substituted or unsubstituted cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0437] Unless otherwise specified, the term "cycloalkyl" refers to a saturated or unsaturated cyclic alkyl group (including cycloalkenyl, the same below) derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic hydrocarbon groups; polycyclic hydrocarbon groups refer to polycyclic groups formed by two or more cyclic alkyl structures connected by spiro, bridge, fusion, or other means. Carbon atoms in the cycloalkyl group may be further oxidized, forming C(O). Monocyclic or polycyclic cycloalkyl groups include "3- to 8-membered cycloalkyl," "3- to 6-membered cycloalkyl," and "3- to 5-membered cycloalkyl." Preferably, the cycloalkyl group is a monocyclic, saturated or unsaturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl group contains an unsaturated structure, the cycloalkyl group is also called a "cycloalkenyl," meaning that one or more of the ring bonds in the cycloalkyl group is a double bond and the cycloalkenyl group is not aromatic. Carbon atoms in the cycloalkenyl group may be further oxidized, forming C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl group", "3-6 membered cycloalkenyl group", "3-5 membered cycloalkenyl group" and "5-6 membered cycloalkenyl group". Specific examples include but are not limited to Unless otherwise specified, a cycloalkyl group may be further linked to a heterocyclic, heteroaryl, or aryl structure in a fused manner to form a polycyclic group, wherein the point of attachment to the parent structure is on the cycloalkyl group.

[0438] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0439] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or unsaturated cyclic group (heterocyclyl includes heterocycloalkenyl, the same below) derived from the replacement of one or more ring carbon atoms in a cycloalkyl group by a heteroatom and / or a heteroatom group. The heteroatom and / or heteroatom group is generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxoed, i.e., forming -C(O); preferably, the heteroatom is independently selected from 1-3 N and / or O. The heterocyclyl includes "3-8 membered heterocyclyl", "3-6 membered heterocyclyl", "3-5 membered heterocyclyl", "4-6 membered heterocyclyl", "5-6 membered heterocyclyl". Specific examples include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and the like. When the heterocyclic group contains an unsaturated structure, the heterocyclic group is also called "heterocycloalkenyl", which means that one or more of the ring bonds in the "heterocyclic group" is a double bond and the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocyclic group includes "3-8 membered heterocycloalkenyl", "3-6 membered heterocycloalkenyl", "3-5 membered heterocycloalkenyl", and "5-6 membered heterocycloalkenyl". Specific examples include but are not limited to: Unless otherwise specified, the heterocyclic group can be further connected to a heterocyclic group or a cycloalkyl group in a fused, spiro, or bridged structure; or connected to a heteroaryl or an aryl structure in a fused manner, with the point of connection to the parent structure being on the heterocyclic group.

[0440] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0441] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6- to 14-membered aromatic group) or 7 to 14 ring atoms (i.e., a 7- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group (such as a 7- to 14-membered fused aromatic group) include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0442] wait.

[0443] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0444] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0445] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0446] The polycyclic heteroaryl (such as 6 to 14 membered fused heteroaryl) includes, but is not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include: wait.

[0447] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0448] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0449] The term "hydroxy" refers to -OH.

[0450] The term "amino" refers to -NH2.

[0451] The term "cyano" refers to -CN.

[0452] The term "oxo" or "oxo" refers to "=0".

[0453] The term "alkylamino" refers to "-alkyl-NH2".

[0454] The term "alkylcyano" refers to "-alkyl-CN".

[0455] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0456] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0457] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and extended drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of this disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium replacement can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0458] The term "prodrug" refers to certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves, which have a cleavable group and decompose into the compounds of the present invention through solvent decomposition or under physiological conditions. The types of prodrugs include, but are not limited to, amides, esters, anhydrides, salts, etc. The "ester" refers to a derivative formed with a suitable alcohol when the compound of the present invention contains an acidic group (such as a carboxylic acid); when the compound of the present invention contains a hydroxyl group, it is formed with a suitable acid (including an organic acid or an inorganic acid). The preparation method of prodrugs is well known to those skilled in the art.

[0459] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. The term "hydrate" may be used when the solvent is water. The solvent molecules may be present in stoichiometric or non-stoichiometric amounts.

[0460] The term "nitrogen oxide" or "N-oxide" refers to a derivative formed by further oxidation of the nitrogen atom in a nitrogen-containing group. Common N-oxides include N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. Synthesis methods of N-oxides are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines using peroxyacids such as peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0461] When a substituent's bond can cross-link to a ring, it means that the substituent can be bonded to any atom on the ring. Represents the substituent R 4 Substitution can occur at any position on ring B, and R 4 The number of is n.

[0462] When any variable (such as R 4 ) appears more than once in the composition or structure of a compound, its definition in each instance is independent. For example, a structural unit Indicates that ring B is surrounded by n R 4 is replaced, and each R 4 There are independent options.

[0463] When a substituent is listed without specifying the atom through which the substituent is attached to a given group or a given structural formula, the substituent may be attached via any bondable atom. For example, a pyrimidine substituent means that any carbon atom or nitrogen atom on the pyrimidine ring is attached to the substituted group.

[0464] When the structure appears , it indicates that the atom is a bonding atom, for example Indicates that the carbon atoms on the pyrimidine ring are bonding atoms.

[0465] The presence of a dash "-" in a substituent structure indicates the point of attachment for the substituent, for example -CH3 is attached through a C atom.

[0466] Specifically, all combinations of substituents and / or variations thereof are permissible only if such combinations result in stable compounds.

[0467] In the examples disclosed herein, the title compound names were derived from the compound structures using ChemDraw. In the event of inconsistencies between the compound name and the compound structure, the compound structure was determined using a combination of relevant information and reaction routes. If other methods were unavailable for confirmation, the given compound structure was used as the standard.

[0468] The preparation methods of some compounds disclosed herein refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0469] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0470] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group having free hydrogens may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

[0471] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0472] The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains relatively acidic functional groups, base addition salts are obtained by reaction with alkali metal or alkaline earth metal hydroxides or organic amines. These salts include cations based on alkali and alkaline earth metals, as well as nontoxic ammonium, quaternary ammonium, and amine cations, and also encompass salts of amino acids. When the compound contains relatively basic functional groups, acid addition salts are obtained by reaction with organic or inorganic acids.

[0473] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0474] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0475] The term "therapeutically effective amount" refers to a sufficient amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the present disclosure includes Formula (I), Formula (IA), Formula (IA-1), Formula (IBF-1), Formula (IC-1), Formula (ID-1), Formula (IE-1), Formula (IG-1), Formula (IGH-1), Formula (IH-1), Formula (IJ-1), Formula (IK-1), Formula (IA-2), Formula (IBF-2), Formula (IC-2), Formula (ID-2), Formula (IE-2), Formula (IG-2), Formula (IGH-2), Formula (IH-2), Formula (IJ-2), Formula (IK-2), Formula (IA-3), Formula (IBF-3) , General Formula (IC-3), General Formula (ID-3), General Formula (IE-3), General Formula (IG-3), General Formula (IGH-3), General Formula (IH-3), General Formula (IJ-3), General Formula (IK-3), General Formula (IM-1), General Formula (IN-1), General Formula (IC), General Formula (IH), General Formula (IIC), General Formula (IIC-1), General Formula (IIH), General Formula (IIH-1) and the compounds shown in Table A thereof, or their stereoisomers, or their prodrugs, or their nitrogen oxides, or their solvates, or their isotopic derivatives, or their pharmaceutically acceptable salts and the total daily dosage of the compositions shall be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors well known in the medical arts. With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" means a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of an effective amount varies from person to person, depends on the age and general condition of the recipient, and on the specific active substance, and the appropriate effective amount in each individual case can be determined by one skilled in the art through routine experimentation.

[0476] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0477] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0478] Technical Effects

[0479] The compounds disclosed herein have a significant inhibitory effect on FGFR2 and selectively inhibit FGFR2 relative to one or more of FGFR1, FGFR3, or FGFR4. They are significantly superior to the reference compound (the reference compound is compound 343 in patent WO2020231990A1) in terms of in vitro kinase activity, cell activity, or pharmacokinetic properties. The structure of the reference compound is as follows: DETAILED DESCRIPTION

[0480] The present disclosure is described in detail below by way of examples, but is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the invention.

[0481] In the embodiments of the present disclosure, the naming of the compounds is converted from the compound structure with the help of Chemdraw. If there is an inconsistency between the compound name and the compound structure, it can be determined by integrating relevant information and reaction routes. The preparation methods of some compounds in the present disclosure quote the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited, the feed ratio of the reactants, the reaction solvent, the reaction temperature, etc. can be appropriately adjusted according to the different reactants. The compounds of the present disclosure can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present disclosure.

[0482] 1. Summary of experimental instruments

[0483] The structures of the compounds disclosed herein are confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS).

[0484] NMR measurements were performed using a Bruker Avance III 400 MHz instrument (H / K instrument: Bruker Avance NEO 400 MHz). The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and deuterated water (D2O). The internal standard was DMSO. NMR chemical shifts (δ) are given in parts per million (ppm).

[0485] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200&6125B single quadrupole mass spectrometer or a Shimadzu LC-20AD XR&MS 2020&MS 2010 single quadrupole mass spectrometer (with electrospray ionization as the ion source).

[0486] HPLC analysis was performed using a Shimadzu 20AD high performance liquid chromatograph.

[0487] Preparative HPLC was performed using a GILSON GX281 332 Pump.

[0488] Chiral HPLC was performed using a Shimadzu LC-20AB with a PDA detector.

[0489] Supercritical fluid chromatography (SFC) was performed using waters UPCC with PDA Detector and QDa Detector.

[0490] The starting materials and intermediates used in this disclosure can be synthesized according to methods known in the art or purchased commercially. Experimental procedures in the examples where specific conditions are not specified were generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents where the specific sources are not specified were purchased commercially.

[0491] The reaction progress in the examples can be monitored by conventional methods such as thin layer chromatography (TLC) and LC-MS. The eluent system of the column chromatography (which can be conventional column chromatography or flash column chromatography) and the developing solvent system of the thin layer chromatography used for purification can be composed of one or more of the following solvents: dichloromethane, methanol, n-hexane, ethyl acetate, petroleum ether, ethyl acetate, acetone, dichloromethane, etc. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine, acetic acid, trifluoroformic acid, etc. can also be added for adjustment.

[0492] 2. Synthesis Example

[0493] Reference Example 1:

[0494] The preparation method refers to patent WO2020231990A1.

[0495] The synthetic routes of some compounds disclosed in this disclosure are described as follows:

[0496] Option 1:

[0497] Option 2:

[0498] Option 3:

[0499] Option 4:

[0500] Option 5:

[0501] Option 6:

[0502] Option 7:

[0503] Option 8:

[0504] The syntheses of the compounds other than TM1 to TM8 in Table A of the present disclosure were prepared by referring to any of the above schemes 1 to 8. The structures of the target compounds prepared according to the above synthetic routes were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0505] Specific compound synthesis example:

[0506] Example C01

[0507] Step 1: Synthesis of Compound C01-1

[0508] A mixture of compound C01-0 (5 g, 18.19 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborane (4.68 g, 23.65 mmol), potassium phosphate (7.72 g, 36.38 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (1.49 g, 1.82 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL), and purged with nitrogen 3 times, and then stirred at 100 ° C under nitrogen for 12 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was diluted with water (50 mL), then extracted twice with ethyl acetate (50 mL), the organic layer was separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The product was purified by flash silica gel chromatography ( The residue was purified by 20 g silica gel column (eluting with 0-6% ethyl acetate / petroleum ether, gradient @ 35 mL / min) to afford 1.43 g of compound C01-1.

[0509] MS (ESI) M / Z: 219.0 [M+H] + .

[0510] 1 H NMR (400MHz, DMSO-d6) δppm 1.29 (t, J = 7.03Hz, 3H), 4.01 (q, J = 7.15Hz, 2H), 5.69 (d, J = 12.99Hz, 1H), 7.34 (d, J = 12.87Hz, 1H), 8.67 (s, 1H).

[0511] Step 2: Synthesis of Compound C01-2

[0512] To a solution of compound C01-1 (1.43 g, 6.53 mmol) in isopropanol (15 mL) was added N,N-diisopropylethylamine (4.22 g, 32.64 mmol, 5.68 mL) and O-methylhydroxylamine hydrochloride (1.64 g, 19.58 mmol, 1.49 mL). The mixture was stirred at 50 ° C for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dried. The product was purified by flash silica gel chromatography ( The residue was purified by 20 g silica gel column with 0-25% ethyl acetate / petroleum ether gradient at 35 mL / min as eluent to afford 1.3 g of compound C01-2.

[0513] MS (ESI) M / Z: 230.1 [M+H] + .

[0514] 1 H NMR (400MHz, DMSO-d6) δppm 1.21-1.32(m,3H),3.79(s,3H),3.84-3.95(m,2H),5.79(br d,J=12.05Hz,1H),7.48(br s,1H),7.95(br d,J=12.05Hz,1H),11.36-11.86(m,1H).

[0515] Step 3: Synthesis of Compound C01-3

[0516] To a 1,2-dichloroethane solution (5 mL) of compound C01-2 (500 mg, 2.18 mmol) was added trifluoroacetic acid (1.24 g, 10.89 mmol, 808.60 μL). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (15 mL), and the mixture was stirred at 20 ° C for 5 minutes, and then extracted twice with dichloromethane (15 mL). The organic layer was separated, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The product was purified by flash silica gel chromatography ( The mixture was purified by 12 g silica gel column with 0-13% ethyl acetate / petroleum ether as eluent, gradient @ 30 mL / min) to afford 320 mg of compound C01-3.

[0517] MS (ESI) M / Z: 184.1 [M+H] + .

[0518] 1 H NMR (400MHz, CHLOROFORM-d) δppm 4.24 (s, 3H), 6.52 (d, J = 3.93Hz, 1H), 7.42 (d, J = 3.81Hz, 1H), 8.67 (s, 1H).

[0519] Step 4: Synthesis of Compound C01-4

[0520] Compound C01-3 (240 mg, 1.31 mmol) was dissolved in aqueous ammonia (27.30 g, 194.75 mmol, 30 mL, 25% purity) and tetrahydrofuran (2.5 mL). The mixture was transferred to a 100 mL tetrafluoroethylene flask and stirred at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. The mixture was filtered through diatomaceous earth. The filter cake was then washed twice with dichloromethane (30 mL). The filtrate was concentrated to obtain 220 mg of compound C01-4.

[0521] MS (ESI) M / Z: 165.1 [M+H] + .

[0522] 1 H NMR (400MHz, DMSO-d6) δppm 4.06 (s, 3H), 6.50 (d, J = 3.70Hz, 1H), 7.28 (br s, 2H), 7.40 (d, J = 3.70Hz, 1H), 8.09 (s, 1H).

[0523] Step 5: Synthesis of Compound C01-5

[0524] To a solution of compound C01-4 (200 mg, 1.22 mmol) and tert-butyl (2-methylpropane-2-yl) oxycarbonyl carbonate (664.72 mg, 3.05 mmol, 699.70 μL) in dichloromethane (2.5 mL) were added N,N-diisopropylethylamine (314.90 mg, 2.44 mmol, 424.40 μL) and 4-dimethylaminopyridine (74.42 mg, 609.15 μmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (4 g silica gel column, ethyl acetate / petroleum ether eluent, 0-22% gradient, 20 mL / min) to obtain 320 mg of compound C01-5.

[0525] MS (ESI) M / Z: 365.2 [M+H] + .

[0526] Step 6: Synthesis of Compound C01-6

[0527] To a solution of compound C01-5 (300 mg, 823.28 μmol) in N,N-dimethylformamide (3 mL) was added N-iodosuccinimide (277.84 mg, 1.23 mmol). The mixture was stirred at 40 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and then washed twice with saturated brine (10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel column, ethyl acetate / petroleum ether eluent, 0-30% gradient, 30 mL / min) to obtain 210 mg of compound C01-6.

[0528] MS (ESI) M / Z: 391.1 [M+H] + .

[0529] 1 H NMR (400MHz, DMSO-d6) δppm 1.48(s,10H),4.13(s,3H),8.12(s,1H),8.58(s,1H),9.54(s,1H).

[0530] Step 7: Synthesis of Compound C01-7

[0531] A solution of compound C01-6 (200 mg, 512.59 μmol), 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-4-methyl-pyrimidine (203.08 mg, 615.11 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (83.72 mg, 102.52 μmol), cesium carbonate (334.02 mg, 1.03 mmol) in water (0.6 mL) and 1,4-dioxane (3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90° C. for 2 hours under nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (4 g silica gel column, ethyl acetate / petroleum ether eluent, 0-100% gradient, 20 mL / min) to obtain 120 mg of compound C01-7.

[0532] MS (ESI) M / Z: 367.1 [M+H] + .

[0533] 1 H NMR(400MHz,DMSO-d6)δppm 2.43(s,3H),4.13(s,3H),6.09-6.60(m,2H),7.20(d,J=5.02Hz,1H),7.33(d,J=8 .28Hz,1H),7.41-7.51(m,2H),7.76(s,1H),8.18(s,1H),8.48(d,J=4.77Hz,1H).

[0534] Step 8: Synthesis of Compound C01-8

[0535] To a solution of compound C01-7 (60 mg, 163.78 μmol) in dichloromethane (3 mL) was added N-iodosuccinimide (73.69 mg, 327.56 μmol) and trifluoroacetic acid (130.72 mg, 1.15 mmol, 85.16 μL). After the mixture was stirred at 40 ° C for 2 hours, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (10 mL), stirred at 20 ° C for 5 minutes, and then extracted twice with dichloromethane (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography (4 g silica gel column, methanol / ethyl acetate eluent, 0-2% gradient, 20 mL / min) to give 66 mg of compound C01-8.

[0536] MS (ESI) M / Z: 493.0 [M+H] + .

[0537] 1H NMR(400MHz,DMSO-d6)δppm 2.45(s,3H),4.12(s,3H),7.22(d,J=5.02Hz,1H),7.26-7.31(m,1H),7.42(dd,J= 11.29,1.76Hz,1H),7.50(t,J=8.28Hz,1H),8.12(s,1H),8.51(d,J=5.02Hz,1H).

[0538] Step 9: Synthesis of Compound C01

[0539] A solution of compound C01-8 (60 mg, 121.89 μmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (35.00 mg, 121.89 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane (19.91 mg, 24.38 μmol), and cesium carbonate (79.43 mg, 243.78 μmol) in water (0.2 mL) and 1,4-dioxane (1 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 95°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography to obtain 22.67 mg of compound C01.

[0540] MS (ESI) M / Z: 526.3 [M+H] + .

[0541] 1 H NMR (400MHz, DMSO-d6) δppm 1.95(s,3H),2.42(s,3H),3.91(s,3H),5.53(s,1H),5.77-5.84(m,1H),7.12-7.23(m,2H),7.27(br d,J=10.04Hz,1H),7.31-7.43(m,3H),7.73(br d,J=8.28Hz,2H),8.21(s,1H),8.48(d,J=4.77Hz,1H),9.92(s,1H).

[0542] Intermediate: Int-A1

[0543] Reaction route:

[0544] Steps:

[0545] To a solution of 4-hydroxyphenylboronic acid xanaxol ester (500 mg, 2.27 mmol) and 2-chloro-4-methylpyrimidine (321.29 mg, 2.50 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.48 g, 4.54 mmol). The mixture was stirred at 100°C for 1.5 hours. After filtration, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel chromatography to give Int-A1 (600 mg).

[0546] 1 H NMR (400MHz, CHLOROFORM-d) δ: 1.35 (s, 12H), 2.50 (s, 3H), 6.90 (d, J = 5.02Hz, 1H), 7.20 (br d, J = 8.03Hz, 2H), 7.88 (br d,J=8.03Hz,2H),8.35(d,J=4.77Hz,1H).

[0547] MS (ESI) M / Z: 313.0 [M+H] + .

[0548] Intermediate: Int-A2

[0549] Reaction route:

[0550] Steps:

[0551] To a mixture of 6-bromo-2-fluoro-pyridin-3-ol (1 g, 5.21 mmol) and 2-bromo-4-methylpyrimidine (1 g, 5.78 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (3.39 g, 10.42 mmol), and the mixture was stirred at 100 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and then extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography to give compound Int-A2 (610 mg).

[0552] 1 H NMR (400MHz, CHLOROFORM-d) δ: 8.37 (d, J = 5.01Hz, 1H), 7.52-7.60 (m, 1H), 7.44 (d, J = 8.11Hz, 1H), 6.99 (d, J = 5.01Hz, 1H), 2.50 (s, 3H).

[0553] MS (ESI) M / Z: 284.1 [M+H] + .

[0554] Intermediate: Int-A3

[0555] Reaction route:

[0556] Steps:

[0557] A solution of 2-hydroxy-5-bromopyridine (1 g, 5.75 mmol), 2-chloro-4-methylpyrimidine (738.87 mg, 5.75 mmol), and potassium carbonate (1.59 g, 11.49 mmol) in N,N-dimethylformamide (10 mL) was stirred at 130°C under microwave for 40 min. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography to obtain 670 mg of compound Int-A3.

[0558] MS (ESI) M / Z: 266.0 & 268.0 [M+H] + .

[0559] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.39(d,J=5.0Hz,1H),8.35(d,J=2.7Hz,1H),7.52-7.58(m,1H),7.45-7.50(m,1H),6.98(d,J=5.0Hz,1H),2.51(s,3H).

[0560] Intermediate: Int-A4

[0561] Reaction route:

[0562] Steps:

[0563] A solution of 6-bromo-3-hydroxypyridine (1 g, 5.75 mmol), 2-chloro-4-methylpyrimidine (738.87 mg, 5.75 mmol) and potassium carbonate (1.59 g, 11.49 mmol) in DMF (10 mL) was stirred at 130 ° C for 40 min under microwave. Saturated brine (20 mL) was added and extracted with ethyl acetate (6 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography to obtain 670 mg of Int-A4.

[0564] MS (ESI) M / Z: 266.0 & 268.0 [M+H] + .

[0565] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.39(d,J=5.0Hz,1H),8.35(d,J=2.7Hz,1H),7.52-7.58(m,1H),7.45-7.50(m,1H),6.98(d,J=5.0Hz,1H),2.51(s,3H).

[0566] Intermediate: Int-B1

[0567] Reaction route:

[0568] Steps:

[0569] A mixture of 4-aminophenylboronic acid xanaxol ester (4 g, 18.26 mmol), 2-methylpropylene-2-enoic acid (3.14 g, 36.52 mmol), diisopropylethylamine (11.80 g, 91.29 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13.88 g, 36.52 mmol) in acetonitrile (50 mL) was stirred at 25° C. for 8 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel chromatography to give Int-B1 (2 g).

[0570] MS (ESI) M / Z: 288.4 [M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ: 1.28 (s, 12H), 1.94 (s, 3H), 5.53 (s, 1H), 5.81 (s, 1H), 7.61 (d, J = 8.03Hz, 2H), 7.71 (d, J = 8.03Hz, 2H), 9.88 (s, 1H).

[0572] Intermediate: Int-B2

[0573] Reaction route:

[0574] Steps:

[0575] To a pyridine (8 mL) solution of 4-amino-2-methylphenylboronic acid naphthalene ester (500 mg, 2.14 mmol) and 2-methylpropylene-2-enoic acid (369.30 mg, 4.29 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (616.76 mg, 3.22 mmol) and the mixture was stirred at 70 ° C for 1 hour. After cooling to room temperature, it was extracted three times with ethyl acetate (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product, which was purified by flash silica gel chromatography to give compound Int-B2 (600 mg).

[0576] 1 H NMR(400MHz,CHLOROFORM-d)δ:7.74(d,J=7.99Hz,1H),7.49(br s,1H),7.35-7.44(m,2H),5.79(s,1H),5.47(d,J=1.31Hz,1H),2.54(s,3H),2.07(s,3H),1.34(s,12H).

[0577] MS (ESI) M / Z: 302.2 [M+H] + .

[0578] Intermediate: Int-B3

[0579] Reaction route:

[0580] Steps:

[0581] 4-Aminophenylboronic acid xanaxol ester (500 mg, 2.28 mmol) was dissolved in N, N-dimethylformamide (8 mL), and 2-fluoroacrylic acid (226.07 mg, 2.51 mmol), O-(7-nitrobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.30 g, 3.42 mmol) and N, N-diisopropylethylamine (884.85 mg, 6.85 mmol, 1.19 mL) were added, and the mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, and the residue was purified by flash silica gel chromatography to give Int-B3 (340 mg).

[0582] 1H NMR(400MHz,CHLOROFORM-d)δ:7.97(br s,1H),7.83(d,J=8.5Hz,2H),7.63(d,J=8.3Hz,2H),5.71-6.10(m,1H),5.28(dd,J=15.3,3.3Hz,1H),1.37(s,12H).

[0583] MS (ESI) M / Z: 291.9 [M+H] + .

[0584] Intermediate: Int-B4

[0585] Reaction route:

[0586] Steps:

[0587] Compound 4-amino-2-fluorophenylboronic acid xanaxol ester (500 mg, 2.11 mmol) and triethylamine (426.82 mg, 4.22 mmol) were dissolved in dichloromethane (8 mL), and 2-methylpropyl-2-enoyl chloride (242.51 mg, 2.32 mmol) was added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, and the residue was purified by flash silica gel chromatography (mobile phase: 0-20% ethyl acetate / petroleum ether) to obtain compound Int-B4 (120 mg).

[0588] 1 H NMR(CHLOROFORM-d)δ:7.62(br t,J=7.3Hz,1H),7.40-7.52(m,2H),7.12(dd,J=8.2,1.5Hz,1H),5.73(s,1H),5.43(s,1H),1.99(s,3H),1.29(s,12H).

[0589] MS (ESI) M / Z: 306.1 [M+H] + .

[0590] Intermediate: Int-C1

[0591] Reaction route:

[0592] Steps:

[0593] Step 1: To a solution of C01-5 (500 mg, 1.37 mmol) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (463.05 mg, 2.06 mmol) and the mixture was stirred at 40 ° C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), and then washed twice with saturated brine (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to give Int-C1-1 (630 mg).

[0594] 1 H NMR(400MHz,CHLOROFORM-d)δ:1.42(s,18H),4.25(s,3H),7.55(s,1H),8.86(s,1H).

[0595] MS (ESI) M / Z: 491.2 [M+H] + .

[0596] Step 2: A solution of Int-C1-1 (400 mg, 815.84 μmol), pinacol borane (156.61 mg, 1.22 mmol), tris(dibenzylideneacetone)dipalladium (74.71 mg, 81.58 μmol), triethylamine (247.66 mg, 2.45 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (77.78 mg, 163.17 μmol) in dioxane (10 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 80° C. under nitrogen for 12 hours. After cooling, water (10 mL) was added to the mixture and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography to give Int-C1 (390 mg).

[0597] 1 H NMR(400MHz,CHLOROFORM-d)δ:8.87(s,1H),7.88(s,1H),4.27(s,3H),1.35(s,12H),1.32(s,18H).

[0598] MS (ESI) M / Z: 491.2 [M+H] + .

[0599] Example C02

[0600] Reaction route:

[0601] Steps:

[0602] Step 1: A mixture of Int-A1 (191.01 mg, 611.88 μmol), Int-C1 (200 mg, 407.92 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33.31 mg, 40.79 μmol), cesium carbonate (265.82 mg, 815.84 μmol), dioxane (4 mL) and water (0.8 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 85 ° C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel chromatography to give C02-1 (150 mg).

[0603] 1 H NMR(400MHz,CHLOROFORM-d)δ:1.34(s,18H),2.53(s,3H),4.30(s,3H),6.93(d,J=4.77Hz,1H),7 .25(d,J=8.53Hz,2H),7.45(s,1H),7.52(d,J=8.53Hz,2H),8.37(d,J=5.02Hz,1H),8.88(s,1H).

[0604] MS (ESI) M / Z: 549.2 [M+H] + .

[0605] Step 2: A solution of C02-1 (150 mg, 273.43 μmol) and trifluoroacetic acid (311.77 mg, 2.73 mmol) in dichloromethane (3 mL) was stirred at 25 ° C for 12 hours. The reaction solution was quenched with aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel chromatography to give C02-2 (80 mg).

[0606] 1 H NMR (400MHz, CHLOROFORM-d) δ: 2.53 (s, 3H), 4.24 (s, 3H), 6.95 (d, J = 5.02Hz, 1H), 7.16 (s, 1H),7.31(d,J=8.53Hz,2H),7.52(d,J=8.53Hz,2H),8.36(s,1H),8.39(d,J=5.02Hz,1H).

[0607] MS (ESI) M / Z: 349.2 [M+H] + .

[0608] Step 3: Trifluoroacetic acid (183.30 mg, 1.61 mmol) and N-iodosuccinimide (103.33 mg, 459.30 μmol) were added to a solution of C02-2 (80 mg, 229.65 μmol) in dichloromethane (5 mL). The mixture was stirred at 40 ° C for 2 hours. The reaction solution was quenched with aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel chromatography to give C02-3 (60 mg).

[0609] 1 H NMR(400MHz,CHLOROFORM-d)δ:2.54(s,3H),4.27(s,3H),6.96(d,J=5.01Hz,1H) ,7.36(d,J=8.58Hz,2H),7.50-7.54(m,2H),8.28(s,1H),8.40(d,J=5.01Hz,1H).

[0610] MS (ESI) M / Z: 475.1 [M+H] + .

[0611] Step 4: A solution of C02-3 (50 mg, 105.43 μmol), Int-B1 (60.55 mg, 210.86 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2′, 4′, 6′-triisopropyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl) palladium (II) (9.07 mg, 10.54 μmol) and potassium phosphate (0.5 M, 2.60 mL) in tetrahydrofuran (0.5 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 70 ° C under nitrogen for 1 hour. After cooling to room temperature, it was extracted three times with ethyl acetate (5 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography to give C02 (20 mg).

[0612] Example C03

[0613] Reaction route:

[0614] Steps:

[0615] A mixture of compound C01-8 (30 mg, 60.95 μmol), compound Int-B3 (44.36 mg, 152.36 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2', 4', 6'-triisopropyl-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (5.24 mg, 6.09 μmol), potassium phosphate (0.5 M, 1.5 mL) and THF (0.7 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 70 ° C under a nitrogen environment for 1 hour. After cooling to room temperature, water (10 mL) was added and extracted three times with ethyl acetate (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to give a crude product, and the residue was purified by flash silica gel chromatography to give C03 (25.0 mg).

[0616] Example C38

[0617] Reaction route:

[0618] Steps:

[0619] Step 1: A mixture of Int-C1 (390 mg, 795.34 μmol, 1 eq), Int-A4 (232.80 mg, 874.87 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (64.95 mg, 79.53 μmol), potassium phosphate (506.47 mg, 2.39 mmol), dioxane (6 mL), and water (1.2 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90°C under nitrogen for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The residue was purified by flash silica gel chromatography (mobile phase: 0-50% ethyl acetate / petroleum ether, 25 mL / min) to afford 220 mg of C38-1.

[0620] MS (ESI) M / Z: 550.2 [M+H] + .

[0621] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.92(s,1H),8.60(s,1H),8.39(d,J=5.0Hz,1H),7.86(s,1H),7.62(s,2H),6.98(d,J=5.0Hz,1H),4.33(s,3H),2.53(s,3H),1.31(s,18H).

[0622] Step 2: Dissolve C38-1 (150 mg, 272.94 μmol) in dichloromethane (2 mL) and add trifluoroacetic acid (311.21 mg, 2.73 mmol). Stir the reaction mixture at 40°C for 1 hour. Pour the reaction mixture slowly into sodium bicarbonate (10 mL) and extract with dichloromethane (10 mL x 3). Combine the organic phases and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to yield 75 mg of C38-2.

[0623] MS (ESI) M / Z: 350.2 [M+H] + .

[0624] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.31(d,J=2.5Hz,1H),8.24(d,J=5.0Hz,1H),8.13(s,1H),7.52-7.58(m, 1H),7.41-7.50(m,2H),6.82(d,J=5.0Hz,1H),4.09(s,3H),2.37(s,3H).

[0625] Step 3: Dissolve C38-2 (65 mg, 186.06 μmol) and N-iodosuccinimide (125.58 mg, 558.19 μmol) in dichloromethane (3 mL). Slowly add trifluoroacetic acid (106.08 mg, 930.31 μmol), and stir the reaction mixture at 40°C for 1 hour. Dilute the reaction mixture with dichloromethane (20 mL) and wash with aqueous sodium bicarbonate (10 mL) and then aqueous sodium thiosulfate (10 mL). Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude product. The residue is purified by preparative thin layer chromatography to yield 36 mg of C38-3.

[0626] MS (ESI) M / Z: 476.0 [M+H] + .

[0627] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.64(d,J=2.5Hz,1H),8.44(d,J=4.8Hz,1H),8.29(s,1H),8.15(d,J=8.8Hz,1H ),7.76(dd,J=8.8,2.8Hz,1H),7.02(d,J=5.0Hz,1H),4.27(s,3H),2.56(s,3H).

[0628] Step 4: A mixture of C38-3 (40 mg, 84.17 μmol), Int-B1 (48.34 mg, 168.34 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.87 mg, 8.42 μmol), cesium carbonate (54.85 mg, 168.34 μmol), water (0.25 mL) and dioxane (1 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90 °C under nitrogen for 1 hour. After cooling to room temperature, the mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product, which was purified by thin layer chromatography to give C38 (22.23 mg).

[0629] Example C46

[0630] Reaction route:

[0631] Steps:

[0632] Step 1: To a solution of compound Int-C1 (0.6 g, 1.22 mmol), compound Int-A2 (417.13 mg, 1.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (99.92 mg, 122.36 μmol) in dioxane (15 mL) and water (3 mL), anhydrous potassium phosphate (779.19 mg, 3.67 mmol) was added, the reaction solution was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 ° C under a nitrogen environment for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography to obtain compound C46-1 (390 mg).

[0633] 1 H NMR(400MHz,CHLOROFORM-d)δ:8.91(s,1H),8.37(d,J=5.02Hz,1H),7.88(s,1H),7.70(t,J=8.66 Hz,1H),7.49(d,J=8.03Hz,1H),6.98(d,J=5.02Hz,1H),4.31(s,3H),2.51(s,3H),1.34(s,18H).

[0634] MS (ESI) M / Z: 568.3 [M+H] + .

[0635] Step 2: To a mixture of compound C46-1 (390 mg, 687.14 μmol) in dichloromethane (20 mL) was added trifluoroacetic acid (3.07 g, 26.92 mmol), and the reaction was stirred at 40°C for 12 hours. After cooling to room temperature, the pH was adjusted to 10 with aqueous sodium bicarbonate solution, and then extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound C46-2 (249 mg).

[0636] 1 H NMR(400MHz,CHLOROFORM-d)δ:8.39(d,J=5.01Hz,1H),8.31(s,1H),7.68-7.76(m,1H), 7.64(s,1H),7.56(d,J=8.23Hz,1H),6.99(d,J=5.01Hz,1H),4.25(s,3H),2.52(s,3H).

[0637] MS (ESI) M / Z: 368.1 [M+H] + .

[0638] Step 3: To a solution of compound C46-2 (140 mg, 381.12 μmol) in dichloromethane (10 mL) were added trifluoroacetic acid (304.20 mg, 2.67 mmol) and N-iodosuccinimide (171.49 mg, 762.24 μmol). The mixture was stirred at 40 ° C for 2 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane (30 mL), and then the reaction solution was poured into a mixture of saturated sodium bicarbonate (25 mL) and saturated sodium bisulfite (25 mL) to quench, and then the mixture was extracted three times with dichloromethane (50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was slurried and stirred with anhydrous methanol (3 mL) at room temperature for 10 minutes, then filtered, the filter cake was collected and dried under reduced pressure to obtain compound C46-3 (140 mg).

[0639] 1 H NMR (400MHz, DMSO-d6) δ: 8.54 (d, J = 5.01Hz, 1H), 8.08-8.24 (m, 2H), 7.95 (br d, J = 8.11Hz, 1H), 7.27 (br d, J = 4.89Hz, 3H), 4.14 (s, 3H), 2.46 (s, 3H).

[0640] MS (ESI) M / Z: 494.0 [M+H] + .

[0641] Step 4: To a solution of compound C46-3 (80 mg, 162.20 μmol) and compound Int-B1 (116.44 mg, 405.49 μmol) in dioxane (7.5 mL) and water (1.5 mL) were added anhydrous potassium phosphate (103.29 mg, 486.59 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (19.87 mg, 24.33 μmol). The reaction mixture was heated to 70°C under nitrogen and stirred for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain a crude product, which was then purified by preparative chromatography to obtain C46 (34.59 mg).

[0642] Example C54

[0643] Reaction route:

[0644] Steps:

[0645] A mixture of compound C38-11 (60 mg, 126.25 μmol), Int-B2 (76.05 mg, 252.50 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.31 mg, 12.63 μmol), cesium carbonate (82.27 mg, 252.50 μmol), water (3 mL), and dioxane (15 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90 °C under nitrogen for 1 hour. After cooling to room temperature, the mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by preparative chromatography to give C54 (11.84 mg).

[0646] Example H01

[0647] Reaction route:

[0648] Steps:

[0649] Step 1: Dissolve compound H01-0 (10 g, 52.36 mmol) in N,N-dimethylformamide (100 mL), and add potassium carbonate (8.68 g, 62.83 mmol) and benzyl bromide (9.85 g, 57.59 mmol, 6.84 mL) respectively. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The reaction mixture was diluted with ethyl acetate (100 mL), and the residue was washed twice with saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 16.0 g of compound H01-1.

[0650] 1 HNMR (400MHz, CHLOROFORM-d) δ: 7.32-7.46 (m, 5H), 7.22-7.30 (m, 1H), 7.13-7.19 (m, 1H), 6.88 (t, J = 8.76Hz, 1H), 5.13 (s, 2H).

[0651] Step 2: Compound H01-1 (16 g, 56.92 mmol) was dissolved in tetrahydrofuran (160 mL), the reaction solution was cooled to -78 ° C, and lithium diisopropylamide (tetrahydrofuran solution) (2M, 42.69 mL) was added dropwise to the reaction solution. After the addition was completed, it was stirred at -78 ° C for 1 hour, and then a solution of N, N-dimethylformamide (6.24 g, 85.37 mmol) in tetrahydrofuran (10 mL) was added dropwise, and then stirred at -78 ° C for 2 hours. The mixture was poured into a saturated aqueous ammonium chloride solution (500 mL), stirred at 20 ° C for 5 minutes, and then extracted twice with ethyl acetate (500 mL). The organic phase was washed with saturated brine (300 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 18.0 g of compound H01-2.

[0652] 1 HNMR (400MHz, DMSO-d6) δppm 10.17 (s, 1H), 7.36-7.52 (m, 7H), 5.24 (s, 2H).

[0653] Step 3: Compound H01-2 (13.3 g, 43.02 mmol) and pentamethylbenzene (19.13 g, 129.07 mmol) were dissolved in dichloromethane (150 mL). After the reaction solution was cooled to -78 ° C, boron trichloride (dichloromethane solution) (2M, 64.54 mL) was added dropwise, and the resulting mixture was stirred at -78 ° C for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (300 mL), the mixture was stirred at 20 ° C for 5 minutes, and then extracted twice with dichloromethane (150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was passed through a flash silica gel column to obtain 8.85 g of compound H01-3.

[0654] 1 HNMR (400MHz, DMSO-d6) δppm 10.30-11.11(m,1H),10.16(s,1H),7.40(dd,J=8.66,1.13Hz,1H),7.16(t,J=8.91Hz,1H).

[0655] Step 4: Compound H01-3 (8.85 g, 40.41 mmol) was dissolved in methanol (100 mL), the reaction solution was cooled to 0°C, sodium borohydride (3.83 g, 101.24 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (200 mL), the mixture was stirred at 20°C for 5 minutes, and then extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8.50 g of compound H01-4.

[0656] Step 5: Compound H01-4 (5 g, 22.62 mmol) was dissolved in N,N-dimethylformamide solution (50 mL), potassium carbonate (14.74 g, 45.24 mmol) and 2-chloro-4-methylpyrimidine (3.20 g, 24.88 mmol) were added, and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with ethyl acetate (50 mL) and then washed twice with saturated brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product. The residue was subjected to flash silica gel chromatography to obtain 2.75 g of compound H01-5.

[0657] 1HNMR(400MHz,DMSO-d6)δppm 8.46(d,J=4.77Hz,1H),7.53(dd,J=8.66,1.63Hz,1H),7.31(t,J=8.41Hz,1H),7.20(d,J =5.02Hz,1H),5.33(t,J=5.52Hz,1H),4.59(dd,J=5.52,2.51Hz,2H),2.41-2.43(m,3H).

[0658] MS (ESI) M / Z: 312.9 [M+H] + .

[0659] Step 6: Dissolve compound H01-5 (2.75 g, 8.78 mmol) and triethylamine (4.44 g, 43.91 mmol, 6.11 mL) in dichloromethane (30 mL). Cool the reaction mixture to 0°C and slowly add methanesulfonyl chloride (2.81 g, 24.53 mmol, 1.90 mL) dropwise. After the addition is complete, slowly return the temperature to 20°C and continue stirring for 2 hours. Pour the reaction mixture slowly into saturated aqueous sodium bicarbonate solution (50 mL), stir the mixture for 5 minutes, and then extract twice with dichloromethane (50 mL). Dry the organic layer over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 4.00 g of compound H01-6.

[0660] MS (ESI) M / Z: 391.0 [M+H] + .

[0661] Step 7: Compound H01-6 (4 g, 10.22 mmol) and compound H01-13 (2.15 g, 9.20 mmol) were dissolved in N, N-dimethylformamide (40 mL) solution, and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.87 g, 12.27 mmol, 1.85 mL) was added dropwise to the reaction solution. The mixed solution was replaced with nitrogen three times and stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. After dilution with ethyl acetate (50 mL), the mixture was washed twice with saturated brine (50 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography to obtain 1.89 g of compound H01-7.

[0662] 1H NMR(400MHz,DMSO-d6)δppm 8.44-8.47(m,1H),7.60(dd,J=8.78,1.51Hz,1H),7.41-7.50(m,1H),7.21(d,J=5.02Hz,1H),5.10(d,J=2.01Hz,2H),2.42(s,3H),1.36(s,18H).

[0663] MS (ESI) M / Z: 428.1 [M-100+H] + .

[0664] Step 8: A mixture of compound H01-7 (1.89 g, 3.58 mmol), bis-pinacol boronate (1.09 g, 4.29 mmol), potassium acetate (1.05 g, 10.73 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane (292.12 mg, 357.71 μmol), and 1,4-dioxane (15 mL) was degassed and purged with nitrogen three times, followed by stirring at 90 ° C. under a nitrogen atmosphere for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The residue was subjected to flash silica gel chromatography to obtain 1.80 g of compound H01-8.

[0665] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.31-8.38(m,1H),7.70(d,J=7.78Hz,1H),7.24-7.27(m,1H),6.91(d,J=5. 02Hz, 1H), 5.40 (d, J = 2.01Hz, 2H), 2.50 (s, 3H), 1.39 (s, 18H), 1.35 (s, 12H).

[0666] MS (ESI) M / Z: 576.3 [M+H] + .

[0667] Step 9: A mixture of compound H01-8 (600 mg, 1.04 mmol), 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-d]pyrimidine (459.03 mg, 1.56 mmol), cesium carbonate (679.46 mg, 2.09 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane (170.30 mg, 208.54 μmol), water (1.2 mL), and 1,4-dioxane (6 mL) was degassed and purged with nitrogen three times, then stirred at 60° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography to give 260 mg of compound H01-9.

[0668] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.69(s,1H),8.37-8.41(m,1H),7.85(s,1H),7.31-7.39(m,1H),7.30(s,1H),6.95( d,J=5.01Hz,1H),5.31(s,2H),3.99(s,3H),2.51-2.54(m,3H),1.37-1.41(m,18H).

[0669] MS (ESI) M / Z: 615.3 [M+H] + .

[0670] Step 10: Compound H01-9 (260 mg, 422.73 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.07 g, 26.93 mmol, 2 mL) was added, and the reaction solution was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 175 mg of compound H01-10.

[0671] MS (ESI) M / Z: 415.1 [M+H] + .

[0672] Step 11: Compound H01-10 (175 mg, 421.87 μmol) and triethylamine (426.89 mg, 4.22 mmol, 587.19 μL) were dissolved in acetonitrile (20 mL) and the reaction solution was stirred at 80 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. Water (50 mL) was added and then extracted twice with dichloromethane (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product. 200 mg of compound H01-11 was obtained.

[0673] 1 H NMR(400MHz,DMSO-d6)δppm 11.11(s,1H),8.44-8.52(m,1H),8.23(s,1H),8.01(s,1H),7.70(d,J=8.78Hz,1H) ,7.35-7.44(m,1H),7.21(d,J=4.89Hz,1H),5.07(s,2H),3.83(s,3H),2.43(s,3H).

[0674] MS (ESI) M / Z: 379.1 [M+H] + .

[0675] Step 12: Compound H01-11 (190 mg, 502.17 μmol) was dissolved in dichloromethane (20 mL). The reaction mixture was cooled to 0°C, and N-iodosuccinimide (225.96 mg, 1.00 mmol) and trifluoroacetic acid (286.29 mg, 2.51 mmol, 186.51 μL) were added. The reaction mixture was stirred at 0°C for 50 minutes. The reaction mixture was poured into a mixed solution of saturated aqueous sodium bicarbonate (25 mL) and saturated aqueous sodium sulfite (5 mL). The mixture was stirred at 20°C for 5 minutes and then extracted twice with dichloromethane (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with methanol (15 mL) for 30 minutes and then filtered. The filter cake was dried to obtain 138 mg of compound H01-12.

[0676] 1 H NMR(400MHz,DMSO-d6)δppm 10.81-11.08(m,1H),8.50(d,J=5.01Hz,1H),8.21(s,1H),7.80(d,J=8.58Hz,1H),7.43 (t,J=8.40Hz,1H),7.21(d,J=4.89Hz,1H),4.88-5.13(m,2H),3.88(s,3H),2.45(s,3H).

[0677] MS (ESI) M / Z: 505.2 [M+H] + .

[0678] Step 13: A mixture of compound H01-12 (40 mg, 79.32 μmol), compound Int-B1 (45.56 mg, 158.65 μmol), potassium phosphate (50.51 mg, 237.97 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane complex (12.96 mg, 15.86 μmol), water (0.8 mL), 1,4-dioxane (2 mL) and N,N-dimethylformamide (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90 ° C for 1 hour under a nitrogen environment. The reaction mixture was diluted with water (10 mL), then extracted twice with ethyl acetate (20 mL), and the combined organic layers were washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography to obtain 9.06 mg of compound H01.

[0679] Example H22

[0680] Reaction route:

[0681] Steps:

[0682] Step 1: To a solution of C01-3 (500 mg, 2.72 mmol) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (919.08 mg, 4.09 mmol). The mixture was stirred at 40 ° C for 18 hours. After cooling to room temperature, the mixture was poured into a saturated aqueous sodium sulfite solution (35 mL), and then the mixture was extracted twice with ethyl acetate (30 mL). The combined organic layer was washed twice with saturated brine (30 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. 670 mg of compound H22-1 was obtained by flash silica gel chromatography.

[0683] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.66(s,1H),7.57(s,1H),4.24(s,3H).

[0684] MS (ESI) M / Z: 310.0 [M+H] + .

[0685] Step 2: H22-1 (129.08 mg, 417.08 μmol), H01-8 (200 mg, 347.56 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane complex (56.77 mg, 69.51 μmol), and cesium carbonate (226.49 mg, 695.13 μmol) were dissolved in dioxane (3 mL) and water (0.6 mL), purged with nitrogen three times, and then stirred at 60 ° C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. Purification by flash silica gel column chromatography gave 106 mg of compound H22-2.

[0686] 1 H NMR (400MHz, CHLOROFORM-d) δppm 8.71 (s, 1H), 8.39 (d, J = 5.02Hz, 1H), 8.03 (s, 1H), 7.33-7.40 (m, 1H), 7.29 (br d,J=1.00Hz,1H),6.95(d,J=5.02Hz,1H),4.50-5.46(m,2H),4.36(s,3H),2.49-2.57(m,3H),1.35-1.42(m,18H).

[0687] MS (ESI) M / Z: 631.3 [M+H] + .

[0688] Step 3: To a solution of H22-2 (100 mg, 158.47 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 70 mg of compound H22-3.

[0689] MS (ESI) M / Z: 431.1 [M+H] + .

[0690] Step 4: To a solution of H22-3 (70 mg, 162.48 μmol) in acetonitrile (20 mL) was added triethylamine (727.00 mg, 7.18 mmol). The mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. Purification by flash silica gel chromatography afforded 34 mg of compound H22-4.

[0691] 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.30-8.48(m,2H),7.65(s,1H),7.52(dd,J=8.66,1.13Hz,1H),7.27-7.32( m,1H),6.95(d,J=5.02Hz,1H),5.25(s,2H),4.29(s,3H),2.49-2.56(m,3H).

[0692] MS (ESI) M / Z: 395.2 [M+H] + .

[0693] Step 5: At 0 ° C, to a solution of H22-4 (34 mg, 86.22 μmol) and trifluoroacetic acid (49.15 mg, 431.08 μmol) in dichloromethane (5 mL), N-iodosuccinimide (38.79 mg, 172.43 μmol) was added, and the mixture was stirred at 0 ° C for 1 hour. After rising to room temperature, the mixture was poured into a saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous sodium sulfite solution (2 mL), and then the mixture was extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. 50 mg of compound H22-5 was obtained by flash silica gel chromatography.

[0694] MS (ESI) M / Z: 521.1 [M+H] + .

[0695] Step 6: H22-5 (40 mg, 76.89 μmol), Int-B1 (33.12 mg, 115.33 μmol), potassium phosphate (48.96 mg, 230.66 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane complex (12.56 mg, 15.38 μmol) were dissolved in dioxane (4 mL) and water (0.8 mL), purged with nitrogen 3 times, and then stirred at 90 ° C for 1 hour under nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by flash silica gel chromatography and then purified by preparative chromatography to obtain 3.86 mg of compound H22.

[0696] The compounds shown in Table B below can be synthesized according to the synthesis methods of the above examples, or according to the synthesis schemes of Schemes 1 to 8, or according to methods in existing literature.

[0697] Table B

[0698] Biological evaluation

[0699] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0700] Test Example 1: Inhibitory effect of the disclosed compounds on FGFR1, FGFR2, FGFR3, and FGFR4 kinases

[0701] The FGFR1, FGFR2, FGFR3, and FGFR4 kinase activities of the disclosed compounds were tested using methods well known to those skilled in the art, such as the HTRF method.

[0702] 1.1 Experimental Materials

[0703] 1.2 Experimental steps

[0704] 1) The disclosed compounds were diluted with DMSO.

[0705] 2) Use Echo 655 to transfer 50 nL of the disclosed compound to a 384-well reaction plate.

[0706] 3) Prepare a 2× kinase solution using 1× kinase reaction buffer (5× Buffer, 5 mM MgCl 2 , 1 mM DTT), and transfer 2.5 μL of FGFR1 / 2 / 3 / 4 (0.1 nM / 0.08 nM / 0.3 nM / 10 nM) solution to a 384-well reaction plate.

[0707] 4) Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 10 minutes.

[0708] 5) Prepare a 2x mixture of substrate (TK: 1 μM) and ATP (40 μM (FGFR1) / 20 μM (FGFR2) / 50 μM (FGFR3) / 50 μM (FGFR4)) in kinase reaction buffer. Add 2.5 μL of the substrate and ATP mixture to the reaction plate to start the reaction. Centrifuge at 1000 rpm for 1 minute.

[0709] 6) Incubate at 25°C for 50 minutes.

[0710] 7) Add 5 μL of HTRF kinase detection reagent to each well of the reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0711] 8) Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0712] 9) Each reaction was tested in duplicate, and IC was analyzed using GraphPad Prism 8.0 software. 50 The experimental results are shown in Table 1.

[0713] Table 1 Enzyme inhibitory activity of the disclosed compounds on FGFR

[0714] The results showed that the disclosed compounds had a significant inhibitory effect on FGFR2 kinase.

[0715] Test Example 2: Inhibitory effect of the disclosed compounds on FGFR1, FGFR2, FGFR3, and FGFR4 kinases

[0716] The FGFR1, FGFR2, FGFR3, and FGFR4 kinase activities of the disclosed compounds were tested using the following methods.

[0717] 1.1 Experimental Materials

[0718] 1.2 Experimental steps

[0719] 1) Prepare 1× kinase reaction buffer: 50 mM HEPES, pH 7.5, 10 mM MgCl2, 4 mM DTT, 0.01% Tween-20, 0.01% BSA.

[0720] 2) The disclosed compounds were diluted with DMSO.

[0721] 3) Use Echo to transfer 200 nL of the disclosed compound to a 384-well reaction plate.

[0722] 4) Prepare a 2× kinase solution using 1× kinase reaction buffer, and transfer 10 μL of FGFR1 / 2 / 3 / 4 (0.02 nM / 0.02 nM / 0.2 nM / 2 nM) solution to the corresponding wells of a 384-well reaction plate.

[0723] 5) Centrifuge with shaking and incubate at 25°C for 60 minutes.

[0724] 6) Prepare a 2× mixture of substrate (Fluorescein-Poly GT: 40 nM) and ATP (56 μM (FGFR1) / 44 μM (FGFR2) / 70 μM (FGFR3) / 476 μM (FGFR4)) in kinase reaction buffer and add 10 μL to the corresponding wells of the reaction plate.

[0725] 7) Centrifuge with shaking and incubate at 25°C for 30 minutes.

[0726] 8) Prepare 2× detection solution (2 nM Tb-PY20 antibody and 40 mM EDTA) with antibody dilution buffer and add 20 μL to each well of the reaction plate.

[0727] 9) Centrifuge with shaking and incubate at 25°C for 60 minutes.

[0728] 10) Detect the fluorescence signals at 520 nm and 495 nm using Envision.

[0729] 11) Analyze IC using XLfit software 50 The experimental results are shown in Table 2.

[0730] Table 2 Enzyme inhibitory activity of the disclosed compounds on FGFR

[0731] The results showed that the compounds of the present disclosure had a significant inhibitory effect on FGFR2 kinase, and relative to FGFR1, FGFR3 or FGFR4, the compounds of the present disclosure had a significant selective inhibitory effect on FGFR2 kinase.

[0732] Test Example 3: Inhibitory effect of the disclosed compounds on the proliferation of FGFR2-driven SNU16 cells

[0733] The FGFR2-driven cell SNU16 proliferation inhibitory activity of the disclosed compounds was tested using methods well known to those skilled in the art, such as the CTG method.

[0734] 1.1 Experimental Materials

[0735] 1.2 Experimental steps

[0736] 1) SNU16 cells were collected, resuspended in RPMI 1640 medium (containing 10% FBS), counted, and seeded into 96-well white clear-bottom plates, with 2,000 cells per well and 100 μL of medium.

[0737] 2) The disclosed compounds were transferred to the 96-well plate using D300e, with a total DMSO content of 0.5%. The plate was placed in a 37° C. 5% CO 2 incubator and incubated for 96 h.

[0738] 3) After incubation, add 50 μL of CTG to each well and shake for 10 minutes. Read the chemiluminescence value using Envision. The reading of the well without cells and containing only DMSO is the low control, and the reading of the well with cells and only DMSO is the high control. Compound inhibition rate = 100% × ((RLU high control -RLU low control )–(RLU compound –RLU low control )) / (RLU high control –RLU low control )

[0739] 4) Analyze the IC values ​​of the disclosed compounds using the log(inhibitor) vs. response--Variable slope (four parameters) method of GraphPad Prism 8.0 software. 50 The experimental results are shown in Table 3.

[0740] Table 3 Inhibitory activity of the disclosed compounds on FGFR2-driven SNU-16 cells

[0741] The results showed that the disclosed compounds had a significant inhibitory effect on the proliferation of FGFR2-driven cells SNU16.

[0742] Test Example 4: Inhibitory effect of the disclosed compounds on the proliferation of FGFR1-driven cells DMS-114, FGFR3-driven cells RT-112 / 84, and FGFR4-driven cells MDAMB453

[0743] The proliferation inhibitory activity of the disclosed compounds on FGFR1-driven cells DMS-114, FGFR3-driven cells RT-112 / 84, and FGFR4-driven cells MDAMB453 was tested using methods well known to those skilled in the art.

[0744] 1.1 Experimental Materials

[0745] 1.2 Experimental steps

[0746] 1) DMS114, RT112 / 84, and MDAMB453 cells were trypsinized and harvested, resuspended in serum-containing RPMI 1640, EMEM, or DMEM complete cell culture medium, and counted. The cells were seeded into 384-well white clear-bottom plates with 45 μL of culture medium per well. Two plates were seeded for each cell type at the following cell densities:

[0747] 2) After plating, cells were cultured in an incubator overnight. The next day, the plate containing the cells was removed and 5 μL of a serially diluted compound (10×, 1% DMSO) was added to one plate. The culture was continued in the incubator for 96 hours. 5 μL of the corresponding culture medium containing 1% DMSO was added to the other plate. After incubation in the incubator for 1 hour, the CTG assay was started (experimental procedures are as follows);

[0748] 3) After incubation, add 25 μL of CTG to each well, shake for 10 minutes, and read the chemiluminescence value using Envision. The CTG reading on the second day of plating serves as the low control, and the reading of the well containing cells and DMSO alone serves as the high control. Compound inhibition rate = 100% × ((RLU high control -RLU low control )–(RLU compound –RLU low control )) / (RLU high control –RLU low control );

[0749] 4) Analyze the IC values ​​of the compounds using the log(inhibitor) vs. response--Variable slope (four parameters) method of GraphPad Prism 8.0 software. 50 The experimental results are shown in Table 4.

[0750] Table 4 Proliferation inhibition activity of the disclosed compounds on FGFR1-driven cells DMS-114, FGFR3-driven cells RT-112 / 84, and FGFR4-driven cells MDAMB453

[0751] The results showed that the disclosed compounds had no significant inhibitory effect on the proliferation of FGFR1-driven cells DMS-114, FGFR3-driven cells RT-112 / 84, and FGFR4-driven cells MDAMB453.

[0752] Test Example 5: Effect of the compounds disclosed herein on FGFR2 k inact / K I Characterization

[0753] The FGFR2 kinase kappa of the disclosed compounds was investigated using the following method: inact / K I To characterize.

[0754] 1.1 Experimental Materials

[0755] 1.2 Experimental steps

[0756] 1) Prepare 1× kinase reaction buffer: 50 mM HEPES, pH 7.5, 10 mM MgCl2, 4 mM DTT, 0.01% Tween-20, 0.01% BSA.

[0757] 2) The disclosed compounds were diluted with DMSO.

[0758] 3) Use Echo to transfer 200 nL of the disclosed compound to a 384-well reaction plate.

[0759] 4) Prepare 2× kinase solution with 1× kinase reaction buffer, and transfer 10 μL of FGFR2 (0.02 nM) solution to the corresponding wells of a 384-well reaction plate.

[0760] 5) Prepare a 2× mixture of substrate (Fluorescein-Poly GT: 40 nM) and ATP (44 μM) using kinase reaction buffer, and add 10 μL to the corresponding wells of the reaction plate.

[0761] 6) Centrifuge with vortexing and incubate at 25°C for 0, 2, 4, 6, 8, 10, 15, 20, 30, 60, 90, and 120 minutes.

[0762] 7) Prepare 2× detection solution (2 nM Tb-PY20 antibody and 40 mM EDTA) with antibody dilution buffer and add 20 μL to each well of the reaction plate.

[0763] 8) Centrifuge with shaking and incubate at 25°C for 60 minutes.

[0764] 9) Detect the fluorescence signals at 520 nm and 495 nm using Envision.

[0765] 10) Analyze k using XLfit software inact and K I The experimental results are shown in Table 5.

[0766] Table 5 k of the compounds disclosed herein for FGFR2 inact / K I Characterization

[0767] The results showed that the disclosed compounds have a strong affinity for FGFR2 kinase.

[0768] Test Example 6: Pharmacokinetics of the Disclosed Compounds in Mice

[0769] Mice were used as test animals to study the pharmacokinetic behavior of the disclosed compounds in mice after oral gavage (PO) administration. Plasma samples were collected at specific time points, and the compound concentrations in plasma were detected by LC-MS / MS. PK parameters were calculated to reflect the pharmacokinetic behavior of the disclosed compounds in mice.

[0770] 1. Experimental Plan

[0771] 1.1 Investigational Drugs:

[0772] Some compounds are disclosed.

[0773] 1.2 Experimental animals

[0774] Mouse, CD-1, male, supplied by Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd.

[0775] 1.3 Administration

[0776] Mouse dosing information: The experimental group consisted of 3 mice, the dosing volume was 5 mL / kg; the dosing dose was 10 mg / kg or 30 mg / kg, the dosing volume was 10 mL / kg, and the dosing solvent was 5% DMSO / 10% Solutol HS15 / 85% water.

[0777] 1.4 Experimental Equipment

[0778] The centrifuge was purchased from Eppendorf, the pipette was purchased from Eppendorf, and the vortexer was purchased from IKA.

[0779] 1.5 Sample collection

[0780] After administration to mice, 0.03 mL of venous blood was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in EDTA-K2 tubes, centrifuged at 4000 g for 5 min at 4°C to separate plasma, and stored at -80°C.

[0781] 1.6 Sample processing

[0782] Mouse plasma sample processing:

[0783] 1) 10 μL of plasma sample was added to 200 μL of acetonitrile for precipitation, vortexed and centrifuged for 15 minutes.

[0784] 2) The supernatant after treatment was diluted with water and analyzed by LC / MS / MS for the concentration of the test compound.

[0785] 2. Experimental Results

[0786] The pharmacokinetic parameters were calculated using WinNonlin 8.3. The pharmacokinetic parameters of the drug administered to mice are shown in Table 6. max Indicates the maximum blood drug concentration, T 1 / 2 Indicates terminal elimination half-life, MRT Inf AUC represents the area under the drug-dose curve.

[0787] Table 6 Pharmacokinetic parameters of the disclosed compounds in mice

[0788] Results: As can be seen from Table 6, the compounds disclosed herein have good pharmacokinetic properties in mice.

[0789] Test Example 7: Pharmacokinetics of the compounds disclosed in rats

[0790] Rats were used as test animals to study the pharmacokinetic behavior of the disclosed compounds in rats after oral gavage (PO) and intravenous injection (IV). Plasma samples were collected at specific time points, and the compound concentrations in plasma were detected by LC-MS / MS. PK parameters were calculated to reflect the pharmacokinetic behavior of the disclosed compounds in rats.

[0791] 1. Experimental Plan

[0792] 1.1 Investigational Drugs:

[0793] Some compounds are disclosed.

[0794] 1.2 Experimental animals

[0795] Male Sprague-Dawley rats were supplied by Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd.

[0796] 1.3 Administration

[0797] Dosing information of the disclosed compounds: IV (intravenous injection) and PO (oral gavage) experimental groups each consisted of 3 rats. The IV dose for rats was 1 mg / kg, the dosing volume was 5 mL / kg, and the dosing vehicle was 5% DMSO / 10% Solutol HS15 / 85% water. The PO doses for rats were 10 mg / kg, 30 mg / kg, and 100 mg / kg, the dosing volume was 10 mL / kg, and the dosing vehicle was 5% DMSO / 10% Solutol HS15 / 85% water.

[0798] Dosing information of the control compound: The IV (intravenous injection) and PO (oral gavage) experimental groups each consisted of 3 rats. The IV dose for rats was 1 mg / kg, the dosing volume was 5 mL / kg, and the dosing vehicle was 5% DMSO / 10% Solutol HS15 / 85% water; the PO doses were 10 mg / kg, 30 mg / kg, and 100 mg / kg. When the PO dose was 10 mg / kg, the dosing vehicle was 5% DMSO / 10% Solutol HS15 / 85% water; when the PO doses were 30 mg / kg and 100 mg / kg, the dosing vehicle was 5% DMSO-10% TPGS-85% (10% PVP K30 in 100 mM citric acid), pH = 2.

[0799] 1.4 Experimental Equipment

[0800] The centrifuge was purchased from Eppendorf, the pipette was purchased from Eppendorf, and the vortexer was purchased from IKA.

[0801] 1.5 Sample collection

[0802] After administration to rats, 0.2 mL of venous blood was collected at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 4°C, 4000g for 5 minutes to separate plasma, and stored at -80°C.

[0803] 1.6 Sample processing

[0804] Rat plasma sample processing:

[0805] 1) 20 μL of plasma sample was added to 400 μL of methanol for precipitation, vortexed and centrifuged for 15 minutes.

[0806] 2) The supernatant after treatment was diluted with water and analyzed by LC / MS / MS for the concentration of the test compound.

[0807] 2. Experimental Results

[0808] The pharmacokinetic parameters were calculated using WinNonlin 8.3. The pharmacokinetic parameters of rats after intravenous injection and oral administration are shown in Table 7. max represents the maximum blood drug concentration, CL represents the clearance rate, Vss represents the steady-state distribution volume, T 1 / 2 Indicates terminal elimination half-life, MRT Inf AUC represents the area under the drug-dose curve.

[0809] Table 7 Pharmacokinetic parameters of the disclosed compounds in rats

[0810] Note: “ / ” indicates not measured

[0811] Results: As can be seen from Table 7, the compounds of the present disclosure have good pharmacokinetic properties in rats.

[0812] Test Example 8: Whole-cell manual patch clamp assay

[0813] 1. Purpose of the experiment

[0814] This experiment used the electrophysiological whole-cell manual voltage clamp method to test the effects of compounds on hERG potassium channel (human Ether-a-go-go Related Gene potassium channel) currents.

[0815] 2. Experimental Materials

[0816] Cisapride, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, HEPES, EGTA, and DMSO were purchased from Sigma. The CHO-hERG cell line (Chinese Hamster Ovary) (Chinese hamster ovary cells stably expressing hERG channels) was constructed in-house by the Ion Channel Research Platform of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0817] 3. Experimental Methods

[0818] 3.1 Cell Culture and Treatment: CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator. The cells were passaged every 48 hours at a 1:5 ratio. The culture medium consisted of 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen), and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed once with extracellular medium, and then digested with 0.25% Trypsin-EDTA (Invitrogen) solution for 3-5 minutes at room temperature. The digestion medium was aspirated, the cells were resuspended in extracellular medium, and then transferred to a dish for electrophysiological recording.

[0819] 3.2 Compound Preparation: On the day of testing, prepare the compound to a 15 mM stock solution in DMSO. Then, serially dilute the stock solution two-fold with DMSO and dilute it again with extracellular fluid to the desired final concentration. For the positive control compound, cisapride: Add 10 μL of a 150 μM cisapride DMSO stock solution to 4990 μL of extracellular fluid and dilute 500-fold to a final concentration of 300 nM. The DMSO content in the final test concentration does not exceed 0.2%, as this concentration of DMSO has no effect on hERG potassium channels.

[0820] 3.3 Electrophysiological Recording Procedure: hERG potassium channel currents were recorded using the whole-cell voltage-clamp technique at room temperature in CHO cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch clamp amplifier by inserting them into the amplifier headstage. Clamp voltage and data recording were controlled and recorded by a computer using pClamp software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -100 mV. To elicit hERG potassium currents (I hERG ), a step voltage was applied from -100 mV to +20 mV for 2 s, followed by repolarization to -50 mV for 1 s before returning to -100 mV. This voltage stimulus was applied every 5 s, and drug administration was initiated after confirming the stability of the hERG potassium current (1 min). Compounds were administered for at least 1 minute to steady state of action or for a maximum of 3 minutes at each test concentration, and at least two cells (n≥2) were tested at each concentration.

[0821] 4. Data Analysis

[0822] Data were analyzed and processed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1 – (I / Io)] × 100%, where Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current before and after drug addition, respectively.

[0823] Compound IC 50 Calculated using GraphPad Prism 8 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0824] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0825] Table 8 IC values ​​of the compounds disclosed herein for inhibition of hERG potassium channel current 50 value.

[0826] Conclusion: It can be seen from Table 8 that the disclosed compounds have weak inhibitory effects on hERG, and the safety risks caused by hERG pathway inhibition are low.

[0827] Test Example 9: Liver Microsome Metabolic Stability

[0828] 1. Purpose of the experiment

[0829] The purpose of this study was to investigate the in vitro metabolic stability of the disclosed compounds in rat liver microsomes. LC / MS / MS was used to measure the concentration of the test compound in the incubation system and to calculate the intrinsic clearance of the disclosed compounds in the microsomal system to assess their stability.

[0830] 2. Experimental Materials

[0831] Rat liver microsomes were purchased from BD Gentest at a concentration of 20 mg / mL; potassium phosphate buffer, 100 mM; NADPH (nicotinamide adenine dinucleotide phosphate), 1 mM; and stop solution, acetonitrile (containing internal standards 100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide).

[0832] 3. Experimental Methods

[0833] 1) Liver microsomes were diluted with 100 mM potassium phosphate buffer to an appropriate concentration to prepare a microsome working solution. A certain amount of NADPH was added to the microsome working solution, and then an appropriate amount of the disclosed compound was added to initiate the reaction, such that the final incubation system had a compound concentration of 1 μM, NADPH concentrations of 1 mM, and rat liver microsome concentrations of 0.5 mg / mL.

[0834] 2) At 0.5, 5, 15, 30, and 60 minutes, take 30 μL of the incubation sample. Terminate the reaction by adding 150 μL of 50% acetonitrile in water (v:v, 1:1) containing the internal standard, and vortex for 10 minutes.

[0835] 3) Centrifuge at 3220 g for 40 minutes. Transfer 100 μL of the supernatant to a sample plate, add 100 μL of pure water, and mix thoroughly for UPLC-MS / MS analysis.

[0836] 4. Data Analysis

[0837] Data analysis was performed using Microsoft Excel software. The in vitro half-life (t 1 / 2 The results of the metabolic stability of the disclosed compounds in rat liver microsomes are shown in Table 9.

[0838] Table 9 Metabolic stability results of the disclosed compounds in rat liver microsomes

[0839] Conclusion: As can be seen from Table 9, the compounds disclosed herein have higher metabolic stability in rat liver microsomes and are superior to the control compounds.

[0840] Test Example 10: Hepatocyte Metabolic Stability

[0841] 1. Purpose of the experiment

[0842] The purpose of this study was to investigate the in vitro metabolic stability of the disclosed compounds in different hepatocyte species. LC / MS / MS was used to measure the concentration of the disclosed compounds in the incubation system and to calculate the intrinsic clearance of the disclosed compounds in the hepatocyte system to assess their stability.

[0843] 2. Experimental Materials

[0844] Human and rat hepatocytes were purchased from BioIVT, monkey hepatocytes were purchased from RILD, and canine hepatocytes were purchased from TPCS. The stop solution was acetonitrile (containing internal standards 100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide).

[0845] 3. Experimental Methods

[0846] 1) Place the hepatocyte culture medium (William's E medium supplemented with GlutaMAX) and hepatocyte thawing medium in a 37°C water bath and warm for at least 15 minutes before use. Transfer the hepatocytes from liquid nitrogen, place them in a 37°C water bath and gently shake the vial for 2 minutes to thaw the cells. After thawing, transfer the hepatocytes to a biosafety cabinet. Transfer the hepatocytes to a 50mL centrifuge tube containing thawing medium. Place the 50mL centrifuge tube in a centrifuge and centrifuge at 100g for 10 minutes. Aspirate the thawing medium, resuspend the hepatocytes in sufficient culture medium, count the cells and determine the viable cell density. Dilute the cells with culture medium to a working cell density of 0.5×10 6 viable cells / ml.

[0847] 2) Pipette 198 μL of hepatocytes into each well of a 96-well uncoated plate. Place the plate in an incubator and allow the hepatocytes to warm up for 10 minutes. Pipette 2 μL of 100 μM test compound or positive control into the corresponding wells of the 96-well plate to initiate the reaction.

[0848] 3) At 0.5, 15, 30, 60, 90, and 120 minutes, a 25 μL sample was added to 300 μL of acetonitrile containing the internal standard to terminate the reaction. Vortex for 5 minutes. Centrifuge the sample at 3,220 g for 45 minutes. Transfer 100 μL of the supernatant to the injection plate, add 100 μL of purified water, and mix thoroughly before analysis by UPLC-MS / MS.

[0849] 4. Data Analysis

[0850] Data analysis was performed using Microsoft Excel software. The in vitro half-life (t 1 / 2 The results of metabolic stability of the disclosed compounds in hepatocytes are shown in Table 10.

[0851] Table 10 Metabolic stability results of the disclosed compounds in hepatocytes

[0852] Conclusion: As can be seen from Table 10, the compounds of the present disclosure have higher metabolic stability in hepatocytes of different species (human, rat, dog, monkey), and are superior to the control compounds.

[0853] Test Example 11: In vivo efficacy study

[0854] 1. Purpose of the experiment

[0855] The effects of oral administration of the disclosed compounds for 14 or 21 consecutive days on AN3CA (FGFR2 K310R / N549K) and SNU16 (FGFR2 amp ) model and its anti-tumor activity and side effects.

[0856] 2. Experimental Materials

[0857] BALB / c-nu female mice, SPF grade, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. and Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd.

[0858] SNU16 cells were purchased from ATCC.

[0859] AN3CA cells were purchased from ATCC.

[0860] 3. Experimental Procedure

[0861] 3.1 Cell culture

[0862] SNU16 cells were cultured in RPMI 1640 medium containing 10% FBS in a 37°C, 5% carbon dioxide incubator; cells in the exponential growth phase were collected for inoculation.

[0863] AN3CA cells were cultured in EMEM medium containing 10% FBS at 37°C in a 5% carbon dioxide incubator; cells in the exponential growth phase were collected for inoculation.

[0864] 3.2 Cell seeding

[0865] Under sterile conditions, the in vitro cultured SNU16 cell suspension was taken and centrifuged to adjust the cell concentration to 1×10 8 cells / mL, and inoculated subcutaneously in the right axilla of mice (1×10 7 + Matrigel (1:1) / 0.1 mL / mouse), and the day of inoculation was designated as day 0.

[0866] Under sterile conditions, the AN3CA cell suspension cultured in vitro was taken and the cell concentration was adjusted to 5×10 7 cells / mL, and inoculated subcutaneously in the right axilla of mice (5×10 6 + Matrigel (1:1) / 0.1 mL / mouse), and the day of inoculation was designated as day 0.

[0867] 3.3 Tumor grouping, drug administration, and measurement

[0868] SNU16 model

[0869] a, when the average tumor volume is about 200 mm 3At the same time, 36 mice with moderate tumor volume were selected and randomly divided into 6 groups according to tumor volume: G1: vehicle control group (Vehicle), G2: compound C46 (30 mg / kg), G3: compound C46 (10 mg / kg), G4: compound C54 (30 mg / kg), G5: compound C54 (10 mg / kg), 6 mice / group, where the solvent was 5% DMSO + 10% Solutol HS-15 + 85% water.

[0870] b. After the animals were grouped, drug administration began. The dosage was 10 mL / kg, administered orally (po), twice a day for 21 consecutive days.

[0871] c. Tumor volume (TV): Tumor volume was measured twice a week to observe changes in tumor volume and growth rate. Tumor volume V = 1 / 2 × a × b2, where a and b represent the major and minor diameters of the tumor, respectively. The inhibitory effect of the compound on tumor tissue growth was evaluated using the tumor growth inhibition rate (TGI) (%). TGI (%) = [1-(average tumor volume of a given dosing group - average tumor volume of the dosing group on the day the dosing group was grouped) / (average tumor volume of the negative control group - average tumor volume of the negative control group on the day the negative control group was grouped)] × 100%. Data for the dosing group and the negative control group were collected on the same day.

[0872] d. Closely observe the living conditions of mice during the experiment, including physical signs, general behavior, mental state, feeding status, respiratory status, feces and urine characteristics, injection site and other toxic manifestations.

[0873] e. After the experiment reached the endpoint, the mice were euthanized, the animal carcasses were frozen in a freezer, and then transferred to a qualified medical waste treatment unit for disposal.

[0874] AN3CA model

[0875] a, when the average tumor volume is about 150 mm 3 At the same time, 42 mice with moderate tumor volume were selected and randomly divided into 7 groups according to the tumor size: G1: vehicle control group (Vehicle), G2: compound C46 (30 mg / kg), G3: compound C46 (10 mg / kg), G4: compound C46 (3 mg / kg), G5: compound C54 (30 mg / kg), G6: compound C54 (10 mg / kg), 6 mice / group, where the solvent was 5% DMSO + 10% Solutol HS-15 + 85% water.

[0876] b. After the animals were grouped, drug administration began. The dosage was 10 mL / kg, administered orally (po), twice a day for 14 consecutive days.

[0877] c. Tumor volume (TV): Tumor volume was measured 2-3 times per week to observe changes in tumor volume and growth rate. Tumor volume V = 1 / 2 × a × b2, where a and b represent the major and minor diameters of the tumor, respectively. The inhibitory effect of the compound on tumor tissue growth was evaluated using the tumor growth inhibition rate (TGI) (%). TGI (%) = [1-(average tumor volume of a given dosing group - average tumor volume of the dosing group on the day the dosing group was grouped) / (average tumor volume of the negative control group - average tumor volume of the negative control group on the day the negative control group was grouped)] × 100%. Data for the dosing group and the negative control group were collected on the same day.

[0878] d. During the experiment, closely observe the living conditions of the mice, including physical signs, general behavior, mental state, feeding status, respiratory status, feces and urine characteristics, injection site and other toxic manifestations.

[0879] e. After the experiment reached the endpoint, the mice were euthanized, the animal carcasses were frozen in a freezer, and then transferred to a qualified medical waste treatment unit for disposal.

[0880] 4 Experimental results

[0881] Table 11 SNU16 efficacy model experimental data

[0882] a, mean ± standard error;

[0883] b, P value for statistical analysis of tumor volume, compared with G1 group, *P﹤0.05; **P﹤0.01.

[0884] Table 12 AN3CA efficacy model experimental data

[0885] a, mean ± standard error;

[0886] b, P value for statistical analysis of tumor volume, compared with G1 group, *P﹤0.05; **P﹤0.01.

[0887] Conclusion: As can be seen from Tables 11 and 12, both Compound C46 and Compound C54 can significantly inhibit tumor growth in a dose-effect relationship. They are also well tolerated by mice.

Claims

1. A compound represented by the general formula (IA), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; in: Ring A is selected from R L Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 and Among them, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is independently optionally selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; Ring C is selected from 5- to 10-membered heteroaryl, 7- to 14-membered aryl, 5- to 14-membered heterocyclyl, and 5- to 14-membered cycloalkyl; x 1 CR x1 or N; x 2 CR x2 or N; x 3 CR x3 or N; x 4 CR x4 or N; x 5 CR x5 or N; x 6 CR x6 or N; x 7 CR x7 or N; x 8 CR x8 or N; Ring B is selected from 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; L and L 3 are the same or different and are each independently selected from a chemical bond, -O-, -NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -; R is selected from a hydrogen atom, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 1 , R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogen, cyano, -C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-C(O)NR n7 OR c , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the C 1-6 alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 alkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, halogen, amino, hydroxyl, hydroxy 1-6 The alkyl group is substituted by one or more substituents; Each R 4 are the same or different and are each independently selected from deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R x , R x1 , R x2 , R x3 , R x4 , R x5 , R x6 , R x7 and R x8 are the same or different and are each independently selected from hydrogen atoms, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, oxo, -NR n7 R n8 、-C(O)NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-OR c 、-S(O) p R c 、-S(O) p NR n7 R n8 , 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; G 1 Selected from O, S, N, CR g1 and NR 8b ; G 2 C or N; G 3 C or N; G 4 C or N; G 5 C or N; G 6 Selected from O, S, N, CR g6 and NR 8b ; G 7 Selected from O, S, N, CR g7 and NR 8b ; R 7 is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 , C 1-6 Alkoxy and halogenated C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 8 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -OR c , C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R 7 and R 8 The atoms connected to it together form a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms, and is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkyl cyano, C 1-6 Alkylamino, -OR c , Hydroxy C 1-6 The alkyl group is substituted by one or more substituents; L 1 and L 2 are the same or different and are each independently selected from a chemical bond, -C(R a )=C(R b )-、-C(R a )=N-、-N=C(R b )-、-O-、-NR n7 -、-(CR a R b ) m -、-OC(R a R b )-、-C(R a R b )-O-、-NR n7 -C(R a R b )-、-C(R a R b )-NR n7 -、-C(O)-、-C(R a R b )-C(O)-、-C(O)-C(R a R b )-, -OC(O)-, -C(O)-O-, -S(O) p -、-NR n7 -C(O)-, -C(O)-NR n7 -、-C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-、-NR n7 -C(O)-C(R a R b )-、-NR n7 -S(O)2- and -S(O)2-NR n7 -; Indicates that when x 6 CR x6 When L 1 and R x6 The connected keys, and L 1 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from deuterium, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted with one or more substituents; provided that, n5 The nitrogen atom connected to R x6 The ring atoms between the connected carbon atoms are not -CH2- and -CH2CH2-; H 1 Selected from O, S(O) p , N, CR h1 and NR 8b ; H 2 , H 3 and H 4 are the same or different and are each independently C or N; R 9 O or NR r ; J is selected from -NR n1 R n2 , C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyl cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; Optionally, when J is -NR n1 R n2 When R n2 and H 1 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p or N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c , Hydroxy C 1-6 The alkyl group is substituted with one or more substituents, and when x 5 、x 6 、x 7 and x 8 When both are CH, Not for Y is N or CR 7b ; G is N or CR g ; Indicates and contains x 5 The bonds connecting the rings; represents the bond connected to ring C; Indicates that when x 6 CR x6 When L 2 and R x6 The connected keys, and L 2 and R x6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 , C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 7c Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR n7 R n8 、-C(O)NR n7 R n8 、-NR n7 -C(O)-NR n7 R n8 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-S(O) p R c 、-S(O) p NR n7 R n8 , C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , hydroxyl, hydroxyl C 1-6 substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 8a Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -OR c , halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 1-6 Alkyl cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 8b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, -OR c , C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 , C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R g1 , R g6 , R g7 , R g and R h1 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, -OR c , C 2-6 Alkenyl, C 2- 6Alkynyl, haloC 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halogen, cyano, C 1-6 Alkyl cyano, -NR n7 R n8 , C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; Optionally, J and H 1 , or R 7a With R 8b , or R 7b With R g , or R 7c With R g Each independently forms a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group contains 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R a and R b are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy; R c are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2- 6-Alkenyl, Halogenated C 2-6 Alkynyl, halogen, cyano, -NR n7 R n8 , C 1-6 Alkylamino, C 1-6 Alkyl cyano, halo C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy; R 5 , R r , R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 , R n8 , R n7a and R n8a are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 alkyl, 3- to 8-membered heterocyclyl, 3- to 8-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R n1 and R n2 , R n3 and R n4 , R n5 and R n6 , R n7 and R n8 , R n7a and R n8a Together with the nitrogen atoms to which they are attached, they each form a 3- to 8-membered heterocyclic group; Optionally, R n6 With x 6 Together they form a 6- to 10-membered heterocyclic group containing 1 to 3 atoms selected from O, S(O) p and N ring atoms and optionally contain 1 or 2 double bonds, wherein the 6 to 10 membered heterocyclyl is optionally selected from oxo, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, -NR n7a R n8a , C 1-6 Alkylamino, C 1-6 Alkyl cyano, -OR c and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; The condition is that the general formula (IA) is not the following compounds, and the CAS numbers of the following compounds are 2924721-14-0, 2920599-68-2, 2920601-26-7, 2924721-16-2, 2939840-00-1, 2939840-08-9, 2920599-66-0, 2939839-78-6 and 2939840-05-6 respectively.

2. The compound represented by the general formula (IA) according to claim 1, or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (I), or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt: in: L is selected from -O-, -NR n7 -, -(CR a R b ) m -, -O-C(R a R b )-, -C(R a R b )-O-, -NR n7 -C(R a R b )-, -C(R a R b )-NR n7 -, -C(O)-, -C(R a R b )-C(O)-, -C(O)-C(R a R b )-, -O-C(O)-, -C(O)-O-, -S(O) p -, -NR n7 -C(O)-, -C(O)-NR n7 -, -C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-, -NR n7 -C(O)-C(R a R b )-, -NR n7 -S(O)2- and -S(O)2-NR n7 -; x 1 to x 8 , Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 and n is as defined in claim 1.

3. The compound represented by the general formula (IA) according to claim 1 or 2, or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R 5 is the same or different at each occurrence and is independently a hydrogen atom or a C 1-6 The alkyl group is preferably a hydrogen atom.

4. The compound represented by the general formula (IA) according to any one of claims 1 to 3, or its stereoisomer, or its prodrug, or its nitrogen oxide, or its solvate, or its isotopic derivative, or its pharmaceutically acceptable salt, wherein R L Selected from C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR n7 R n8 and R n7 , R n8 , Ring B, L, R 4 and n is as defined in any one of claims 1 to 3.

5. A compound of the general formula (IA) according to any one of claims 1 to 4, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -C(O) and -C(O)NH.

6. A compound represented by the general formula (IA) according to any one of claims 1 to 5, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IA-1), general formula (IBF-1), general formula (IC-1), general formula (ID-1), general formula (IE-1), general formula (IG-1), general formula (IGH-1), general formula (IH-1), general formula (IJ-1), general formula (IK-1), general formula (IM-1) or general formula (IN-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in: x 1 to x 8 , Ring B, R 1 , R 2 , R 3 , R 4 , G 6 , G 7 , R 6 , R 7 , R 8 , R 8a , R 8b , R g , R c , R 7a , R 7c , H 1 , H 2 , H 3 , G, Y, L 1 , L 2 , J and n are as defined in any one of claims 1 to 5.

7. A compound represented by the general formula (IA) according to any one of claims 1 to 6, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIC), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in: Ring B is selected from 6-membered heteroaryl groups; x 1 to x 8 , R 1 , R 2 , R 3 , R 4 , R 6 and n is as defined in any one of claims 1 to 6.

8. A compound represented by the general formula (IA) according to any one of claims 1 to 7, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIC-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in: x 1 to x 8 , R 1 , R 2 and R 3 As defined in any one of claims 1 to 7.

9. A compound represented by the general formula (IA) according to any one of claims 1 to 6, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IH), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in: L 4 Selected from chemical bonds, -C(R a )=C(R b )-, -C(R a )=N-, -N=C(R b )-, -O-, -NR n7 -, -(CR a R b ) m -, -O-C(R a R b )-, -C(R a R b )-O-, -NR n7 -C(R a R b )-, -C(R a R b )-NR n7 -, -C(O)-, -C(R a R b )-C(O)-, -C(O)-C(R a R b )-, -O-C(O)-, -C(O)-O-, -S(O) p -, -NR n7 -C(O)-, -C(O)-NR n7 -, -C(R a R b )-NR n7 -C(O)-, -C(O)-NR n7 -C(R a R b )-, -NR n7 -C(O)-C(R a R b )-, -NR n7 -S(O)2- and -S(O)2-NR n7 -; x 1 to x 5 、x 7 、x 8 , Ring B, R c , R 1 , R 2 , R 3 , R 4 , R 6 ,n,R a , R b , R n7 , m, p as defined in any one of claims 1 to 6.

10. A compound represented by the general formula (IA) according to any one of claims 1 to 6 and 9, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIH-1), or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in: L 4 As defined in claim 9; x 1 to x 5 、x 8 , R x7 , R 1 , R 2 and R 3 As defined in any one of claims 1 to 6.

11. A compound represented by the general formula (IA) according to any one of claims 1 to 10, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein x 1 N or CR x1 , x 2 N or CR x2 , x 3 N or CR x3 , x 4 N or CR x4 ; R x1 , R x2 , R x3 , R x4 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, x 1 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 2 is selected from N, CH, CF, C-CH3, C-CN and C-OCH3, x 3 is N or CH, x 4 is N or CH; more preferably, x 1 、x 2 、x 3 and x 4 All are CH.

12. A compound represented by the general formula (IA) according to any one of claims 1 to 11, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R x3 and R x4 are all hydrogen atoms; and / or R x1 and R x2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, -CN and C 1-6 Alkoxy; preferably, R x3 and R x4 are all hydrogen atoms; and / or R x1 and R x2 are the same or different and are each independently selected from a hydrogen atom, F, and a methyl group.

13. A compound represented by the general formula (IA) according to any one of claims 1 to 12, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 are the same or different at each occurrence and are independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 6 A hydrogen atom.

14. A compound represented by the general formula (IA) according to any one of claims 1 to 13, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein x 5 N or CR x5 , x 6 N or CR x6 , x 7 CR x7 , x 8 N or CR x8 ; R x5 , R x6 , R x7 , R x8 As defined in any one of claims 1 to 13; preferably, x 5 CR x5 , x 6 N or CR x6 , x 7 CR x7 , x 8 CR x8 ; R x5 , R x6 , R x7 , R x8 As defined in any one of claims 1 to 13; more preferably, x 5 CR x5 , x 6 N, x 7 CR x7 , x 8 CR x8 ; R x5 , R x7 , R x8 As defined in any one of claims 1 to 13.

15. A compound represented by the general formula (IA) according to any one of claims 1 to 14, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkoxy; preferably, R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from a hydrogen atom or a halogen; more preferably, R x5 and R x6 are all hydrogen atoms; and / or R x7 and R x8 are the same or different and are each independently selected from a hydrogen atom or F.

16. A compound represented by the general formula (IA) according to any one of claims 1 to 15, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from 17. A compound represented by the general formula (IA) according to any one of claims 1 to 16, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein for 18. A compound represented by the general formula (IA) according to any one of claims 1 to 17, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from x 1 、x 2 、x 3 and x 4 As defined in any one of claims 1 to 17.

19. A compound represented by the general formula (IA) according to any one of claims 1 to 18, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from 20. A compound of formula (IA) according to any one of claims 1 to 19, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5- to 10-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a 6- to 10-membered aryl group, preferably a 5- to 6-membered heteroaryl group or a phenyl group, more preferably a 6-membered heteroaryl group, and most preferably a pyrimidinyl group or a pyridinyl group.

21. A compound represented by the general formula (IA) according to any one of claims 1 to 20, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 22. A compound of formula (IA) according to any one of claims 1 to 21, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 Alkyl; preferably, R 1 Selected from hydrogen atoms, C 1- 6-alkyl, deuterated C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxy C 1-6 More preferably, R 1 is selected from the group consisting of a hydrogen atom, a methyl group, -CD3, F, -CH2OCH3, -OCH3, -CH2CH2OH and -CH2OH; most preferably, R 1 Selected from methyl.

23. A compound of formula (IA) according to any one of claims 1 to 22, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogenated C 1-6 alkyl, C optionally substituted by a 3- to 6-membered heterocyclic group 1-6 Alkyl, hydroxy C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 wherein the 3 to 6 membered heterocyclic group is optionally substituted by one or more halogens; preferably, R 2 Selected from hydrogen atom, -CH3, -CH2F, -CH2OH, -CH2OCH3, Most preferably, R 2 Selected from hydrogen atoms.

24. A compound of formula (IA) according to any one of claims 1 to 23, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and cyano, the C 1-6 The alkyl group is optionally replaced by -NR n7a R n8a Replaced by R n7a and R n8a are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 3 Selected from hydrogen atoms, C 1-6 Alkyl and More preferably, R 3 A hydrogen atom.

25. A compound of formula (IA) according to any one of claims 1 to 24, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 4 Selected from C 1-6 Alkyl, deuterated C 1-6 alkyl, halogen and 3 to 6 membered cycloalkyl, or n is 0; preferably, n is 1, and R 4 Selected from C 1-6 Alkyl, deuterated C 1-6 alkyl and 3 to 6 membered cycloalkyl, or n is 0; more preferably, n is 1, and R 4 is selected from methyl, isopropyl, -CD3 and cyclopropyl; most preferably, n is 1, and R 4 It is methyl.

26. A compound of formula (IA) according to any one of claims 1 to 25, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R x7 and R x8 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R x7 and R x8 are the same or different and are each independently a hydrogen atom or a halogen; more preferably, R x7 and R x8 are the same or different and are each independently a hydrogen atom or F.

27. A compound of formula (IA) according to any one of claims 1 to 26, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from C 1-6 Alkoxy, hydroxy 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 2-6 alkynyl, -C(O)NH2, -NHC(O)NH2, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl.

28. A compound of formula (IA) according to any one of claims 1 to 27, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 7c Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and -NR n7 R n8 ; R n7 and R n8 As defined in any one of claims 1 to 27.

29. A compound of formula (IA) according to any one of claims 1 to 28, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 7a and R 7b are the same or different at each occurrence and are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NH2, -NHC(O)NH2, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl.

30. A compound of formula (IA) according to any one of claims 1 to 29, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein for R 8b and J as defined in any one of claims 1 to 29.

31. A compound of formula (IA) according to any one of claims 1 to 30, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein J is a halogenated C 1-6 Alkyl or -NR n1 R n2 ; R n1 and R n2 As defined in any one of claims 1 to 30.

32. A compound represented by the general formula (IA) according to any one of claims 1 to 31, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from R 8b , R n1 and R n2 As defined in any one of claims 1 to 31.

33. A compound of formula (IA) according to any one of claims 1 to 32, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 are the same or different at each occurrence and are independently selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and hydroxy C 1-6 alkyl.

34. A compound of formula (IA) according to any one of claims 1 to 33, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R c is the same or different at each occurrence and is independently C 1-6 Alkyl, 3 to 6 membered cycloalkyl or deuterated C 1-6 The alkyl group is preferably methyl, isopropyl, cyclopropyl or deuterated methyl, more preferably methyl or -CD3.

35. A compound of formula (IA) according to any one of claims 1 to 34, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 is the same or different at each occurrence and is each independently selected from methyl, -CD3, methoxy, -OCD3, -CH2OH and -(CH2CH2)OH.

36. A compound of formula (IA) according to any one of claims 1 to 35, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 8a are the same or different at each occurrence and are independently selected from C 1-6 Alkoxy, deuterated C 1-6 alkoxy and 3 to 6-membered cycloalkyloxy; preferably, R 8a are the same or different at each occurrence and are independently selected from methoxy, -OCD3, and / or R 8b is the same or different at each occurrence and is independently C 1-6 Alkyl or C 1-6 Alkoxy.

37. A compound according to any one of claims 1 to 36, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -OCH2-, -C(O)CH2-, -C(O)NH-, -CH2C(O)-, -CH=CH-, -CH=N-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CF2CH2- and -CH2CF2-; and / or L 4 is selected from -OCH2-, -NHCH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH2-, -CF2CH2- and -CH2CF2-; preferably, L 1 Selected from -OCH2-; and / or L 4 Selected from -OCH2-.

38. A compound of formula (IA) according to any one of claims 1 to 37, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

40. Use of a compound according to any one of claims 1 to 38, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39 in the preparation of a medicament for inhibiting FGFR2, preferably in the preparation of a medicament for selectively inhibiting FGFR2.

41. Use of a compound according to any one of claims 1 to 38, or a stereoisomer thereof, or a prodrug thereof, or a nitrogen oxide thereof, or a solvate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39 in the preparation of a medicament for treating and / or preventing FGFR2-mediated tumors.

42. The use according to claim 41, wherein the tumor is cancer; the cancer is preferably selected from bile duct cancer, breast cancer, gastric cancer and endometrial cancer.

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