Heteroaryl compounds as multi-target protein kinase inhibitors

Abstract

The present disclosure provides compounds of Formula (I) that are active against receptor protein tyrosine kinases, and pharmaceutically acceptable salts, stereoisomers, isotopologues thereof. The compounds of the present disclosure have high biological activity and are useful in the treatment of diseases or disorders associated with the target.

Description

[0001] Priority Statement This disclosure claims priority to Chinese Patent Application No. 2024107886661, filed on June 18, 2024. The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference.

[0002] This disclosure claims priority to Chinese Patent Application No. 2024107883201, filed on June 18, 2024. The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference.

[0003] This disclosure claims priority to Chinese Patent Application No. 2023118584567, filed on December 30, 2023. The full text of the aforementioned Chinese patent application is incorporated herein by reference.

[0004] This disclosure claims priority to Chinese Patent Application No. 2024107886464, filed on June 18, 2024. The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference. Technical Field

[0005] This disclosure relates to a compound with kinase inhibitory activity and its application in the pharmaceutical field. More specifically, this disclosure provides a heteroaryl compound with protein tyrosine kinase activity. Background Technology

[0006] Clinical and preclinical evidence demonstrates that tumor-associated macrophages (TAMs), as key regulatory immune cells, can promote tumor development. Macrophages primarily exist in two polarized states: the alternately activated M2 subtype TAMs promote tumor development by secreting anti-inflammatory cytokines (e.g., IL-10, TGFβ), while the activated M1 subtype TAMs promote immune-mediated tumor killing by producing pro-inflammatory cytokines. To overcome the immunosuppressive and tumor-promoting functions of TAMs, current therapeutic strategies focus on TAM depletion and reprogramming within the tumor microenvironment to enhance anti-tumor function (leading to M2 polarization to M1). Macrophage colony-stimulating factor receptor (CSF-1R) kinase is a product encoded by the proto-oncogene c-fms and belongs to the class III receptor tyrosine kinase family, along with FLT3, c-kit, FDGFR, and PDGFR. CSF-1R binds to its ligands, colony-stimulating factor receptor (CSF-1) and interleukin (IL-34), activating CSF-1R and playing a crucial role in the proliferation, differentiation, and growth of monocytes and macrophages. In the tumor microenvironment, a large number of tumor-associated macrophages (TAMs) exist, expressing the CSF-1R receptor on their cell surface. When this receptor binds to its ligand CSF-1, macrophages undergo pro-tumor transformation, driving immunosuppression and promoting tumor cell growth. Furthermore, high expression of CSF1R on tumor cells is associated with low survival rates in some cancer patients, indicating tumor dependence and thus representing a potential therapeutic target. Developing CSF-1R / CSF-1 inhibitors targeting CSF-1R can effectively reduce the number of TAMs in tumor tissue, promote the generation of tumor suppressor macrophages, and help relieve immunosuppression; simultaneously, it can facilitate the infiltration of various immune cells, including T cells and lymphocytes, into tumor tissue.

[0007] Cancer cell growth and metastasis depend on angiogenesis. Vascular endothelial growth factor (VEGF) is the most effective pro-angiogenic factor because solid tumors rely on angiogenesis to provide oxygen and nutrients for their growth, and thus as a pathway for invasion and metastasis. Furthermore, the VEGFa-VEGFR2 signaling pathway plays a crucial role in the tumor microenvironment, significantly promoting the proliferation and infiltration of Tregs (regulatory T cells) in tumor tissues in animal models. Inhibiting the VEGFa-VEGFR2 signaling pathway can suppress tumor growth by regulating Tregs, MDSCs, and M2 macrophages. VEGFR2 inhibition significantly reduces Treg levels in tumor tissues, further helping to relieve immunosuppression.

[0008] PDGFR is a transmembrane glycoprotein with tyrosine kinase activity, primarily expressed in mesenchymal-derived cells such as fibroblasts, peridermocytes, vascular smooth muscle cells, and mesenchymal stem / progenitor cells. PDGFR has α and β subunits; generally, PDGFRα and PDGFRβ exist as monomers in a self-inhibited state. After binding with PDGF, PDGFR monomers dimerize to form isomers PDGFR-αα, PDGFR-αβ, and PDGFR-ββ, mediating a series of downstream signaling responses. Platelet-derived growth factor / receptor (PDGF / PDGFR) mainly promotes angiogenesis and maturation, playing a role in growth and development, and is also closely related to the occurrence and development of various diseases. Because microvessels in tumor tissues are characterized by rapid but immature growth, irregularity, and high leakage, the transport and distribution of chemical drugs and oxygen into the tumor tissue are hindered, allowing tumor cells to easily metastasize and invade other areas through leaky blood vessels. Abnormal vascular systems create a malignant tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial pressure, interfering with the function of intratumoral immune cells and reducing the efficiency of radiotherapy and chemotherapy. Therefore, current anti-angiogenic therapies have shifted their focus from simply destroying blood vessels to "standardizing" tumor microvascular formation, thereby increasing oxygen supply and drug delivery. The root cause of abnormal angiogenesis within tumor tissue lies in the dysregulation of various growth factors within the microenvironment. The PDGF / PDGFR pathway, as a key factor in planning angiogenesis pathways and recruiting pericytes to promote angiogenesis maturation, plays an indispensable role in this process.

[0009] Disk-domain receptor 1 (DDR1) is a novel receptor tyrosine kinase (RTK) that, upon activation, regulates matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT), playing a crucial role in tumor cell migration. Studies have shown that inhibiting DDR1 expression can induce autophagy and improve the sensitivity of tumor cells to radiotherapy and chemotherapy.

[0010] As is well known, multi-target drugs have significant advantages over combination therapy and multi-component drugs: being a single component, they are superior to combination therapy and multi-component drugs in terms of drug metabolism; they overcome adverse reactions caused by interactions between components; they are convenient to administer, without the dosage or ratio issues associated with combination therapy; they possess predictable pharmacodynamics (PD) and pharmacokinetics (PK) properties; under the premise of the same efficacy, the synergistic effect can reduce the drug dosage, thereby improving the adverse reactions of highly selective single-target drugs; and they slow down the development of drug resistance. Summary of the Invention

[0011] The purpose of this disclosure is to provide a compound with tyrosine kinase inhibitory activity that achieves better tumor suppression through multi-target synergistic effects and reduces the occurrence of drug resistance.

[0012] This disclosure provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0013] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Among them, W5 independently represents CR 1 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a Rb NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NRa S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C3-C6 heterocyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CR a Rb NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; and when R 1 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl, halogenated C3-C6 heterocyclic alkyl, C1-C6 alkyl-substituted C3-C6 heterocyclic alkyl, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 yuan heteroaryl); and when R 2 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each of these can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, (CH3)2N-(C1-C6 alkyl), C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or RT R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0014] In one technical solution, the compound has a structure as shown in formula (I):

[0015] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Among them, W5 independently represents CR 1 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)Ra -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NRa -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R bHalogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a-SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0016] In one technical solution, the compound has a structure as shown in formula (I):

[0017] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Among them, W5 independently represents CR 1 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R bHalogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR aR b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)ORa -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R bTogether with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0018] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0019] In one technical solution, W1 represents N.

[0020] In one technical solution, W2 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0021] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0022] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0023] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0024] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0025] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0026] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0027] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0028] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0029] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0030] In one technical solution, R 1 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b-CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0031] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0032] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10Aryl, 5-10 heteroaryl.

[0033] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0034] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0035] In one technical solution, R 1 express .

[0036] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0037] In one technical solution, W5 and W2 together form a ring that is fused with ring A and has the following structure: , , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0038] In one technical solution, W5 and W 2 Together they form a ring that fuses with ring A and has the following structure: , , , , , or The wavy line represents the point connected to L1.

[0039] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -ORa , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0040] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0041] In one technical solution, R 2Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0042] In one technical solution, R 3 It represents hydrogen or CH3.

[0043] This disclosure provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0044] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where W5 independently represents N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR aR b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or RT R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0045] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0046] In one technical solution, W1 represents N.

[0047] In one technical solution, W2 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0048] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0049] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0050] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0051] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0052] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0053] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0054] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0055] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0056] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0057] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0058] In one technical solution, W5 and W2 together form a ring that is fused with ring A and has the following structure: , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0059] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0060] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a Rb NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0061] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0062] In one technical solution, R 3 It represents hydrogen or CH3.

[0063] This disclosure provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0064] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3Ra -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a-、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; and when R 1 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Or, R 1 Together with W2 and the atoms attached thereto, they form a 5-6 member saturated or unsaturated ring fused with ring A, and may also contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N; furthermore, the ring may also be arbitrarily divided by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl, halogenated C3-C6 heterocyclic alkyl, C1-C6 alkyl-substituted C3-C6 heterocyclic alkyl, -SO3R a -SR a -S(O)2R a-S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 yuan heteroaryl); and when R 2 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 membered protected or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R bThe substituents are replaced; Among them, R a R b Each of these can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, (CH3)2-N(C1-C6 alkyl), C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0065] In one technical solution, the compound has the structure shown in formula (II):

[0066] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a-OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CRa R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Or, R 1Together with W2 and the atoms attached thereto, they form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Among them, R 3Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 membered protected or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0067] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0068] In one technical solution, W1 represents N.

[0069] In one technical solution, W2 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, CN(CH3)2, CH2NCH3, CH2N(CH3)2, C(CN) or N.

[0070] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0071] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, C(CN) or N.

[0072] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0073] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0074] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0075] In one technical solution, X1 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0076] In one technical solution, X2 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0077] In one technical solution, L1 represents CH2, CF2, O, NH, or NCH3.

[0078] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0079] In one technical solution, R 1 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0080] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SRa -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0081] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0082] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0083] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0084] In one technical solution, R 1 express .

[0085] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a Rb -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0086] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)Ra -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0087] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , or The wavy line represents the point connected to L1.

[0088] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0089] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0090] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0091] In one technical solution, R 3 It represents hydrogen or CH3.

[0092] Specifically, this disclosure provides compounds having the following structures: .

[0093] On the other hand, this disclosure provides a compound having the structure of formula (III) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0094] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR bHalogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a Rb O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0095] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0096] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0097] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0098] In one technical solution, Y1 represents CH, CCH3, CF, -CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0099] In one technical solution, Y2 represents CH, CCH3, CF, -CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0100] In one technical solution, Y3 represents CH, CCH3, CF, -CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0101] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0102] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0103] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0104] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0105] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, and -NH-.

[0106] In one technical solution, L2 represents -C(O)NH-.

[0107] In one technical solution, R W2 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a Rb Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0108] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0109] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0110] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0111] In one technical solution, R W2Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0112] In one technical solution, R W2 express .

[0113] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0114] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CRa R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0115] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0116] In one technical solution, L2 represents -C(O)NH-; R 2Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0117] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b-CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0118] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , or The wavy line represents the point connected to L1.

[0119] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0120] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a, oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0121] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0122] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0123] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0124] In one technical solution, L2 represents -C(O)NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0125] In one technical solution, R 3 It represents hydrogen or CH3.

[0126] This disclosure provides a compound having a structure of formula (III) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0127] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 ; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 RY3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b-, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a-S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R bEach can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0128] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0129] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0130] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0131] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0132] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0133] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0134] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0135] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0136] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0137] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0138] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, and -NH-.

[0139] In one technical solution, L2 represents -C(O)NH-.

[0140] In one technical solution, R W2 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b-CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0141] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0142] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0143] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0144] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0145] In one technical solution, R W2 express .

[0146] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0147] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0148] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a-OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0149] In one technical solution, L2 represents -C(O)NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0150] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0151] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , or The wavy line represents the point connected to L1.

[0152] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0153] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0154] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0155] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0156] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a Rb NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0157] In one technical solution, L2 represents -C(O)NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0158] In one technical solution, R 3 It represents hydrogen or CH3.

[0159] This disclosure provides a compound having a structure of formula (III) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0160] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, RW1 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b )o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a Rb -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0161] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0162] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0163] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0164] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0165] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0166] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0167] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0168] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

[0169] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0170] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0171] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, and -NH-.

[0172] In one technical solution, L2 represents -C(O)NH-.

[0173] In one technical solution, R 2Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0174] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a Rb -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0175] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0176] In one technical solution, L2 represents -C(O)NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a-SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl.

[0177] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0178] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: The wavy line represents the point connected to L1.

[0179] In one technical solution, R 2Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0180] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0181] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b-CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0182] In one technical solution, L2 represents -NHC(O)-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0183] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0184] In one technical solution, L2 represents -C(O)NH-; R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0185] In one technical solution, R 3 It represents hydrogen or CH3.

[0186] This disclosure provides a compound having a structure of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0187] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SRa -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR aS(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Or, R 1Together with W2 and the atoms attached thereto, they form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10Aryl, 5-10 heteroaryl; Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 membered protected or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T RT’ Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0188] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0189] In one technical solution, W1 represents N.

[0190] In one technical solution, W2 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, CN(CH3)2, CH2NCH3, CH2N(CH3)2, C(CN) or N.

[0191] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0192] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, C(CN) or N.

[0193] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0194] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0195] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0196] In one technical solution, X1 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0197] In one technical solution, X2 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0198] In one technical solution, L1 represents CH2, CF2, O, NH, or NCH3.

[0199] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0200] In one technical solution, R 1 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0201] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CRa R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0202] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0203] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0204] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0205] In one technical solution, R 1 express .

[0206] In one technical solution, R 2Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0207] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b-CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0208] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , or The wavy line represents the point connected to L1.

[0209] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0210] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NRa R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0211] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0212] In one technical solution, R 3 It represents hydrogen or CH3.

[0213] Specifically, this disclosure provides compounds having the following structures: .

[0214] On the other hand, this disclosure provides a compound having the structure of formula (V) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0215] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR aCOR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents -C(O)NR a-、-NR a C(O)-; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 aryl groups that are replaced; Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONRa R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5-10 quinone heteroaryl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0216] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCF2H, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0217] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0218] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0219] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0220] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0221] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0222] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0223] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0224] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0225] In one technical solution, R W2 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)Ra -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0226] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0227] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0228] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0229] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0230] In one technical solution, R W2 express .

[0231] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 heteroaryl groups that are replaced.

[0232] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, or -C(O)R aThe 5-10 heteroaryl groups that are replaced.

[0233] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0234] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , or The wavy line represents the point connected to L1.

[0235] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a, oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0236] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , or .

[0237] In one technical solution, R 3 It represents hydrogen or CH3.

[0238] This disclosure provides a compound having a structure of formula (V) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0239] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 ; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a-SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents -C(O)NR a -、-NR a C(O)-; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b-CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 aryl groups that are replaced; Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5-10 quinone heteroaryl or R a R bTogether with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0240] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCF2H, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0241] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0242] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0243] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0244] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0245] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0246] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0247] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0248] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0249] In one technical solution, R W2 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10Aryl, 5-10 heteroaryl.

[0250] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0251] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0252] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0253] In one technical solution, R W2 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0254] In one technical solution, R W2 express .

[0255] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 heteroaryl groups that are replaced.

[0256] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a-SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0257] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , or The wavy line represents the point connected to L1.

[0258] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0259] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , or .

[0260] In one technical solution, R 3 It represents hydrogen or CH3.

[0261] This disclosure provides a compound having a structure of formula (V) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0262] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b-CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a-、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents -C(O)NR a -、-NRaC(O)-; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 aryl groups that are replaced; Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a-SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5-10 quinone heteroaryl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0263] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCF2H, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

[0264] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0265] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN) or N.

[0266] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0267] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0268] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

[0269] In one technical solution, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0270] In one technical solution, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2.

[0271] In one technical solution, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

[0272] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b-CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The 5-10 heteroaryl groups that are replaced.

[0273] In one technical solution, W1 and W2 together form a ring that is fused with ring A and has the following structure: , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0274] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a, oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0275] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , or .

[0276] In one technical solution, R 3 It represents hydrogen or CH3.

[0277] This disclosure provides a compound having the structure of formula (VI) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

[0278] Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SRa -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Or, W 1 W 2 Together with the atoms attached thereto, they form a 5-6 saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N. Or, W 1 W 4 Together with the atoms attached thereto, they form a 5-6 saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; Where L2 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -、-O-、-C(O)-、-NR a-、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -、-NR a C(O)NR b -、-NR a C(O)NR b CR a R b -、-NR a C(O)O-、-NR a C(O)-、-C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C10 Aryl, 5-10 heteroaryl; Or, R 1 W 2 Together with the atoms attached thereto, they form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 W 3 Together with the atoms attached thereto, they form a 5-7 membered protected or unsaturated ring fused with ring A. This ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may arbitrarily be surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R L R L’Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

[0279] In one technical solution, W1 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0280] In one technical solution, W1 represents N.

[0281] In one technical solution, W2 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, CN(CH3)2, CH2NCH3, CH2N(CH3)2, C(CN) or N.

[0282] In one technical solution, W3 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0283] In one technical solution, W4 represents CH, CCH3, CF, CCF3, CCHF2, CHF2, COCH3, CNH2, CNHCH3, C(CN) or N.

[0284] In one technical solution, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0285] In one technical solution, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0286] In one technical solution, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CHF2, COCH3, C(CN) or N.

[0287] In one technical solution, X1 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0288] In one technical solution, X2 represents CH2, CF2, CHF, O, S, CHOH, CH2CH2, or C(CH3)2.

[0289] In one technical solution, L1 represents CH2, CF2, O, NH, or NCH3.

[0290] In one technical solution, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

[0291] In one technical solution, R 1 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0292] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0293] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0294] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

[0295] In one technical solution, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR aHydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

[0296] In one technical solution, R 1 express .

[0297] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0298] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , , , , , , , , , , , or The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

[0299] In one technical solution, R 1 Together with W2, they form a ring that fused with ring A and has the following structure: , , , , or The wavy line represents the point connected to L1.

[0300] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

[0301] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0302] In one technical solution, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

[0303] In one technical solution, R 3 It represents hydrogen or CH3.

[0304] Specifically, this disclosure provides compounds having the following structures: .

[0305] In addition, this disclosure also provides a pharmaceutical composition comprising: the above-described compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.

[0306] It should be understood that, within the scope of this disclosure, the above-described technical features and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0307] definition: Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0308] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0309] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of this disclosure in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0310] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the descriptions in this disclosure. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on the descriptions in several summary and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0311] Unless otherwise indicated, the compounds disclosed herein may be interpreted in a broader sense, in addition to their specific structures, to include pharmaceutically acceptable salts, stereoisomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites of the compounds, i.e., pharmaceutically acceptable salts, stereoisomers, isotopic isomers, solvates, hydrates, prodrugs, and metabolites of the compounds, which also fall within the scope of protection of the compounds.

[0312] Preferably, the pharmaceutical composition disclosed above may further include a second active substance, wherein the second active substance is an antitumor drug, and the antitumor drug includes one or more of chemotherapy drugs, targeted tumor therapy drugs, or tumor therapy antibody drugs.

[0313] In addition, this disclosure also provides a method for treating a disease by inhibiting CSF1R, VEGFR, PDGFR or DDR1 (or a combination thereof) of the compound of this disclosure, which is a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, preferably a tumor.

[0314] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched, or cyclic hydrocarbon group, or a combination thereof, which may be saturated, monounsaturated or polyunsaturated, and may include divalent or polyvalent groups having a specified number of carbon atoms (i.e., C1-C2). 10This refers to one to ten carbon atoms. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and homologues and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl. An unsaturated alkyl group is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. An alkyl group defined as a hydrocarbon group is called a "homoalkyl". The alkyl group is optionally substituted with one or more halogen atoms.

[0315] The term "halogenated alkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogen atoms.

[0316] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, and -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have 1 to 24 carbon atoms, and this disclosure preferably includes groups having 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having eight or fewer carbon atoms. The alkylene group may optionally be substituted with one or more halogen atoms.

[0317] The term "alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond, obtained by removing a hydrogen atom from a single carbon atom of a parent alkene. This group can be in a Z- or E-form (cis or trans) surrounding one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl); butenyl (e.g., buten-1-en-1-yl, buten-1-en-2-yl, 2-methyl-propen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, and buten-1,3-dien-2-yl); and so on. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, and in other embodiments, it has 2 to 6 carbon atoms. Alkenyl groups having 2 to 6 carbon atoms can be called (C2-C6) alkenyl groups.

[0318] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptynyl, etc. The alkynyl group may optionally be substituted with one or more halogen atoms.

[0319] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each having 3 to 10 carbon atoms. "Fused analogues" of cycloalkyl refer to a monocyclic ring fused with an aryl or heteroaryl group, wherein the linking site is in the non-aromatic portion. Examples of cycloalkyl and fused analogues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindenyl, etc. The cycloalkyl group may optionally be substituted with one or more halogen atoms. Further, the term "cycloalkyl" in this disclosure includes bridged ring systems and spirocyclic systems.

[0320] The term "cycloalkenyl" refers to a cyclic hydrocarbon group with a carbon-carbon double bond within the ring. The number of carbon-carbon double bonds is not limited, provided it conforms to the valence bond principle; for example, it can have one, two, or three bonds. The definition of cycloalkenyl also includes fused cycloalkenyl groups formed by fusion with cycloalkyl or other cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, 1,3,5-cycloheptanetriene, and 1,3,5,7-cyclooctatetraene.

[0321] The term "heterocyclic alkenyl" refers to a heterocyclic hydrocarbon group with a carbon-carbon double bond within the ring. In a heterocyclic alkenyl, in addition to carbon atoms, the atoms constituting the ring include at least one heteroatom selected from nitrogen, oxygen, or sulfur. Heterocyclic alkenyl groups may not be aromatic.

[0322] The term "oxo" refers to a group formed when two hydrogen atoms on a carbon atom are replaced by the same oxygen atom; it is also called a carbonyl group (=O). N-oxides of aromatic heterocycles can also be represented as oxo-aromatic heterocycles, such as pyridine N-oxides.

[0323] The term "alkathioyl" refers to -SR, where R represents any straight-chain or branched alkyl group. Examples of alkathioyl groups include, but are not limited to, -SCH3, -SCH2CH3, etc.

[0324] The term "hydroxyl (C1-C6 alkyl)" or "hydroxyl C1-C6 alkyl" refers to a group formed by replacing any hydrogen atom of a C1-C6 alkyl group with a hydroxyl group.

[0325] The term "halogenated (C1-C6 alkyl)" refers to a group obtained by halogenating any hydrogen atom of a C1-C6 alkyl group.

[0326] The term "(CH3)2N-(C1-C6 alkyl)" refers to a group obtained by replacing any hydrogen atom of a C1-C6 alkyl group with a dimethylamino group.

[0327] The term "alkoxy group" refers to a straight-chain or branched alkoxy group that indicates the number of carbon atoms. 1-6 Alkyl groups, for example, include methoxy, ethoxy, propoxy, isopropoxy, etc.

[0328] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S, wherein the nitrogen atom, phosphorus atom, or sulfur atom may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heteroatoms O, N, P, S, and Si may be placed at any position within the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms can be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" itself, or in combination with other terms, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, the heteroatom can be at either end or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the linking group's molecular formula is written does not indicate the orientation of the linking group. For example, the molecular formula -C(O)OR'- represents -C(O)OR'- and -R'OC(O)-. As stated above, heteroalkyl as used herein includes those groups attached to the remainder of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is referred to, followed by specific heteroalkyl groups such as -NR'R'', it should be understood that the terms heteroalkyl and -NR'R'' are not repetitive and are not mutually exclusive. Rather, these specific heteroalkyl groups are referred to for clarity. Therefore, the term “heteroalkyl” should not be construed herein as excluding specific heteroalkyl groups such as -NR'R''.

[0329] The term "cycloalkoxy" refers to a cycloalkyl group as defined above, such as a cyclopropoxy group, which is bonded to an oxygen atom.

[0330] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are halogenated.

[0331] The term "aryl" refers to a monocyclic or bicyclic aryl group containing only a carbon atom. A "fused analogue" of an aryl group refers to the fusion of an aryl group with a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the connecting point is located at the aryl moiety. Examples of aryl groups and their fused-ring analogues include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxane, etc.

[0332] The term "heteroaryl" refers to a monocyclic or bicyclic aryl group containing at least one heteroatom selected from N, O, and S. "Fused analogues" of heteroaryls refer to the fusion of a heteroaryl group with a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the connecting point is located at the aryl moiety. Examples of heteroaryls include pyrroleyl, isozolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, triazinyl, thiopheneyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, furano(2,3-b)pyridinyl, quinolinyl, indolyl, isoquinolinyl, etc.

[0333] The term "substituted or unsubstituted" means that the alkyl, aryl, and heteroaryl groups defined are unsubstituted or substituted by at least one substituent selected from the group consisting of substituents. The substituents are selected from the group consisting of: halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, haloalkoxy groups having 1 to 6 carbon atoms, -CN, alkynyl groups having 2 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, arylalkoxy groups having 7 to 10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, and groups having 2 to 10 carbon atoms. Alkenyl groups with 5 to 5 carbon atoms, alkylthio groups with 1 to 6 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxyl groups, -SF5, hydroxyalkyl groups with 1 to 4 carbon atoms, nitro groups, amino groups, carboxyl groups, alkoxycarbonyl groups with 2 to 5 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms, alkylsulfonyl groups with 1 to 4 carbon atoms, alkanoylamino groups with 1 to 6 carbon atoms, and in... Alkylaminoalkyl groups having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties; alkanoyl(alkyl)aminoalkyl groups having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties; alkylsulfonylamino groups having 1 to 4 carbon atoms; monoalkylaminocarbonyl or dialkylaminocarbonyl groups having 1 to 6 carbon atoms; monoalkylaminosulfinyl or dialkylaminosulfinyl groups having 1 to 6 carbon atoms; monoalkylaminosulfonyl or... Dialkylaminosulfonyl, aminoalkyl having 1 to 4 carbon atoms, monoalkylamino or dialkylamino having 1 to 6 carbon atoms, monoalkylaminoalkyl or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonamide having 1 to 4 carbon atoms.

[0334] As used herein, the terms "heterocyclic," "heterocyclic," "heterocyclic alkyl," or "heterocyclic group" refer to a saturated, partially saturated, or unsaturated group (but not aromatic) having a monocyclic or fused ring (including bridged and spirocyclic systems, having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen within the ring; in fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided the junction passes through a non-aromatic ring). In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized. To provide N-oxide, sulfinyl, and sulfonyl moieties. Examples of "heterocyclic groups" and their fused and analogues include pyrrolidinyl, piperidinyl, piperazinyl, imidazoalkyl, 2,3-dihydrofuran(2,3-b)pyridinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, etc. The term also includes non-aromatic, partially unsaturated monocyclic compounds such as 2- or 4-pyridones linked by a nitrogen atom or N-substituted -(1H,3H)-pyrimidine-2,4-diones (N-substituted uracil).

[0335] As used herein, the terms “substituted heterocyclic” or “substituted heterocyclic alkyl” or “substituted heterocyclic group” refer to a heterocyclic group substituted by 1 to 5 (e.g., 1 to 3) substituents, which are the same substituents defined as substituted cycloalkyl.

[0336] Unless otherwise stated, the terms "halogenated" or "halogen" on their own or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "halogenated alkyl" refers to both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C6)alkyl" refers to, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0337] Optical isomers - diastereomers - geometric isomers - tautomers: Compounds of formula (I) contain one or more asymmetric centers and are therefore possible as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomeric forms. This disclosure is intended to include all such isomers of compounds of formula (I).

[0338] Some of the compounds described herein contain olefinic double bonds, which, unless otherwise stated, include both E and Z geometric isomers.

[0339] Some compounds disclosed herein may contain one or more ring systems, and therefore may have cis- and trans-isomers. This disclosure is intended to include all such cis- and trans-isomers.

[0340] Some of the compounds described herein can exist at different sites of hydrogen atom bonding, referred to as tautomers. Examples of such tautomers can be ketones and their enol forms, known as keto-enol tautomers. Individual tautomers and mixtures thereof are included in the compounds disclosed herein.

[0341] The compounds disclosed herein can be isolated into diastereoisomeric pairs of enantiomers, for example by fractional crystallization from a suitable solvent, such as methanol or ethyl acetate or mixtures thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, such as using an optically active amine or acid as a resolving agent or in a chiral HPLC column.

[0342] Alternatively, any enantiomer of the compounds disclosed herein may be obtained by stereo-directional synthesis using optically pure raw materials or reagents with known configurations.

[0343] Stable isotope-labeled analogs: One or more protons in the compounds disclosed herein may be replaced with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.

[0344] Salt and dosage form It should be understood that, as used herein, references to compounds disclosed herein also include pharmaceutically acceptable salts. Detailed Implementation

[0345] The information provided in this disclosure is intended to assist the reader in understanding only. The information provided and the references cited are not an admission of prior art. Each cited reference is incorporated herein by reference in its entirety and is used for any purpose.

[0346] All documents mentioned in this disclosure are incorporated herein by reference as if each document were individually incorporated herein by reference. Furthermore, it should be understood that after reading the foregoing teachings of this disclosure, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope defined by the appended claims.

[0347] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present disclosure and should not be considered a limitation on the scope of protection of the present disclosure. Based on a full understanding of the present disclosure, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present disclosure, and such modifications should be considered to be included within the scope of protection of the present disclosure.

[0348] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0349] This application has the following definitions: Symbols or units: IC 50 The half-maximum inhibitory concentration (MCC) refers to the concentration at which half of the maximum inhibitory effect is achieved. Example 1 N-(1-((2-amino-5-bromopyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-3-methoxybenzamide

[0350] N-(1-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-3-methoxybenzamide

[0351] Compounds 1f and 1 were prepared by the following steps:

[0352] Step 1: Sodium borohydride (454 mg, 12 mmol) was added to a methanol (20 mL) solution of 1.77 g (10.0 mmol) of 4-nitro-2,3-dihydro-1H-inden-1-one 1a at 0 °C. The resulting mixture was allowed to stand at 0 °C for 10 min. Thin-layer chromatography (TLC) analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum and purified by ISCO chromatography to give solid product 1b (1.68 g, yield: 93.9%). ESI-MS (m / z): 162.1 [M-17] + . Step 2: DIAD (2.85 g, 14.09 mmol) was added dropwise to a solution of 4-nitro-2,3-dihydro-1H-inden-1-ol (1b) (1.68 g, 9.39 mmol), 5-bromo-2-nitropyridin-3-ol (2.47 g, 11.27 mmol), and PPh3 (3.69 g, 14.09 mmol) in 20 mL of dichloromethane at -10 °C. The resulting mixture was allowed to stand at -10 °C for 3 hours. TLC analysis indicated that the reaction was complete. A large amount of solid precipitate formed during the reaction. After filtering the solid, the filter cake was washed with dichloromethane and dried to give a solid product (2.05 g, yield: 57.6%). ESI-MS (m / z): 378.0 [M-1] - 380.0 [M-1] - . Step 3: To a 20 mL ethanol solution containing 1 c (1.14 g, 3 mmol), activated charcoal (230 mg), and ferric chloride (98 mg, 0.6 mmol), hydrazine hydrate (1.88 g, 30 mmol) was added. The solution was heated to reflux. After refluxing the reaction mixture for 30 minutes, TLC showed that the reaction was complete. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by ISCO chromatography to give a solid product (0.82 g, yield: 85.4%). ESI-MS (m / z): 320.0 [M+1] + , 322.0[M+1] + . Step 4: Dissolve 1 d (320 mg, 1 mmol), 3-methoxybenzoic acid (183 mg, 1.2 mmol), EDCI (289 mg, 1.5 mmol), and DMAP (13 mg, 0.1 mmol) in dichloromethane (1 mL) and stir overnight at room temperature. TLC analysis showed that the reaction was complete. The resulting mixture was concentrated under vacuum and purified by ISCO chromatography to give a solid product (320 mg, yield: 70.5%). ESI-MS (m / z): 454.1 [M+1] + , 456.1 [M+1] + . 1 H NMR (62 MHz, DMSO- d 6) δ 10.00 (s, 1H), 7.64 – 7.09 (m, 9H), 6.02 – 5.84 (t, 1H), 5.75 (s, 2H), 3.84 (s, 3H), 3.20– 2.53 (m, 3H), 2.30 – 1.90 (m, 1H). Step 5: A mixed solution of 1 f (272 mg, 0.6 mmol), 1 g (175 mg, 0.84 mmol), K3PO4 (382 mg, 1.8 mmol), and Pd(dppf)Cl2·CH2Cl2 (49 mg, 0.06 mmol) (solvent: 2 mL ethanol and 1 mL water) was degassed under vacuum and purged three times with N2, followed by stirring at 90 °C for 30 min. TLC showed the reaction was complete. The resulting mixture was concentrated under vacuum and purified by ISCO chromatography to give a solid product (168 mg, yield: 61.5%). ESI-MS (m / z): 456.2 [M+1] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.14 (s, 1H), 7.88 – 7.03 (m, 11H), 6.08 – 5.90 (m, 1H), 5.11 (s, 2H), 3.88 (s, 6H), 3.7 – 2.89 (m, 2H), 2.76 – 2.21 (m, 2H). Example 2 The synthesis steps of compounds 2a-2c are the same as those of compound 1 in Example 1.

[0353] Table 1

[0354] Example 3 The synthesis steps of compounds 3a-3j are the same as those of compound 1 in Example 1, wherein the chiral center is constructed from 1a via the Corey-Bakshi-Shibata reaction: ( S )-4-nitro-2,3-dihydro-1 H-Indene-1-ol (3ab): 1.77 g (10 mmol) of 4-nitro-2,3-dihydro-1H-indene-1-one 1a was dissolved in 20 mL of THF. Under nitrogen protection, this solution was added dropwise to a 4 mL THF solution containing DEANB (2 mL, 10.4 mmol) and (R)-2-methyl-CBS-oxaborane (R-CBS) (0.5 mL, 0.5 mmol). The reaction was continued for 3 hours. The reaction mixture was allowed to stand at 0 °C for 10 minutes, and TLC analysis indicated that the reaction was complete. After quenching the reaction with methanol, the reaction mixture was concentrated under vacuum. The residue was purified by ISCO chromatography to give a solid product (1.55 g, yield: 86.6%). ESI-MS (m / z): 162.1 [M-17] + . ( R )-4-nitro-2,3-dihydro-1 H -Indene-1-ol (3bb): 1.77 g (10 mmol) of 4-nitro-2,3-dihydro-1H-indene-1-one 1a was dissolved in 20 mL of THF. Under nitrogen protection, this solution was added dropwise to a 4 mL THF solution containing DEANB (2 mL, 10.4 mmol) and (S)-2-methyl-CBS-oxaborane (S-CBS) (0.5 mL, 0.5 mmol). The reaction was continued for 3 hours. The reaction mixture was allowed to stand at 0 °C for 10 minutes, and TLC analysis indicated that the reaction was complete. After terminating the reaction with methanol, the residue was concentrated under vacuum and purified by ISCO chromatography to give a solid product (1.58 g, yield: 88.3%). ESI-MS (m / z): 162.1 [M-17] + . Table 2

[0355] Example 4 (S)-1-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-N-(3-cyclopropylphenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0356] Compound 4 was prepared by the following steps:

[0357] Step 1: A 20 mL solution of 4a (3.0 g, 19.1 mmol) in THF was added dropwise to a 5 mL solution of THF containing DEANB (3.8 mL, 19.1 mmol) and S-CBS (1.0 mL, 1.0 mmol) under nitrogen protection at -5 to 0 °C. The reaction was continued for 3 hours. The reaction mixture was allowed to stand at 0 °C for 30 minutes, and TLC analysis showed that the reaction was complete. The reaction was terminated by adding methanol, and the reaction mixture was concentrated under vacuum. The residue was washed successively with ethyl acetate, dilute sulfuric acid (10%, w / w), saturated sodium bicarbonate solution, and brine. The organic layer was dried and concentrated under vacuum. Toluene was added to the residue and evaporated to dryness to give a solid product (2.87 g, yield: 94.4%). ESI-MS (m / z): 142.1 [M-17] + . Step 2: To a dichloromethane solution (40 mL) containing 4b (1.0 g, 6.4 mmol), 4c (prepared via a Suzuki coupling reaction of 5-bromo-2-nitropyridine-3-phenol with 1 g of the compound, see step 5 in Example 1 for synthesis) (1.54 g, 7.0 mmol), and PPh3 (2.14 g, 8.2 mmol), DIAD (1.90 g, 9.4 mmol) was added dropwise at -15 to -10 °C. The resulting mixture was allowed to stand at -10 °C for 16 hours. TLC analysis indicated that the reaction was complete, with a large amount of solid precipitating. After filtration, the filter cake was washed with dichloromethane and dried to give a solid product (1.34 g, yield: 58.9%). ESI-MS (m / z): 362.1 [M+1] + . Step 3: Dissolve 4 d (361 mg, 1.0 mmol) and iron powder (280 mg, 5.0 mmol) in acetic acid (5 mL) and stir at 40–45 °C for 20 min. TLC showed the reaction was complete. Add water to the mixture and extract with ethyl acetate. Wash the combined organic layers successively with water, saturated sodium bicarbonate solution, and brine, dry over sodium sulfate, filter, and concentrate. Purify the residue by ISCO chromatography to give a solid product (323 mg, yield: 97.6%). ESI-MS (m / z): 330.1 [M-1] - 332.1[M+1] + . Step 4: Compound 4e (166 mg, 0.5 mmol), sodium hydroxide (0.5 g, 12.5 mmol), water (0.5 g), DMSO (1.0 g), and ethylene glycol (0.5 g) were added to a round-bottom flask. The resulting mixture was stirred at 100–105 °C for 16 hours, and TLC analysis indicated that the reaction was complete. The mixture was diluted with water and the pH was adjusted to 5–6 with aqueous hydrochloric acid, followed by extraction with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over sodium sulfate, and filtered. After concentration, the residue was purified by ISCO chromatography to give a solid product (70 mg, yield: 40.0%). ESI-MS (m / z): 349.1 [M-1] - , 351.1[M+1] + . Step 5: 4f (83 mg, 0.22 mmol), 3-cyclopropylaniline (38.6 mg, 0.29 mmol), EDCI (64.1 mg, 0.33 mmol), and DMAP (2.7 mg, 0.02 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 1.5 hours. TLC showed that the reaction was complete. The reaction mixture was diluted with dichloromethane (2 mL) and washed twice with water (1 mL). The organic layer was concentrated under vacuum and purified by ISCO chromatography to give a solid product (30.5 mg, yield: 29.8%). ESI-MS (m / z): 464.2 [M-1] - , 466.2[M+1] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.34 (s, 1H), 7.99 – 7.77 (m, 2H), 7.77 – 7.64 (m, 2H), 7.64 – 7.41 (m, 4H), 7.40 – 7.06 (m, 2H), 7.02 – 6.67 (m, 1H), 6.15 – 5.80 (m, 1H), 5.10 (s, 2H), 3.89 (s, 3H), 3.58 – 3.14 (m, 2H), 2.76 – 2.20 (m, 2H), 1.95 – 1.68 (m, 1H), 1.15 – 0.52 (m, 4H). Example 5 The synthesis steps of compounds 5a-5e are the same as those of compound 4 in Example 4.

[0358] Table 3

[0359] Example 6 (S)-N-(1-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-4-fluoro-3-methylbenzamide

[0360] Compound 6 was prepared by the following steps:

[0361] Step 1: 5-Bromo-3-fluoro-2-nitropyridine 6a (221 mg, 1.0 mmol), (1S)-4-nitro-2,3-dihydro-1H-indane-1-amine 6b (178 mg, 1.0 mmol), and potassium carbonate (138 mg, 1.0 mmol) were dissolved in DMF (5.0 mL) and stirred at room temperature for 16 hours. The reaction was complete by TLC. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over sodium sulfate, and filtered. After concentration, the mixture was purified by ISCO chromatography to give compound 6c (289 mg, yield: 76.2%). ESI-MS (m / z): 378.0 / 378.9 [M-1] - , 379.0 / 380.9[M+1] + . Step 2: Add 6c (289 mg, 0.8 mmol), iron powder (426 mg, 8.0 mmol), and acetic acid (2.5 mL) to the flask. Stir the resulting mixture at 50–55 °C for 4 hours. TLC showed the reaction was complete. Add water to the mixture and extract with ethyl acetate. Wash the combined organic layers successively with water, saturated sodium bicarbonate solution, and brine, dry over sodium sulfate, and filter. After concentration, purify the mixture by ISCO chromatography to give compound 6d (146 mg, yield: 57.2%). ESI-MS (m / z): 317.0 / 318.9 [M-1] - 319.0 / 320.9[M+1] + . Step 3: 6d (157 mg, 0.49 mmol), 1 g (136 mg, 0.65 mmol), K3PO4 (313 mg, 1.48 mmol), and Pd(dppf)Cl2·CH2Cl2 (4 mg, 0.005 mmol) were mixed in 0.5 mL of ethanol and 0.25 mL of water, degassed under vacuum, and purged three times with N2. The reaction mixture was stirred at 85–95 °C for 2 hours. TLC showed the reaction was complete. After cooling, the mixture was concentrated under vacuum and purified by ISCO chromatography to give solid compound 6e (133 mg, yield: 84.8%). ESI-MS (m / z): 319.2 [M-1] - , 321.2[M+1] + . Step 4: 6e (32 mg, 0.1 mmol), 4-fluoro-3-methylbenzoic acid (23.1 mg, 0.15 mmol), EDCI (38.3 mg, 0.2 mmol), and DMAP (1.2 mg, 0.01 mmol) were dissolved in dichloromethane (1 mL) and stirred overnight at room temperature. TLC analysis indicated that the reaction was complete. After concentration, the mixture was purified by ISCO chromatography to give compound 6 as a solid (20 mg, yield: 43.8%). ESI-MS (m / z): 455.2 [M-1] - , 457.2[M+1] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.14 (s, 1H), 8.08 – 7.76 (m, 3H), 7.75 – 7.45 (m, 3H), 7.20 (m, 4H), 5.43 – 4.74 (m, 3H), 4.42 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 3.06 (d, 2H), 2.79 – 2.43 (m, 1H), 2.34 (s, 3H), 1.95 – 1.56 (m, 1H). Example 7 (S)-1-((2-amino-5-chloropyridin-3-yl)oxy)-N-(3-cyclopropylphenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0362] Compound 7 was prepared by the following steps:

[0363] Step 1: DIAD (526 mg, 2.6 mmol) was added dropwise to a solution of (1R)-1-hydroxy-2,3-dihydro-1H-indene-4-carboxynitrile 4b, 5-chloro-2-nitropyridine-3-ol (419 mg, 2.4 mmol), and PPh3 (682 mg, 2.6 mmol) in dichloromethane (4 mL) cooled to -10 °C. The resulting mixture was incubated at -10 °C for 3 hours. TLC analysis indicated that the reaction was complete. A large amount of solid precipitated during the reaction was filtered, and the filter cake was washed with dichloromethane and dried to give solid compound 7a (367 mg, yield: 58.0%). ESI-MS (m / z): 316.7 [M+1] + . Step 2: 7a (366.5 mg, 1.2 mmol), iron powder (403 mg, 7.2 mmol), and acetic acid (6 mL) were mixed and heated to 40°C with stirring for 30 minutes. TLC showed the reaction was complete. The suspension was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by ISCO chromatography to give solid compound 7b (300 mg, yield: 90.5%). ESI-MS (m / z): 286.7 [M+1] + . Step 3: Add 50% sodium hydroxide solution (1 g, 26 mmol) to a solution containing 2 mL of DMSO and 1 mL of ethylene glycol. Heat the mixture at 100 °C overnight. TLC analysis showed that the reaction was complete. After cooling, acidify with hydrochloric acid (aqueous solution) to pH 5. Collect the precipitate by filtration and dry to give compound 7c (68 mg, yield: 21%). ESI-MS (m / z): 305.7 [M+1] + . Step 4: Compound 7c (68 mg, 0.22 mmol), 3-cyclopropylaniline (36 mg, 0.27 mmol), EDCI (56 mg, 0.29 mmol), and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (0.3 mL) and stirred overnight at room temperature. TLC analysis indicated that the reaction was complete. After concentration, the mixture was purified by ISCO chromatography to give compound 7 as a solid (42.7 mg, yield: 46.7%). ESI-MS (m / z): 410.9 [M+1] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.32 (s, 1H), 7.80 – 7.65 (m, 1H), 7.64 – 7.53 (m, 3H), 7.49 (s, 1H), 7.47 – 7.29 (m, 2H), 7.28 – 6.98 (m, 1H), 6.96 – 6.70 (m, 1H), 6.01 (d, 1H), 5.33 (s, 1H),3.35 – 2.93 (m, 2H), 3.14 – 2.90 (m, 1H), 2.66 – 2.28 (m, 1H), 1.39 – 0.54 (m, 5H). Example 8 N-(1-((5-bromopyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-methylbenzamide

[0364] 3-methyl-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)benzamide

[0365] Compounds 8d and 8 were prepared by the following steps:

[0366] Step 1: A toluene solution (10 mL) of 5-bromo-3-aminopyridine 8a (541 mg, 3.0 mmol), 4-nitro-2,3-dihydro-1H-inden-1-one 1a (344 mg, 2.0 mmol), and TsOH (34 mg, 0.2 mmol) was mixed and heated to 120 °C, and water was removed using a Dean-Stark trap. The reaction was continued until TLC showed completion. The reaction mixture was cooled to room temperature, concentrated to dryness, and purified by column chromatography to obtain a viscous oil. Sodium borohydride (780 mg, 20.0 mmol) was added fractionally to a methanol solution (10 mL) cooled to 0 °C. The resulting mixture was heated to room temperature and stirred until TLC showed completion. After concentration, it was purified by column chromatography to give compound 8b (351 mg, yield: 52.0%). ESI-MS (m / z): 334.1 [M+H] + . Step 2: To a 5 mL ethanol solution containing 8b (334 mg, 1.0 mmol), ferric chloride (16 mg, 0.1 mmol), and activated carbon (33 mg) heated to reflux, 80% hydrazine hydrate (320 mg, 5.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was refluxed until TLC analysis showed that the reaction was complete. The mixture was cooled to room temperature and filtered. The filter cake was washed with a mixture of dichloromethane and methanol (1:1 v / v). The filtrates were combined and concentrated to dryness to give the crude product; it was then purified by grinding with ethanol (5 mL) to give compound 8c (250 mg, yield 83.0%). ESI-MS (m / z): 304.1 [M+H] + . Step 3: 8c (250 mg, 0.8 mmol), 3-methylbenzoic acid (136 mg, 1.0 mmol), EDCI (192 mg, 1.0 mmol), and DMAP (12 mg, 1.0 mmol) were dissolved in dichloromethane (0.3 mL) and stirred at room temperature until TLC showed complete reaction. The reaction mixture was concentrated to dryness and purified by column chromatography to give compound 8d (240 mg, yield: 71.0%). ESI-MS (m / z): 422.0 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.87 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.88 – 7.56 (m, 3H), 7.48 –7.13 (m, 5H), 7.07 (d, J = 2.9Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 5.19 – 4.87 (m, 1H), 2.86 – 2.69 (m, 2H), 2.68 – 2.48 (m, 1H), 2.32 (s, 3H), 1.81 – 1.48 (m, 1H). Step 4: Pd(dppf)Cl2·CH2Cl2 (3 mg, 0.003 mmol) was added to a mixed solvent of ethanol (1 mL) and water (0.5 mL) containing 8d (107 mg, 0.3 mmol), 1 g (104 mg, 0.5 mmol), and K3PO4 (212 mg, 1.0 mmol). The resulting mixture was degassed three times with N2, then heated under reflux and stirred until TLC showed complete reaction. After natural cooling to room temperature, the separated organic layer was concentrated to dryness and purified by column chromatography to obtain the crude product; this product was then ground with a mixture of dichloromethane and diethyl ether (1:1 v / v) to give compound 8 (33 mg, yield 8%). ESI-MS (m / z): 424.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.96 (s, 1H), 8.16 (s, 1H), 8.05 – 7.92 (m, 2H), 7.86 – 7.71 (m, 3H), 7.51 – 7.10 (m, 6H), 6.25 (d, J = 8.4 Hz, 1H), 5.21 – 5.08(m, 1H), 3.87(s, 3H), 2.90 – 2.79 (m, 2H), 2.64 – 2.44 (m, 1H), 2.40 (s, 3H), 1.99 – 1.81 (m, 1H). Example 9 2,2-difluoro-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0367] Compound 9 was prepared by the following steps:

[0368] The synthesis steps of compound 9 are the same as those of compound 8 in Example 8.

[0369] 1 H NMR (62 MHz, DMSO- d 6) δ 9.90 (s, 1H), 8.03 – 7.65 (m, 6H), 7.46 – 6.94 (m, 5H), 6.16 – 6.03 (m, 1H), 5.17 – 4.80 (m, 1H), 3.71 (s, 3H), 3.71 – 3.40 (m, 3H), 1.82 – 1.43 (m, 1H). Example 10 (S)-1-((5-bromopyridin-3-yl)amino)-N-(3-cyclopropylphenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0370] Compound 10 was prepared by the following steps:

[0371] Step 1: Pd2(dba)3 (458 mg, 0.5 mmol) was added to a toluene solution (10 mL) containing 3,5-dibromopyridine 10a (2.83 g, 12.0 mmol), (1S)-1-amino-2,3-dihydro-1H-indene-4-carboxynitrile 10b (1.58 g, 10.0 mmol), sodium tert-butoxide (2.88 g, 30.0 mmol), and BINAP (1.25 g, 2.0 mmol). The resulting mixture was degassed three times with N2, then heated to 90 °C and stirred until TLC showed complete reaction. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), and dried over sodium sulfate. The residue was concentrated to dryness and purified by column chromatography to give compound 10c (2.13 g, yield: 68.0%). ESI-MS (m / z): 314.2 [M+H] + . Step 2: Add water (5 mL) and potassium hydroxide (2.5 g) to a solution containing 10 c (1.90 g, 6.0 mmol) of a mixed solvent of DMSO (10 mL) and ethylene glycol (6 mL). Heat the mixture to 110 °C and stir until the TLC chromatogram shows the reaction is complete. After cooling to room temperature, dilute the reaction mixture with distilled water (20 mL), adjust the pH to 6-7 with 1N hydrochloric acid (aqueous solution), and extract with ethyl acetate (50 mL). Wash the organic layer with brine (50 mL), dry over sodium sulfate, and concentrate to dryness to give crude product 10 d (1.66 g, yield: 83.0%). ESI-MS (m / z): 333.2 [M+H] + . Step 3: EDCI (96 mg, 0.5 mmol) was added to a 0.5 mL solution of dichloromethane containing 10d (101 mg, 0.3 mmol), 3-cyclopropylaniline (66 mg, 0.5 mmol), DMAP (4 mg, 0.03 mmol), and triethylamine (66 mg, 0.6 mmol). The reaction mixture was stirred at room temperature until TLC showed complete reaction, then concentrated to dryness and purified by column chromatography to give compound 10 (67 mg, yield: 51.0%). ESI-MS (m / z): 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.62 (d, J= 7.5 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.38 – 7.33 (m2H), 7.21 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.12 – 5.06 (m, 1H), 3.25 – 3.17 (m, 1H), 3.08 – 3.00 (m, 1H), 2.62 – 2.54 (m, 1H), 1.94 – 1.87 (m, 1H), 1.85 – 1.71 (m, 1H), 1.04 – 0.92 (m, 2H), 0.71 – 0.60 (m, 2H). Example 11 (S)-N-(1-((5-bromopyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-cyclopropylbenzamide

[0372] Compound 11 was prepared by the following steps:

[0373] Step 1: Diphenyl azide phosphate (DPPA) (413 mg, 1.5 mmol) and triethylamine (202 mg, 2.0 mmol) were added to a 2 mL solution of toluene containing 10 d (333 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 24 hours, followed by the addition of methanol (3 mL). The resulting mixture was heated to 60 °C and stirred continuously until the reaction was complete as indicated by TLC. After natural cooling to room temperature, the mixture was concentrated to dryness and purified by column chromatography to give compound 11a (275 mg, yield: 76.0%). ESI-MS (m / z): 362.2 [M+H] + . Step 2: Add water (0.5 mL) and potassium hydroxide (250 mg) to a methanol (1 mL) solution of 11a (275 mg, 0.8 mmol). Heat the reaction mixture to reflux and stir until TLC shows complete reaction. After naturally cooling to room temperature, concentrate the mixture to dryness and purify by column chromatography to give compound 11b as a solid (159 mg, yield: 69.0%). ESI-MS (m / z): 304.2 [M+H] + . Step 3: Add EDCI (96 mg, 0.5 mmol) to a dichloromethane solution (0.5 mL) containing 11b (100 mg, 0.3 mmol), 3-cyclopropylbenzoic acid (81 mg, 0.5 mmol), and DMAP (4 mg, 0.03 mmol). Stir the reaction mixture at room temperature until TLC analysis shows the reaction is complete. Concentrate the resulting mixture to dryness and purify by column chromatography to give compound 11 (86 mg, yield: 64.0%). ESI-MS (m / z): 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.97 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H),7.65 (s, 1H), 7.44 – 7.35 (m, 2H), 7.35 – 7.29 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.13 – 5.07 (m, 1H), 3.01 – 2.74 (m, 2H), 2.61 – 2.52 (m, 1H), 2.06 – 1.99 (m, 1H), 1.79 – 1.70 (m, 1H), 1.02 – 0.98 (m, 2H), 0.80 – 0.76 (m, 2H). Example 12 (S)-3-methyl-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)benzamide

[0374] Compound 12 was prepared by the following steps:

[0375] Step 1: Pd(dppf)Cl2·CH2Cl2 (31 mg, 0.039 mmol) was added to a solution of 11b (234 mg, 0.77 mmol), 1 g (239 mg, 1.15 mmol), and K3PO4 (490 mg, 2.31 mmol) in a mixed solvent of ethanol (3 mL) and water (0.6 mL). The resulting mixture was degassed three times with N2, then heated under reflux and stirred until TLC showed complete reaction. After natural cooling to room temperature, the separated organic layer was concentrated to dryness and purified by column chromatography to give compound 12a (146 mg, yield: 62.0%). ESI-MS (m / z): 305.2 [M+H] + . Step 2: EDCI (58 mg, 0.3 mmol) was added to a 0.5 mL solution of dichloromethane containing 12a (61 mg, 0.2 mmol), 3-methylbenzoic acid (34 mg, 0.3 mmol), and DMAP (1 mg, 0.01 mmol). The reaction mixture was stirred at room temperature until TLC showed completion. The resulting mixture was concentrated to dryness under vacuum and purified by column chromatography to give the target product 12 (35 mg, yield: 42.0%). ESI-MS (m / z): 424.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.09 (s, 1H), 8.13 – 8.01 (m, 3H), 8.78 – 8.74 (m, 3H), 7.68 – 7.59 (m, 1H), 7.44 – 7.17 (m, 5H), 5.62 – 5.20 (m, 2H), 3.92 (s, 3H), 3.01 – 2.85 (m, 2H), 2.65– 2.44 (m, 1H), 2.41 (s, 3H), 1.90 – 1.62 (m, 1H). Example 13 (S)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-N-(m-tolyl)-2,3-dihydro-1H-indene-4-carboxamide

[0376] Compound 13 was prepared by the following steps:

[0377] Step 1: To a 12 mL ethanol solution (2370 mg, 10 mmol) of 3,5-dibromopyridine 10a, Pd(dppf)Cl2·CH2Cl2 (82 mg, 0.1 mmol), 1 g (2195 mg, 10.5 mmol), water (2.5 mL), and K3PO4 (6360 mg, 30 mmol) were added. The resulting mixture was degassed three times with N2, followed by heating under reflux and stirring for 2 hours. TLC showed that the reaction was complete. After natural cooling to room temperature, the separated organic layer was concentrated under vacuum and purified by column chromatography to give the target product 13a (1888 mg, yield: 80.0%). ESI-MS (M / S): 238.1 [M+H] + . Step 2: To a 4 mL solution of 13a (947.2 mg, 4.1 mmol) in toluene, add (1S)-1-amino-2,3-dihydro-1H-indane-4-carboxynitrile 10b (530 mg, 3.4 mmol), Pd2(dba)3 (153.6 mg, 0.05 mmol), S-Tol-BINAP (456 mg, 0.2 mmol), and sodium tert-butoxide (646.4 mg, 2.0 mmol). The resulting mixture was degassed three times with N2, then heated to 80 °C and stirred for 6 hours. TLC analysis indicated that the reaction was complete. The mixture was concentrated under vacuum and purified by column chromatography to give the target product 13b (711 mg, yield: 55.0%). ESI-MS (M / S): 316.3 [M+H] + . Step 3: Add 0.9 mL of 50% sodium hydroxide aqueous solution and 0.9 mL of ethylene glycol to a solution of 13b (158 mg, 0.5 mmol) in DMSO (1.8 mL). Reflux the reaction mixture overnight. TLC analysis indicated that the reaction was complete. Dilute the reaction mixture with water and adjust the pH to 4 with concentrated hydrochloric acid. Collect a large amount of precipitated solid by filtration to give the target product 13c (105 mg, yield: 63%). ESI-MS (M / S): 335.3 [M+H] + . Step 4: To a dichloromethane solution (0.5 mL) containing 13c (100 mg, 0.3 mmol), 3-methylaniline (64 mg, 0.6 mmol), DMAP (7 mg, 0.06 mmol), triethylamine (40 mg, 0.4 mmol), and EDCI (115 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 8 hours. TLC analysis indicated that the reaction was complete. The mixture was washed twice with water, and the separated organic layer was dried, concentrated, and purified by column chromatography to give the target product 13 (98 mg, yield: 77.0%). ESI-MS (M / S): 424.1 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 10.10 (s, 1H), 8.18 – 7.81 (m, 4H), 7.64 – 6.80 (m, 8H), 6.35 – 6.03 (m, 1H), 5.33 – 4.93 (m, 1H), 3.87 (s, 3H), 3.17 – 2.60 (m, 3H), 2.31 (s, 3H), 2.07 – 1.55 (m, 1H). Example 14 (S)-N-(5-chloropyridin-3-yl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0378] Compound 14aa was prepared by the following steps:

[0379] To a solution of 13c (100 mg, 0.3 mmol) in dichloromethane (0.5 mL), 3-amino-5-chloropyridine (77.1 mg, 0.6 mmol), DMAP (7.3 mg, 0.06 mmol), triethylamine (40.4 mg, 0.4 mmol), and EDCI (115.2 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 8 hours. TLC analysis indicated that the reaction was complete. The mixture was washed twice with water, and the separated organic layer was dried, concentrated, and purified by column chromatography to give the target product 14aa (91 mg, yield: 68%).

[0380] The preparation methods of compounds 14ab-14ba are the same as those of compound 13 in Example 13 or compound 14aa in Example 14.

[0381] Table 4

[0382] Example 15 (S)-3-methyl-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)benzamide

[0383] Compound 15 was prepared by the following steps:

[0384] Step 1: To a toluene solution (10 mL) of stirred 3bb (537 mg, 3.0 mmol), 5-bromo-3-hydroxypyridine (870 mg, 5.0 mmol), and PPh3 (1.31 g, 5.0 mmol), DIAD (1.10 g, 5.0 mmol) was added dropwise while maintaining the internal temperature below -10°C under nitrogen protection. The resulting mixture was allowed to stand at -10°C until TLC analysis indicated that the reaction was complete. Water (0.5 mL) was then added to the reaction mixture, and stirring was continued at 0°C for 1 hour. The precipitated solid was filtered and washed with toluene. The combined filtrates were washed with 1N sodium hydroxide aqueous solution (20 mL), dried over sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by column chromatography to give the target product 15a (651 mg, yield: 65.0%). ESI-MS (m / z): 335.1 [M+H] + . Step 2: To a stirred mixture containing 15a (500 mg, 1.5 mmol), ferric chloride (24 mg, 0.15 mmol), and activated charcoal (50 mg), 80% hydrazine hydrate (470 mg, 7.5 mmol) was added dropwise. The mixture was heated to reflux. The resulting mixture was refluxed until TLC showed completion. After cooling to room temperature, the reaction mixture was concentrated to dryness under vacuum. The residue was redissolved in ethyl acetate (20 mL) and washed with water (20 mL × 2). The organic layer was dried over sodium sulfate, concentrated to dryness under vacuum, and purified by column chromatography to give the target product 15b (402 mg, yield: 88%). ESI-MS (m / z): 305.1 [M+H] + . Step 3: To a solution containing 3,5-dibromopyridine 15b (305 mg, 1.0 mmol), 1 g (312 mg, 1.5 mmol), and K3PO4 (636 mg, 3.0 mmol) in a mixed solvent of ethanol (5 mL) and water (1 mL), Pd(dppf)Cl2·CH2Cl2 (40 mg, 0.05 mmol) was added. The resulting mixture was degassed three times with N2, then heated under reflux and stirred until TLC showed the reaction was complete. After naturally cooling to room temperature, the separated organic layer was concentrated to dryness under vacuum and purified by column chromatography to give the target product 15c (208 mg, yield: 68.0%). ESI-MS (m / z): 307.2 [M+H] + .

[0385] Step 4: EDCI (96 mg, 0.5 mmol) was added to a 0.5 mL solution of dichloromethane containing 15c (91 mg, 0.3 mmol), 3-methylbenzoic acid (68 mg, 0.5 mmol), and DMAP (4 mg, 0.03 mmol). The reaction mixture was stirred at room temperature until TLC showed complete reaction, then concentrated to dryness under vacuum and purified by column chromatography to give compound 15 (72 mg, yield: 58.0%). ESI-MS (m / z): 425.1 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ9.99 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.01 (s, 1H), 7.79-7.70 (m, 3H), 7.45-7.23 (m, 5H), 6.15-6.06 (m, 1H), 3.88 (s, 3H), 3.13-2.76 (m, 2H), 2.70-2.60 (m, 1H), 2.40 (s, 3H), 2.07 (s, 1H). Example 16 (R)-3-methyl-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)benzamide

[0386] The synthesis steps of compound 16 are the same as those of compound 15 in Example 15.

[0387] ESI-MS (m / z): 425.1 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ9.99 (s, 1H),8.45 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.79-7.70 (m, 3H),7.44-7.22 (m, 5H), 6.12-6.05 (m, 1H), 3.88 (s, 3H), 3.13-2.76 (m, 2H), 2.70-2.60 (m, 1H), 2.40 (s, 3H), 2.08 (s, 1H). Example 17 (S)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0388] Compound 17 was prepared by the following steps:

[0389] Step 1: Under nitrogen protection and with the internal temperature maintained below -10°C, DIAD (3.6 g, 17.9 mmol) was added dropwise to a toluene solution (19 mL) containing 4b (1.9 g, 11.9 mmol), 5-bromo-3-hydroxypyridine (3.1 g, 17.9 mmol), and PPh3 (5.0 g, 17.9 mmol). The resulting mixture was stirred at -10°C for 1 hour. TLC analysis indicated that the reaction was complete. Water (1 mL) was then added to the reaction mixture, and the mixture was heated to room temperature and stirred for 0.5 hours. The resulting solid precipitate was filtered and washed with toluene. The combined filtrates were concentrated to dryness under vacuum and purified by column chromatography to obtain the target product 17a (1.9 g, yield: 43.6%). ESI-MS (m / z): 315.1 [M+H] + . Step 2: DME (8.4 mL) and water (3.2 mL) were added to a mixture consisting of 17a (1.9 g, 6.0 mmol), 1 g (1.9 g, 9.0 mmol), K3PO4 (3.8 g, 18.0 mmol), and Pd(dppf)Cl2·CH2Cl2 (245 mg, 0.3 mmol). The resulting mixture was refluxed under nitrogen protection for 1 hour. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with dichloromethane (200 mL), washed with water (50 mL × 2), and dried over sodium sulfate. After concentration, the product 17b (1.7 g, yield: 89.6%) was purified by column chromatography. ESI-MS (m / z): 317.1 [M+H] + . Step 3: 30% hydrogen peroxide (7.2 mL) was slowly added dropwise to a DMSO (14.4 mL) suspension containing 17b (1235 mg, 3.9 mmol) and potassium carbonate (1619 mg, 11.7 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (150 mL × 4 times). The combined organic layers were washed with distilled water (30 mL × 2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give product 17c (412 mg, yield: 31.6%). ESI-MS (m / z): 335.1 [M+H] + . Step 4: 17c (100 mg, 0.3 mmol), 4-iodotrifluorotoluene (98 mg, 0.36 mmol), K3PO4 (127 mg, 0.6 mmol), cuprous iodide (6 mg, 0.03 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4.3 mg, 0.03 mmol) were dissolved in 1,4-dioxane (1 mL), degassed three times with nitrogen, and then reacted at 80 °C until TLC showed completion. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with ammonia (10 mL × 2) and water (10 mL). The organic layer was dried over sodium sulfate, concentrated to dryness under vacuum, and purified by column chromatography to give product 17 (91 mg, yield: 63.3%). ESI-MS (m / z): 479.1[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.64(s, 1H), 8.47 (d, J = 1.9 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.05–7.96 (m, 3H), 7.79–7.70 (m, 4H), 7.65 (d, J = 7.4 Hz, 1H), 7.45 (t, J =7.6 Hz, 1H), 6.08 (dd, J = 6.6, 3.7 Hz, 1H), 3.89 (s, 3H), 3.34–3.25 (m, 1H), 3.20–3.08 (m, 1H), 2.69–2.59 (m, 1H), 2.18–2.05 (m, 1H). Example 18 (S)-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0390] Compound 18 was prepared by the following steps:

[0391] Step 1: Add 50% sodium hydroxide aqueous solution (5.0 mL) and ethylene glycol (5.0 mL) to a solution of 17b (948 mg, 3.0 mmol) in DMSO (5.0 mL) under stirring. Heat the reaction mixture to 110 °C and stir continuously until the TLC chromatogram shows that the reaction is complete. After naturally cooling to below 30 °C, adjust the pH of the mixture to 6-7 with 1N hydrochloric acid. Filter off a large amount of precipitated solid, wash the filter cake with water (5.0 mL) and dry under vacuum at 50 °C to give a light brown solid product 18a (665 mg, yield: 66.5%).

[0392] Step 2: Triethylamine (40 mg, 0.4 mmol) and HATU (152 mg, 0.4 mmol) were added to a solution of dichloromethane (0.5 mL) containing 18a (67 mg, 0.2 mmol) and 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine (65 mg, 0.4 mmol). The reaction mixture was stirred at 25 °C until TLC showed complete reaction, then concentrated to dryness under vacuum and purified by column chromatography to give product 18 (18 mg, yield: 19.0%). ESI-MS (m / z): 480.2[M+H]+. 11H NMR(400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H),8.19 (d, J = 2.7 Hz, 1H), 8.03 (s, 1H), 7.73-7.67 (m, 2H), 7.61 (d, J = 7.5Hz, 1H), 7.54-7.45 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.3 Hz,1H), 6.07 (dd, J = 6.6, 3.7 Hz, 1H), 3.89 (s, 3H), 3.54 (s, 2H), 3.30-3.25(m, 1H), 3.20-3.05 (m, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.69-2.57 (m, 3H), 2.39(s, 3H), 2.16-2.04 (m, 2H). Example 19 (S)-N-(5-chloropyridin-3-yl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0393] Compound 19a was prepared by the following steps:

[0394] Triethylamine (20 mg, 0.2 mmol) and HATU (76 mg, 0.2 mmol) were added to a solution of dichloromethane (0.5 mL) containing 18a (34 mg, 0.1 mmol) and 3-amino-5-chloropyridine (33 mg, 0.2 mmol). The reaction mixture was stirred at 25 °C until TLC showed complete reaction, then concentrated to dryness under vacuum and purified by column chromatography to give product 19a (18 mg, yield: 38.0%).

[0395] (S)-N-(2,6-dimethylpyridin-4-yl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0396] Compound 19k was prepared by the following steps:

[0397] 3d (50 mg, 0.12 mmol), 4-bromo-2,6-dimethylpyridine (49 mg, 0.18 mmol), K3PO4 (64 mg, 0.3 mmol), cuprous iodide (4 mg, 0.02 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5.3 mg, 0.04 mmol) were dissolved in 1,4-dioxane (0.5 mL), degassed three times with nitrogen, and then reacted at 80 °C until TLC showed completion. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with ammonia (20 mL × 2) and water (20 mL). The organic layer was dried over sodium sulfate, concentrated to dryness under vacuum, and purified by column chromatography to give product 19k (42 mg, yield: 58.1%).

[0398] The synthesis steps for compounds 19b-19w are the same as those for compounds 17 in Example 17 or compounds 18 in Example 18 or compounds 19a and 19k.

[0399] Table 5

[0400] Example 20 (S)-1-(methyl(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0401] Compound 20 was prepared by the following steps:

[0402] At 0 °C, 40% formalin (188 mg, 2.5 mmol) and sodium cyanoborohydride (158 mg, 2.5 mmol) were added sequentially to a solution of 1,2-dichloroethane (2 mL) containing 14Al (120 mg, 0.25 mmol) and acetic acid (0.2 mL) at 3-hour intervals, and this process was repeated three times. After each addition, the reaction mixture was heated to room temperature and stirred until the next addition; the reaction was terminated when no further product was formed as confirmed by TLC monitoring. The reaction mixture was concentrated to dryness under vacuum and purified by column chromatography to give the target product 20 (solid, 38 mg, yield: 31.0%). ESI-MS (m / z): 492.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.64 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 8.06-7.93 (m, 3H), 7.73 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 7.4 Hz,1H), 7.48 (s, 1H), 7.40 (t,J = 7.5 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 5.79-5.75(m, 1H), 3.88 (s, 3H), 3.30-3.22 (m, 1H), 3.13-3.05 (m, 1H), 2.66 (s, 3H),2.50-2.38 (m, 1H), 2.04-1.89 (m, 1H). Example 21 (S)-N-(5-chloropyridin-3-yl)-1-(methyl(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0403] Compound 21 was prepared by the following steps:

[0404] Step 1: At 0°C, NaH (60%, 880 mg, 22.0 mmol) was added in portions to a solution of 21a (5.16 g, 20.0 mmol) dissolved in DMF (25 mL) under stirring. After stirring for 15 minutes, MeI (3.55 g, 25.0 mmol) was added. The resulting mixture was stirred at 25°C until TLC analysis showed the reaction was complete. The reaction was terminated by adding water (100 mL) and stirring, followed by extraction with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL × 2), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The resulting pale yellow solid (4.5 g, 16.7 mmol) was stirred with a solution of CF3COOH (10 mL) in dichloromethane (30 mL) at 25°C until TLC analysis showed the reaction was complete. The solution was then diluted with dichloromethane (30 mL) and the pH was adjusted to >13 with 10% sodium hydroxide aqueous solution. After briefly stirring the resulting mixture, the aqueous phase was discarded. The organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to dryness to give a brown solid compound 21b (2.6 g, yield: 91%).

[0405] Step 2: Add Pd2(dba)3 (274 mg, 0.3 mmol), BINAP (934 mg, 1.5 mmol), and other active ingredients to a toluene solution (25 mL) containing 21b (2.6 g, 15.1 mmol) and 3,5-dibromopyridine (5.4 g, 22.1 mmol). t -BuONa (4.3 g, 45.3 mmol). The resulting mixture was degassed three times with N2, then heated at 90 °C until TLC analysis indicated the reaction was complete. The mixture was cooled to 30 °C, diluted with ethyl acetate (75 mL), washed with water (100 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by ISCO chromatography to give compound 21c as a brown, viscous oil (2.7 g, yield: 55%).

[0406] Step 3: To a solution of 21c (2.7 g, 8.2 mmol) in a mixed solvent of 1 g (2.6 g, 12.3 mmol) of DME (12 mL) and water (6 mL), K3PO4 (3.0 g, 24.6 mmol) and Pd(dppf)Cl2·CH2Cl2 (335 mg, 0.41 mmol) were added. The resulting mixture was degassed three times with N2, and then stirred at 90 °C until TLC analysis showed that the reaction was complete. After naturally cooling to 30 °C, the reaction mixture was allowed to stand and the aqueous phase was removed. The collected organic layer was concentrated to dryness under reduced pressure. The resulting viscous oil was redissolved in dichloromethane (30 mL), washed with water (30 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by ISCO chromatography to give compound 21d as a yellow viscous oil (1.8 g, yield: 67%).

[0407] Step 4: Add 50% sodium hydroxide aqueous solution (9.0 mL) and ethylene glycol (9.0 mL) to a solution of 21d (1.8 g, 5.5 mmol) in DMSO (9.0 mL) under stirring. Heat the resulting mixture to 110 °C and stir continuously until TLC analysis shows that the reaction is complete. After naturally cooling to 30 °C, adjust the pH of the reaction mixture to 6–7 with 1N hydrochloric acid. Collect the precipitate by filtration, wash with water (9.0 mL), and dry under vacuum at 50 °C to give a light brown solid compound 21e (1.6 g, yield: 88%).

[0408] Step 5: Add EDCI (48 mg, 0.25 mmol) to a dichloromethane solution (0.5 mL) containing 21e (57.7 mg, 0.17 mmol), 3-amino-5-chloropyridine (32.0 mg, 0.25 mmol), and DMAP (4 mg, 0.03 mmol). Stir the resulting mixture at room temperature until TLC analysis shows the reaction is complete. Concentrate the mixture to dryness under reduced pressure, and purify the residue by chromatography to give compound 21 (54 mg, yield: 71%). ESI-MS (m / z): 459.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.88 (s, 1H), 8.87-8.83 (m, 1H), 8.52-8.49 (m, 1H), 8.35-8.31 (m, 1H), 8.21-8.18 (m, 2H), 8.05 (s, 1H), 7.86-7.34 (m, 5H), 5.88-5.62 (m, 1H), 3.92 (s, 3H), 3.46-3.25 (m, 2H), 2.73 (s, 3H), 2.68-2.21 (m, 2H). Example 22 (S)-N-(3-cyclopropylphenyl)-1-(methyl(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0409] Compound 22a was prepared by the following steps:

[0410] EDCI (48 mg, 0.25 mmol) was added to a 0.5 mL solution of dichloromethane containing 21e (57.7 mg, 0.17 mmol), 3-cyclopropylaniline (33.3 mg, 0.25 mmol), and DMAP (4 mg, 0.03 mmol). The resulting mixture was stirred at room temperature until TLC analysis showed that the reaction was complete. The mixture was then concentrated to dryness under reduced pressure, and the residue was purified by chromatography to give compound 22a (51 mg, yield: 65%).

[0411] The synthesis steps of compounds 22a-22g are the same as those for the synthesis of compound 20 in Example 20 or compound 21 in Example 21.

[0412] Table 6

[0413] Example 23 (S)-N-(1-(methyl(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)benzamide

[0414] The synthesis steps of compound 23 are the same as those of compound 20 in Example 20.

[0415] ESI-MS (m / z): 492.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.26 (s, 1H),8.26-8.14 (m, 5H), 8.00-7.88 (m, 3H), 7.50-7.39 (m, 2H), 7.28 (t, J = 7.6 Hz,1H), 7.06-6.99 (m, 1H), 5.78 (t, J = 7.7 Hz, 1H), 3.87 (s, 3H), 3.01-2.85 (m,2H), 2.68 (s, 3H), 2.46-2.37 (m, 1H), 1.99-1.90 (m, 1H). Example 24 (S)-2,2-difluoro-N-(1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0416] Compound 24 was prepared by the following steps:

[0417] Step 1: At 0 °C, NaH (60%, 960 mg, 24.0 mmol) was added fractionally to a stirred solution of 21a (5683 mg, 22.0 mmol) in DMF (15 mL). The mixture was stirred at 0 °C for 30 min, followed by the addition of a DMF solution (5 mL) of 2,6-dichloropyrazine (2979 mg, 20.0 mmol). After 1 hour of reaction, TLC analysis indicated that the reaction was complete. The reaction was terminated by adding saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were concentrated to dryness, and the residue was purified by chromatography to give a white solid product (5340 mg, yield: 72%). ESI-MS (m / z): 371.1 [M+H] + . Step 2: 24a (5340 mg, 14.4 mmol), 1 g (4494 mg, 21.6 mmol), Pd(dppf)Cl2·CH2Cl2 (1167 mg, 1.44 mmol), and K3PO4 (9170 mg, 43.2 mmol) were dissolved in a mixed solvent of ethanol (30 mL) and water (15 mL), heated to 80 °C, and reacted under a nitrogen atmosphere for 3 hours. TLC analysis showed that the reaction was complete. The separated organic phase was purified by chromatography to give a reddish-brown solid product (5098 mg, yield: 85%). ESI-MS (m / z): 417.2 [M+H] + . Step 3: Potassium carbonate (2902 mg, 21.0 mmol) and hydrogen peroxide (30%, 7 mL) were added to a solution of 24b (2915 mg, 7.00 mmol) in DMSO (15 mL) under stirring. The resulting mixture was stirred at room temperature for 1 hour. TLC analysis indicated that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were concentrated to dryness. The resulting residue was purified by chromatography to give a white solid product (2616 mg, yield: 86%). ESI-MS (m / z): 435.2 [M+H] + . Step 4: Trichloroisocyanurate (TCCA) (232 mg, 1.00 mmol) and DBU (1713 mg, 11.2 mmol) were added to a solution of 24c (2171 mg, 5.00 mmol) stirred at 0 °C in 10 mL of methanol. The resulting mixture was stirred at room temperature for 1 hour. TLC analysis indicated that the reaction was complete. Silica gel was added to the reaction mixture and the solvent was evaporated under vacuum. The residue was purified by chromatography to give a white solid product (1641 mg, yield: 73%). ESI-MS (m / z): 465.2 [M+H] + . Step 5: Add 50% potassium hydroxide aqueous solution (5 mL) to the stirred 24-day solution (1535 mg, 3.5 mmol) in MeOH (10 mL). The mixture was reacted at 50 °C for 12 hours. After TLC analysis confirmed the reaction was complete, the MeOH was removed by concentration, and the residue was partitioned with dichloromethane (10 mL) and water (5 mL). The separated organic phase was purified by silica gel chromatography to give a white solid product (933 mg, yield: 87%). ESI-MS (m / z): 307.2 [M+H] + . Step 6: DMAP (3 mg, 0.02 mmol) and EDCI (29 mg, 0.15 mmol) were added sequentially to a dichloromethane solution (0.5 mL) containing 24e (31 mg, 0.10 mmol) and 24f (31 mg, 0.15 mmol). The resulting mixture was stirred at room temperature. After 5 hours of reaction, TLC analysis indicated that the reaction was complete. The mixture was washed with 5% sodium bicarbonate (0.5 mL) and purified by silica gel chromatography to give a pale yellow solid product (35 mg, yield: 71%). ESI-MS (m / z): 491.10 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.25 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 8.04–7.79 (m, 4H), 7.72–7.32 (m, 2H), 7.25 (s, 1H), 7.17 (s, 1H), 6.52 (d, J =8.4 Hz, 1H), 5.86–5.62 (m, 1H), 3.93 (s, 3H), 3.34–2.87 (m, 2H), 2.71–2.38(m, 1H), 1.93–1.71 (m, 1H). Example 25 The synthesis steps of compounds 25a-25f are as described in Example 24, which describes the synthesis of compound 24.

[0418] Table 7

[0419] Example 26 (S)-1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-N-(m-tolyl)-2,3-dihydro-1H-indene-4-carboxamide

[0420] Compound 26 was prepared by the following steps:

[0421] Step 1: 2 mL of 50% sodium hydroxide aqueous solution was added to a solution of 24b (2082 mg, 5.0 mmol) in a mixed solvent of DMSO (8.0 mL) and ethylene glycol (2 mL). The resulting mixture was heated to 100 °C and stirred for 12 hours. TLC analysis indicated that the reaction was complete. After cooling to room temperature, concentrated hydrochloric acid (3 mL) was added. The precipitate was collected by filtration and dried to give a light green solid compound 26a (1459 mg, yield: 87%). ESI-MS (m / z): 336.1 [M+H] + . Step 2: To a solution of dichloromethane (0.5 mL) containing 26a (34 mg, 0.10 mmol) and 3-methylaniline (16 mg, 0.15 mmol), EDCI (29 mg, 0.15 mmol) and DMAP (3 mg, 0.02 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 5 hours. TLC analysis indicated that the reaction was complete. The mixture was washed with 5% sodium bicarbonate aqueous solution, and the separated organic phase was purified by silica gel chromatography to give compound 26 as a white solid (32 mg, yield: 76%). ESI-MS (m / z): 425.15 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ9.28 (s, 1H), 8.14 (s, 1H), 8.08(s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.78–7.51 (m, 3H), 7.46 (s, 1H), 7.37(s, 1H), 7.23 (s, 1H), 7.18–6.92 (m, 1H), 6.54 (d, J = 7.9 Hz, 1H), 6.07–5.61(m, 1H), 3.93 (s, 3H), 3.46–3.05 (m, 2H), 2.75–2.41 (m, 1H), 2.34 (s, 3H),1.96–1.74 (m, 1H). Example 27 (S)-N-(1-methyl-1H-indazol-3-yl)-1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0422] Compound 27g was prepared by the following steps:

[0423] To a solution of 26a (34 mg, 0.10 mmol) and 1-methyl-1H-indazole-3-amine (16 mg, 0.12 mmol) in dichloromethane (0.5 mL), EDCI (29 mg, 0.12 mmol) and DMAP (3 mg, 0.02 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 5 hours. TLC analysis indicated that the reaction was complete. The mixture was washed with 5% sodium bicarbonate aqueous solution (0.5 mL), and the separated organic phase was purified by silica gel chromatography to give 27 g of the compound as a white solid (30 mg, yield: 72%). ESI-MS (m / z): 465.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.76 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 8.05-7.87 (m, 2H), 7.84 (s, 1H), 7.78 (d, J=1.6Hz,1H), 7.73-7.49 (m, 2H), 7.48-7.36 (m, 2H), 7.35-6.95 (m, 2H), 6.60 (d, J =7.9Hz, 1H), 5.74 (t, J =7.6Hz, 1H), 3.96 (d, J =4.9Hz, 6H), 3.66-3.05 (m, 2H), 2.85-2.23 (m, 1H), 1.93-1.00 (m, 1H). The synthesis steps of compounds 27a-27o are as described in Example 26, which describes the synthesis of compound 26, or in Example 27, which describes the synthesis of compound 27g.

[0424] Table 8

[0425] Example 28 The synthesis steps for compounds 28a and 28b are the same as those for the synthesis of compound 12 in Example 12.

[0426] Table 9

[0427] Example 29 methyl(S)-(1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)carbamate

[0428] Compound 29 was prepared by the following steps:

[0429] CF3COOH (0.2 mL) was added to a 24d (23 mg, 0.05 mmol) solution of dichloromethane (0.5 mL), and the mixture was stirred at room temperature for 3 hours. TLC analysis indicated that the reaction was complete. A 10% sodium hydroxide aqueous solution (2 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (5 mL × 3 times). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give a white solid product (7 mg, yield: 38%). ESI-MS (m / z): 365.10 [M+H] + . 1H NMR (62 MHz, acetone- d 6) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.96 (s,1H), 7.82 (s, 1H), 7.73–7.58 (m, 1H), 7.30–7.01 (m, 2H), 6.47 (d, 1H), 5.93–5.48 (m, 1H), 5.43–5.27 (m, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 3.30–3.12 (m,1H), 2.71–2.40 (m, 2H), 1.96–1.69 (m, 1H). Example 30 (S)-N-(1-((6-chloropyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-methylbenzamide

[0430] Compound 30 was prepared by the following steps:

[0431] Step 1: To a toluene solution (1 mL) containing 2,6-dichloropyrazine (75 mg, 0.50 mmol) and 6b (98 mg, 0.55 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (32 mg, 0.05 mmol), and... t -BuONa (145 mg, 1.50 mmol). The resulting mixture was refluxed under nitrogen atmosphere for 5 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (8 mL) and washed with water (4 mL). The separated organic phase was purified by silica gel chromatography to give a yellow solid product (39 mg, yield: 27%). ESI-MS (m / z): 291.1 [M+H] + . Step 2: Iron powder (56 mg, 1.00 mmol) was added to a solution of 30a (30 mg, 0.10 mmol) dissolved in acetic acid (1 mL). The mixture was reacted at 50 °C for 2 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (8 mL) and washed with 5% sodium bicarbonate aqueous solution (5 mL). The separated organic phase was purified by silica gel chromatography to give a white solid product (22 mg, yield: 85%). ESI-MS (m / z): 261.1 [M+H] + . Step 3: EDCI (23 mg, 0.12 mmol) and DMAP (3 mg, 0.02 mmol) were added sequentially to a solution of dichloromethane (0.5 mL) containing 30b (22 mg, 0.08 mmol) and 3-methylbenzoic acid (16 mg, 0.12 mmol). The resulting mixture was reacted at room temperature for 5 hours. TLC analysis indicated that the reaction was complete. The mixture was washed with 5% sodium bicarbonate aqueous solution, and the separated organic phase was purified by silica gel chromatography to give a pale yellow solid product (26 mg, yield: 81%). ESI-MS (m / z): 379.00 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.97 (s, 1H), 8.01 (d, J = 7.9 Hz,1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.45–7.36 (m,3H), 7.23 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 5.50–5.37 (m, 1H), 3.07–2.91 (m, 1H), 2.90–2.74 (m, 1H), 2.59–2.52 (m, 1H), 2.41 (s, 3H), 1.94–1.76(m, 1H). Example 31 (S)-3-methyl-N-(1-((6-(4-methylpiperazin-1-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)benzamide

[0432] Compound 31 was prepared by the following steps:

[0433] The following were added: 30 (20 mg, 0.05 mmol), N-methylpiperazine (10 mg, 0.10 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), BINAP (6 mg, 0.01 mmol) and t A 0.1 mL solution of BuONa (10 mg, 0.10 mmol) in toluene was degassed three times with nitrogen, then heated to 90 °C and stirred until TLC analysis indicated completion of the reaction. After natural cooling to room temperature, the mixture was concentrated to dryness, and the residue was purified by silica gel chromatography to give the product (5 mg, yield: 21%). ESI-MS (m / z): 443.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.95 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H),7.47-7.39 (m, 2H), 7.37-7.27 (m, 3H), 7.21-7.17 (m, 1H), 7.10-7.08 (m, 2H),5.50-7.44 (m, 1H), 3.45 (s, 4H), 2.95-2.89 (m, 1H), 2.84-2.75 (m, 1H), 2.41-2.37 (m, 8H), 2.20 (s, 3H), 1.88-1.78 (m, 1H). Example 32 (S)-N-(1-((6-((2-(dimethylamino)ethyl)(methyl)amino)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-methylbenzamide

[0434] The synthesis of compound 32 is described in Example 31.

[0435] ESI-MS (m / z): 445.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ9.13 (s, 1H),7.82 (s, 1H), 7.77–7.49 (m, 2H), 7.48–7.29 (m, 3H), 7.28–7.01 (m, 3H), 6.20(d, 1H), 5.92–5.22 (m, 1H), 3.73 (t, J = 7.1 Hz, 2H), 3.24 (s, 3H), 3.05–2.51(m, 5H), 2.41 (s, 3H), 2.34 (s, 6H), 1.95–1.75 (m, 1H). Example 33 (S)-1-((6-chloropyrazin-2-yl)amino)-N-(m-tolyl)-2,3-dihydro-1H-indene-4-carboxamide

[0436] (S)-1-((6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)amino)-N-(m-tolyl)-2,3-dihydro-1H-indene-4-carboxamide

[0437] Compounds 33c and 33 were prepared by the following steps:

[0438] Step 1: CF3COOH (20 mL) was added to a solution of 24a (2.85 g, 6.9 mmol) dissolved in dichloromethane (50 mL). The resulting mixture was stirred at room temperature for 3 hours. TLC analysis indicated that the reaction was complete. The mixture was washed with 10% sodium hydroxide aqueous solution (50 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure to give the product (1.61 g, yield: 90%). ESI-MS (m / z): 271.1 [M+H] + . Step 2: Potassium carbonate (2.07 mg, 15.0 mmol) and 30% hydrogen peroxide (4 mL) were added sequentially to a solution of 33a (1.35 g, 5.0 mmol) in DMSO (12 mL) under stirring. The resulting mixture was stirred at room temperature for 1 hour. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were concentrated to dryness, and the residue was purified by silica gel chromatography to give the product (878 mg, yield: 61%). ESI-MS (m / z): 289.1 [M+H] + . Step 3: A mixture of 30b (870 mg, 3.0 mmol), 3-iodobenzylamine (1.30 g, 6.0 mmol), Cs₂CO₃ (1.95 g, 6.0 mmol), cuprous iodide (58 mg, 0.3 mmol), and (1S,2S)-(+)-N,N'-dimethylcyclohexanediamine (85 mg, 0.6 mmol) was dissolved in dioxane (3 mL). The mixture was heated to 80 °C and stirred under nitrogen protection until TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography to give the product (682 mg, yield: 60%). ESI-MS (m / z): 379.1 [M+H] + . Step 4: Dissolve 33c (50 mg, 0.13 mmol), 33d (39 mg, 0.17 mmol), Pd(dppf)Cl2·CH2Cl2 (1 mg, 0.001 mmol), and K3PO4 (85 mg, 0.40 mmol) in a mixed solvent of DME (0.6 mL) and water (0.3 mL). Purge three times with N2, then heat to 90 °C and stir until TLC analysis indicates completion. After natural cooling to room temperature, concentrate the reaction mixture to dryness. Purify the residue by silica gel chromatography to give product 33 (31 mg, yield: 53%). ESI-MS (m / z): 440.1 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 9.24 (s, 1H), 7.69 (s, 1H),7.58 (s, 1H), 7.54 (s, 1H), 7.40 (s, 2H), 7.35 (s, 2H), 7.24 (s, 1H), 7.16–6.81 (m, 1H), 6.20 (d, J= 7.9 Hz, 1H), 5.82–5.31 (m, 1H), 3.71–3.40 (m, 4H), 3.39–3.02 (m, 2H), 2.80–2.57 (m, 1H), 2.56–2.36 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 1.96–1.79 (m, 1H). Example 34 (S)-1-((6-(4-methylpiperazin-1-yl)pyrazin-2-yl)amino)-N-(m-tolyl)-2,3-dihydro-1H-indene-4-carboxamide

[0439] The synthesis steps of compound 34 are the same as those of compound 31 in Example 31.

[0440] ESI-MS (m / z): 443.1 [M+H] + 1H NMR (62 MHz, acetone- d 6) δ 9.24 (s, 1H),7.69 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.40 (s, 2H), 7.35 (s, 2H), 7.24(s, 1H), 7.16–6.81 (m, 1H), 6.20 (d, J = 7.9 Hz, 1H), 5.82–5.31 (m, 1H), 3.71–3.40 (m, 4H), 3.39–3.02 (m, 2H), 2.80–2.57 (m, 1H), 2.56–2.36 (m, 4H), 2.33(s, 3H), 2.24 (s, 3H), 1.96–1.79 (m, 1H). Example 35 (S)-N 4 -(4-isopropylthiazol-2-yl)-N 1 -(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0441] Compound 35 was prepared by the following steps:

[0442] Step 1: N,N'-thiocarbonyldiimidazole (107 mg, 0.6 mmol) was added to a solution containing 24e (153 mg, 0.5 mmol) dissolved in dichloromethane (0.6 mL). The mixture was stirred at room temperature for 1 hour, then ammonia (25%, 68 mg) was added, and stirring continued for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give an oily product (180 mg, yield: 98.5%). ESI-MS (m / z): 366.1 [M+H] + . Step 2: A 2 mL ethanol solution of 35a (73 mg, 0.2 mmol) and 1-bromo-3-methyl-2-butanone (36 mg, 0.22 mmol) was heated to 80 °C and stirred for 2 hours. The resulting mixture was concentrated, and the residue was purified by silica gel chromatography to give a white solid product 35 (50 mg, yield: 57.9%). ESI-MS (m / z): 432.2 [M+H] + . 1 H NMR (62MHz, acetone- d 6) δ 8.54 (s, 1H), 8.29-7.73 (m, 5H), 7.38-6.89 (m, 2H), 6.67-6.25 (m, 2H), 5.94-5.66 (m, 1H), 3.92 (s, 3H), 3.21-1.75 (m, 5H), 1.26 (d, J =6.8 Hz, 6H). Example 36 The synthesis steps of compounds 36a-36c are the same as those of compound 35 in Example 35.

[0443] Table 10

[0444] Example 37 (S)-N 4 -(5-isopropylthiazol-2-yl)-N 1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0445] Compound 37 was prepared by the following steps:

[0446] To a reaction flask containing dioxane (0.5 mL), 24e (31 mg, 0.1 mmol), Cs₂CO₃ (82 mg, 0.25 mmol), 5-isopropyl-2-bromothiazole (31 mg, 0.15 mmol), Xantphos (6 mg, 0.01 mmol), and Pd₂(dba)₃ (9 mg, 0.01 mmol) were added sequentially. The resulting mixture was degassed under vacuum and purged with N₂, then heated to 100 °C and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give product 37 as a white solid (10 mg, yield: 23%). ESI-MS (m / z): 432.2 [M+H] + . 1 H NMR (62 MHz, DMSO- d 6) δ 9.25(s, 1H), 8.21 (s, 1H), 8.09-7.83 (m, 3H), 7.74 (s, 1H), 7.47-6.77 (m, 4H),5.82-5.34 (m, 1H), 3.86 (s, 3H), 3.17-1.62 (m, 5H), 1.29 (s, 3H), 1.18 (s, 3H). Example 38 (S)-N 4 -(1-(tert-butyl)-1H-pyrazol-3-yl)-N 1 -(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0447] Compound 38 was prepared by the following steps:

[0448] To a reaction flask containing toluene (0.5 mL), 24e (31 mg, 0.1 mmol), potassium tert-butoxide (44 mg, 0.39 mmol), 3-bromo-1-tert-butylpyrazole (31 mg, 0.32 mmol), and BrettPhos Pd(II) (12 mg, 0.013 mmol) were added sequentially. The resulting mixture was degassed under vacuum and purged with N2, then heated to 100 °C and stirred for 4 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give product 38 as a white solid (45 mg, yield: 75%). ESI-MS (m / z): 429.3 [M+H] + . 1 H NMR (62 MHz, Acetone- d 6) δ 8.14 (s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.90-7.62 (m, 2H), 7.55 (d, J = 2.4 Hz, 1H), 7.29-6.63 (m, 3H), 6.54-6.22 (m, 1H), 5.89 (d, J = 2.4 Hz, 1H), 5.79-5.39 (m, 1H), 3.92 (s, 3H), 3.17-1.73 (m, 4H), 1.56 (s, 9H). Example 39 The synthesis steps for compounds 39a and 39b are the same as those for the synthesis of compound 38 in Example 38.

[0449] Table 11

[0450] Example 40 (S)-N 4 -(5-(tert-butyl)-4-methylisoxazol-3-yl)-N 1 -(5-chloropyridin-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0451] (S)-N 4-(5-(tert-butyl)-4-methylisoxazol-3-yl)-N 1 -(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0452] Compounds 40c and 40 were prepared by the following steps:

[0453] Step 1: A toluene solution (10 mL) of 40a (1.35 g, 5.66 mmol), (1S)-4-bromo-2,3-dihydro-1H-indene-1-amine (1.00 g, 4.7 mmol), sodium tert-butoxide (1.63 g, 16.98 mmol), BINAP (146.5 mg, 0.235 mmol), and Pd2(dba)3 (215 mg, 0.235 mmol) was refluxed at 100 °C for 3 hours under a nitrogen atmosphere. TLC analysis indicated that the reaction was complete. Ethyl acetate (100 mL) was added to the reaction mixture, which was washed with water (50 mL × 2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give a white solid product 40b (530 mg, yield: 35.5%). ESI-MS (m / z): 323.0 [M+H] + . Step 2: 40b (162 mg, 0.5 mmol), 40c (84.7 mg, 0.55 mmol), RuPhos Pd G3 (41.8 mg, 0.05 mmol), and sodium tert-butoxide (144 mg, 1.5 mmol) were dissolved in toluene (0.5 mL) and refluxed at 100 °C for 3 hours under nitrogen atmosphere. TLC analysis indicated that the reaction was complete. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed twice with water (50 mL each time), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give a white solid product 40d (100 mg, yield: 55.5%). ESI-MS (m / z): 397.0 [M+H] + 1H NMR (62 MHz, DMSO- d 6) δ 7.97 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.50 (d, J= 2.1 Hz, 1H), 7.05–6.72 (m,2H), 6.45 (m, 3H), 4.83 (m, 1H), 2.54 (m, 2H), 2.20 (s, 1H), 1.67 (s, 4H), 1.07 (s, 9H). Step 3: 40d (100 mg, 0.25 mmol), 1 g (72.8 mg, 0.35 mmol), Pd(dppf)Cl2·CH2Cl2 (20.4 mg, 0.025 mmol), and K3PO4 (159 mg, 0.75 mmol) were dissolved in a mixed solvent of ethanol (0.4 mL) and water (0.2 mL), and the mixture was refluxed at 90 °C for 6 hours under a nitrogen atmosphere. After TLC analysis showed that the reaction was complete, ethyl acetate (50 mL) was added to the reaction mixture. The resulting mixture was washed twice with water (50 mL each time), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give a pale yellow solid product 40 (20 mg, yield: 55.5%). ESI-MS (m / z): 443.0 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 8.05 (d, J = 5.5 Hz, 3H), 7.80(s, 1H), 7.42–6.67 (m, 5H), 5.22 (s, 1H) 3.92 (s, 3H), 3.00 (s, 2H), 2.51 (s,1H), 2.12 (s, 3H), 1.84 (s, 2H), 1.35 (s, 9H). Example 41 (S)-N 4 -(5-(tert-butyl)isoxazol-3-yl)-N 1 -(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0454] Compound 41 was prepared by the following steps:

[0455] Step 1: Cuprous iodide (192 mg, 1.0 mmol) and N,N'-dimethylethylenediamine (232 mg, 2.0 mmol) were added to a 5 mL solution of dioxane containing 13a (1.19 g, 5.0 mmol) and sodium iodide (1.49 g, 10.0 mmol). The resulting mixture was degassed three times with nitrogen, then heated to 110 °C and stirred for 24 hours. After cooling to room temperature, dichloromethane (50 mL) was added to the reaction mixture. The resulting mixture was washed with 12% ammonia (50 mL) and water (50 mL) and dried over sodium sulfate. After concentrating to dryness, the crude product was used directly for the next step without further purification (1.27 g, purity: 100%, yield: 89%). ESI-MS (m / z): 286.1 [M+H] + . Step 2: Sodium tert-butoxide (864 mg, 9.0 mmol) was added to a toluene solution (3.0 mL) containing 41a (850 mg, 3.0 mmol), (1S)-4-bromo-2,3-dihydro-1H-indene-1-amine (690 mg, 3.0 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), and BINAP (373 mg, 0.6 mmol). The resulting mixture was degassed three times with nitrogen, then heated to 90 °C and stirred until TLC analysis indicated the reaction was complete. After naturally cooling to room temperature, ethyl acetate (30 mL) was added to the reaction mixture. The resulting mixture was washed with water (30 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography to give the product (221 mg, yield: 19%). ESI-MS (m / z): 387.2 [M+H] + . Step 3: 41b (37 mg, 0.1 mmol), sodium tert-butoxide (29 mg, 0.3 mmol), 3-amino-5-tert-butylisoxazole (21 mg, 0.15 mmol), and RuPhos Pd G3 (8 mg, 0.01 mmol) were added sequentially to a reaction flask containing toluene (0.5 mL). The resulting mixture was degassed under vacuum and purged with N2, then heated to 100 °C and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (20 mL × 3 times). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give a white solid product (30 mg, yield: 70%). ESI-MS (m / z): 429.2 [M+H] + . 1 H NMR (400 MHz, CDCl3)δ 8.14 – 8.10 (m, 1H), 7.99 – 7.94 (m, 1H), 7.76 – 7.72 (m, 1H), 7.63 (s, 1H), 7.61 – 7.57 (m, 1H), 7.31 – 7.22 (m, 1H), 7.05 – 7.00 (m, 2H), 6.04 (s, 1H), 5.79 (s, 1H), 5.16 – 5.03 (m, 1H), 4.07 – 4.01 (m, 1H), 3.95 (s, 3H), 3.02 – 1.89 (m, 4H), 1.34 (s, 9H). Example 42 The synthesis steps of compounds 42a-42t are as described in Example 40, which describes the synthesis of compounds 40d and 40, or Example 41, which describes the synthesis of compound 41.

[0456] Table 12

[0457] Example 43 N-(5-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-methylbenzamide

[0458] Compound 43 was prepared by the following steps:

[0459] Step 1: Dissolve 8a (10.0 g, 57.8 mmol), 1 g (14.4 g, 69.4 mmol), Pd(dppf)Cl2·CH2Cl2 (62 mg, 0.1 mmol), and K3PO4 (18.4 g, 86.7 mmol) in a mixed solvent of ethanol (80 mL) and water (20 mL). After degassing with N2, heat to 85 °C (Ambient temperature) and stir for 3 hours. After concentration, dilute the residue with water (200 mL) and extract with ethyl acetate (200 mL × 3). Combine the organic layers, wash with brine (200 mL), dry over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography to give a yellow solid product (7.5 g, yield: 75%). ESI-MS (m / z): 175.1 [M+H] + . Step 2: Trimethylsilyltrifluoromethanesulfonate (TMSOTf) (556 mg, 2.5 mmol) and a THF solution of borane (1 M, 1 mL, 1.0 mmol) were added sequentially to a DMF solution containing 43a (175 mg, 1.0 mmol) and 43b (252 mg, 1.1 mmol). The resulting mixture was stirred at room temperature under nitrogen protection for 12 hours. TLC analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (8 mL), washed with 5% sodium bicarbonate aqueous solution (4 mL), and purified by chromatography to give a yellow solid product (104 mg, yield: 27%). ESI-MS (m / z): 385.1 [M+H] + . Step 3: Sodium borohydride (19 mg, 0.50 mmol) was added to a 2 mL solution of 43°C (97 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 2 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was purified by chromatography to give a white solid product (71 g, yield: 73%). ESI-MS (m / z): 387.1 [M+H] + . Step 4: To a toluene solution (0.5 mL) containing 43d (70 mg, 0.18 mmol) and 3-methylbenzamide (37 mg, 0.27 mmol), cuprous iodide (4 mg, 0.02 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexanediamine (3 mg, 0.02 mmol), and potassium carbonate (50 mg, 0.36 mmol) were added sequentially. The resulting mixture was degassed with N2 and refluxed for 3 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (6 mL), washed with water (3 mL), and purified by silica gel chromatography to give a white solid product (65 mg, yield: 81%). ESI-MS (m / z): 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 10.04 (s, 1H), 8.17 (s, 1H), 7.93–7.73 (m, 3H), 7.43 (d, J =4.7 Hz, 2H), 7.36–7.05 (m, 3H), 6.31 (s, 1H), 5.15 (d, J = 7.9 Hz, 1H), 3.87(s, 3H), 2.89 (s, 1H), 2.79 (dt, J = 16.4, 8.1 Hz, 1H), 2.61 (dd, J = 13.9, 6.1Hz, 1H), 2.41 (s, 3H), 1.83 (s, 1H). Example 44 The synthesis steps of compounds 44a-44e are as described in Example 43, which describes the synthesis of compound 43.

[0460] Table 13

[0461] Example 45 (S)-N-(7-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-3-methylbenzamide

[0462] Compound 45 was prepared by the following steps:

[0463] Step 1: Under nitrogen protection, DEANB (3.26 g, 20.0 mmol) cooled to 0°C and stirred was reacted with (S)-( A solution of 2-methyl-CBS-oxaborhecclobutane (1 M toluene solution, 2 mL, 2.0 mmol) in 10 mL of THF was slowly added dropwise over 3 hours to a solution of 7-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one 45a (4.58 g, 20.0 mmol) in 50 mL of THF. The reaction mixture was stirred continuously at 0 °C until TLC analysis indicated that the reaction was complete. The reaction was then quenched by slowly adding methanol (5 mL) at 0 °C, and stirred for 1 hour after warming to room temperature. The mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), and washed successively with 10% sulfuric acid aqueous solution (50 mL × 2), saturated sodium bicarbonate aqueous solution (50 mL), and brine (50 mL). The solution was dried over sodium sulfate and concentrated to dryness under reduced pressure to give a light brown solid product. This crude product could be used directly in the next reaction without further purification (yield: 100%).

[0464] Step 2: DBU (7.6 g, 50.0 mmol) was added to a 35 mL solution of 45b (3.30 g, 20.0 mmol) in THF, followed by DPPA (11.0 g, 40.0 mmol) at 0 °C. The resulting mixture was heated to 30 °C and stirred for 12 hours. TLC analysis indicated that the reaction was complete. The mixture was concentrated to dryness and purified by chromatography to obtain the azide intermediate. Water (50 mL) was added to a 100 mL solution of the above azide compound in THF at 0 °C, followed by PPh3 (15.72 g, 60.0 mmol) and potassium hydroxide (3.36 g, 60.0 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was separated in a separatory funnel: the aqueous phase was discarded, and the organic phase was concentrated to dryness. Water (100 mL) was added to the residue, and the pH was adjusted to 1-2 with 6N hydrochloric acid (aqueous solution). The acidic aqueous solution was washed with dichloromethane (100 mL × 2), and the pH was adjusted to >13 with 10% sodium hydroxide aqueous solution. The resulting suspension was extracted with dichloromethane (100 mL), the aqueous phase was discarded, and the organic phase was dried over sodium sulfate and concentrated to dryness to obtain the crude product (3.20 g, yield: 70%).

[0465] Step 3: Add to a 3 mL toluene solution containing 40a (850 mg, 3.0 mmol), 45c (690 mg, 3.0 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), and BINAP (373 mg, 0.6 mmol) t -BuONa (864 mg, 9.0 mmol). The resulting mixture was degassed three times with N2, then heated to 90 °C and stirred until TLC analysis indicated completion. After natural cooling to room temperature, ethyl acetate (30 mL) was added to the mixture. The mixture was washed with water (30 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography to give the product (221 mg, yield: 19%). ESI-MS (m / z): 387.2 [M+H] + . Step 4: A mixture of 45d (77 mg, 0.2 mmol), 3-methylbenzamide (82 mg, 0.6 mmol), potassium carbonate (83 mg, 0.6 mmol), cuprous iodide (4 mg, 0.02 mmol), and (1S,2S)-(+)-N,N'-dimethylcyclohexanediamine (6 mg, 0.04 mmol) was dissolved in toluene (0.2 mL), degassed three times with nitrogen, and heated at 90 °C for 3 hours. TLC analysis indicated that the reaction was complete. After natural cooling to room temperature, the reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 12% ammonia (10 mL) and water (10 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by chromatography to give the product (61 mg, yield: 68%). ESI-MS (m / z): 442.5 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.00(s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.81–7.76(m, 2H), 7.45–7.40 (m, 3H), 7.21–7.20 (m, 1H), 7.05 (t, J = 8.8 Hz, 1H), 6.35 (d, J= 8.1 Hz, 1H), 5.33–5.28 (m, 1H), 3.88 (s, 3H), 3.10–3.02 (m, 1H), 2.91–2.83 (m, 1H), 2.49–2.44 (m, 1H), 2.41 (s, 3H), 2.01–1.93 (m, 1H). Example 46 The synthesis steps of compounds 46a-46d are as described in Example 45, which describes the synthesis of compound 45.

[0466] Table 14

[0467] Example 47 N-(3-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)benzamide

[0468] Compound 47 was prepared by the following steps:

[0469] Step 1: 40a (256 mg, 0.9 mmol), 47a (150 mg, 0.6 mmol), RuPhosPdG3 (25.2 mg, 0.03 mmol), and t-BuONa (231 mg, 2.4 mmol) were added to toluene (3 mL). The resulting mixture was heated at 90 °C for 2 hours under a nitrogen atmosphere. When TLC analysis indicated the reaction was complete, the reaction solution was concentrated to dryness and purified by chromatography to give the product (46 mg, yield: 16.0%). ESI-MS (m / z): 371.1 [M+H] + . Step 2: 47b (46 mg, 0.12 mmol), 4-trifluoromethylbenzamide (70 mg, 0.37 mmol), cuprous iodide (25.2 mg, 0.03 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.025 mmol), and potassium carbonate (51 mg, 0.37 mmol) were added to toluene (0.12 mL). The resulting mixture was heated to 90 °C for 1 hour under a nitrogen atmosphere. When TLC analysis indicated that the reaction was complete, ethyl acetate (30 mL) was added. The mixture was washed twice successively with ammonia (10 mL) and water (10 mL), dried over sodium sulfate, and concentrated to dryness. The product (20 mg, yield: 34%) was purified by chromatography. ESI-MS (m / z): 480.6 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.23 (s, 1H), 8.16 (d, J = 7.4 Hz, 3H), 8.08 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 11.4, 2.7 Hz, 4H), 7.49 (d, J = 8.0 Hz, 1H), 7.29–7.19 (m, 2H), 6.95 (t, J = 7.7 Hz, 1H), 6.47(d, J = 7.9 Hz, 1H), 5.47 (q, J = 3.0 Hz, 1H), 4.87 (dd, J = 9.5, 7.8 Hz, 1H), 4.31(dd, J = 9.5, 4.7 Hz, 1H), 3.87 (s, 3H). Example 48 N 4 -(5-(tert-butyl)isoxazol-3-yl)-N 1 -(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0470] Compound 48 was prepared by the following steps:

[0471] Step 1: At 0°C with stirring, trimethylsilyltrifluoromethanesulfonate (TMSOTf) (8.3 g, 37.5 mmol) and 1 M boranetetrahydrofuran solution (30 mL, 30 mmol) were added to a DMF (30 mL) solution of compound 43a (2.6 g, 15.0 mmol) and 4-bromoindanone (3.5 g, 16.5 mmol). The reaction mixture was stirred at 0°C for 10 minutes, then heated to room temperature and stirred for 18 hours. Subsequently, 100 mL of water was added to the reaction mixture, and the pH was adjusted to 9–10 with 5% potassium hydroxide aqueous solution. The resulting mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed successively with water (150 mL × 2) and brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 48a (2.0 g, yield: 36%) as a black viscous substance. ESI-MS (m / z): 369.1 [M+H] + . Step 2: Follow a similar process to step 3 in Example 41, with a yield of 65%.

[0472] ESI-MS (m / z): 429.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 8.24-7.71 (m,5H), 7.68-7.04 (m, 3H), 7.04-6.82 (m, 1H), 5.93 (s, 1H), 5.51-4.91 (m, 2H),3.91 (s, 3H), 3.18-1.60 (m, 4H), 1.32 (s, 9H). Example 49 (S)-N 4 -(5-(tert-butyl)isoxazol-3-yl)-N 1 -methyl-N1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0473] The preparation of compound 49 is based on the synthesis of compound 20 in Example 20.

[0474] ESI-MS (M / S): 443.2 [M+H] + . 1 1H NMR (62 MHz, CDCl3) δ 8.41 – 8.01 (m, 2H), 7.89 – 7.32 (m, 4H), 7.23 – 6.72 (m, 2H), 6.10 (s, 1H), 5.82 (s, 1H), 5.58 (t, J =7.7 Hz, 1H), 3.96 (s, 3H), 3.12 – 1.77 (m, 7H), 1.35 (s, 9H). Example 50 (S)-N-(3-cyclopropylphenyl)-7-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0475] Compound 50 was prepared by the following steps:

[0476] Step 1: Compound 45d (1000 mg, 2.60 mmol) was stirred with tri-tert-butylphosphine tetrafluoroborate ( t In a 5 mL solution of acetonitrile containing 188 mg of 1-Bu3P·HBF4 (0.65 mmol), triethylamine (525 mg, 5.2 mmol), phenyl formate (634 mg, 5.2 mmol), and palladium acetate (29 mg, 0.13 mmol) were added sequentially. The resulting mixture was degassed three times with N2 and stirred at 80 °C until TLC showed complete reaction, then concentrated to dryness. The residue was purified by ISCO chromatography to give compound 50a (755 mg, yield: 68%).

[0477] Step 2: To a toluene (1.0 mL) solution of compound 50a (43 mg, 0.1 mmol) and 3-cyclopropylaniline (27 mg, 0.2 mmol) under stirring, LiHMDS (0.3 mL, 1N THF solution, 0.3 mmol) was added. The resulting mixture was stirred at 25 °C until the reaction was complete (detected by TLC), and then quenched with a saturated ammonium chloride aqueous solution (10 mL). The resulting mixture was extracted with ethyl acetate (5 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness, and the residue was purified by ISCO chromatography to give compound 50 (28 mg, yield: 59%). ESI-MS (m / z): 468.2 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ 10.14 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.88 (d, J =2.8 Hz, 2H), 7.73 (dd, J = 8.5, 4.8 Hz, 1H), 7.57 – 7.51 (m, 1H), 7.47 (t, J = 1.9Hz, 1H), 7.27 – 7.13 (m, 3H), 6.88 – 6.81 (m, 1H), 6.29 (d, J = 8.3 Hz, 1H), 5.30(td, J = 7.7, 3.8 Hz, 1H), 3.88 (s, 3H), 3.29 (t, J = 7.9 Hz, 1H), 3.12 (ddd, J =17.1, 8.7, 4.7 Hz, 1H), 1.99 (tt, J = 8.3, 4.2 Hz, 1H), 1.91 (ddd, J = 13.4, 8.7, 5.2 Hz, 1H), 0.99 – 0.93 (m, 2H), 0.67 – 0.62 (m, 2H). Example 51 The synthesis steps of compounds 51a-51b are the same as those of compound 50 in Example 50.

[0478] Table 15

[0479] Example 52 (S)-N-(3-cyclopropylphenyl)-6-fluoro-1-(methyl(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0480] The preparation of compound 52 is described in Example 20, which describes the synthesis of compound 20.

[0481] ESI-MS (m / z): 482.55 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.21 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.6Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 – 7.45 (m, 3H), 7.22 (t, J = 7.8 Hz, 1H), 7.11 (dd, J = 8.3, 2.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.74 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.18 (d, J = 8.6 Hz, 1H), 3.01 (dt, J = 16.9, 8.5 Hz, 1H), 2.68 (s, 3H), 2.47 – 2.39 (m, 1H), 2.05 – 1.96 (m, 1H), 1.92 (tt, J = 8.7, 4.9 Hz, 1H), 1.00 –0.94 (m, 2H), 0.68 – 0.63 (m, 2H). Example 53 (S)-N-(3-cyclopropylphenyl)-5-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0482] Compound 53 was prepared by the following steps:

[0483] Step 1: Compound 53a (6.5 g, 50.2 mmol), compound 1 g (12.5 g, 60.2 mmol), potassium phosphate (16.0 g, 75.3 mmol), and Pd(dppf)Cl2·CH2Cl2 (407 mg, 0.50 mmol) were added sequentially to a reaction flask containing ethanol (50 mL) and water (25 mL). The resulting mixture was degassed with N2, heated to 85 °C, and stirred for 3 hours. After concentrating to remove ethanol, the reaction solution was diluted with water (130 mL) and extracted with ethyl acetate (130 mL × 3). The combined organic phases were washed with brine (130 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 53b (6.6 g, 75% yield) as a yellow solid. ESI-MS (m / z): 176.1 [M+H] + . Step 2: Under nitrogen protection, compound 53b (6.6 g, 37.7 mmol) and (1R)-4-bromo-5- fluorine DIAD (1.90 g, 9.4 mmol) was slowly added dropwise to a toluene solution (60 mL) of 2,3-dihydro-1H-inden-1-ol (10.4 g, 45.2 mmol) and PPh3 (14.8 g, 56.5 mmol) while maintaining an internal temperature of -10 °C. After the addition was complete, the mixture was allowed to react for another hour. TLC analysis indicated that the reaction was complete. Water (1 mL) was then added to the reaction mixture, and the resulting mixture was heated to room temperature and stirred for 30 minutes. The suspension was filtered, the filter cake was washed with toluene, and the combined filtrates were concentrated to dryness. The residue was purified by column chromatography to give compound 53c (7.7 g, yield: 53%). ESI-MS (m / z): 389.1 [M+H] + . Steps 3 and 4: Following the synthetic method for compound 50 in Example 50, compound 53 (20.2 mg, yield 46%) was obtained. ESI-MS (m / z): 469.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.44 (s, 1H), 8.17 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.88 (s, 1H), 7.53 – 7.45 (m, 2H), 7.39 (dd, J = 8.4, 4.9 Hz, 1H), 7.26 (t, J = 2.2 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 9.9, 8.4 Hz, 1H), 6.87 – 6.82 (m, 1H), 6.25 (d, J =8.3 Hz, 1H), 5.11 (q, J = 7.5 Hz, 1H), 3.87 (s, 4H), 2.91 (dt, J = 16.3, 8.0 Hz, 1H), 1.94 – 1.83 (m, 3H), 1.00 – 0.93 (m, 2H), 0.68 – 0.62 (m, 2H). Example 54 (S)-N-(3-cyclopropylphenyl)-5-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0484] The preparation of compound 54 is described in Example 53, which describes the synthesis of compound 53.

[0485] ESI-MS (m / z): 452.2 [M+H]+ . 1 H NMR (400 MHz, DMSO- d 6) δ 10.53 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.23 ​​(d, J = 2.7Hz, 1H), 8.03 (s, 1H), 7.77 – 7.66 (m, 3H), 7.61 (d, J = 2.0 Hz, 1H), 7.23 (t, J =7.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.15 (t, J = 6.0 Hz, 1H), 3.89 (s, 3H), 3.55 (ddd, J = 17.8, 8.8, 4.9 Hz, 2H), 2.74 (dq, J = 13.5, 7.9 Hz, 1H), 2.10 (dq, J = 14.0, 6.2 Hz, 1H), 1.91 (td, J = 8.6, 4.3 Hz, 1H), 1.00 – 0.94 (m, 2H), 0.71 – 0.66 (m, 2H). Example 55 (S)-N-(3-cyclopropylphenyl)-7-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxamide

[0486] Compound 55 was prepared by the following steps:

[0487] Step 1: With stirring, a solution of dioxane in 4 M hydrochloric acid (7 mL, 7 mmol) was added to a solution of compound 55a (586 mg, 3.5 mmol) in THF (5 mL). The mixture was stirred at room temperature for 0.5 h, followed by evaporation to remove the solvent under reduced pressure. Sodium iodide (3.49 g, 21 mmol) and acetonitrile (10 mL) were added to the residue. The resulting mixture was stirred overnight at 80 °C. The reaction was detected by TLC. The mixture was partitioned between water and ethyl acetate, and the separated organic phase was concentrated and purified by ISCO chromatography to give compound 55b (726 mg, yield: 80.1%). ESI-MS (m / z): 260.0 [M+1] + . Step 2: Formic acid (386 mg, 8.4 mmol) was added to a solution of compound 55b (726 mg, 2.8 mmol), triethylamine (566 mg, 5.6 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (89 mg, 0.14 mmol) in dichloromethane (20 mL) under stirring at 0 °C. The resulting mixture was stirred at this temperature for 3 hours. The reaction was monitored by TLC. After concentration, the residue was purified by ISCO chromatography to give compound 55c (666 mg, yield: 91.1%). ESI-MS (m / z): 262.0 [M+1] + . Step 3: DIAD (774 mg, 3.83 mmol) was added to a 10 mL THF solution containing 55c (666 mg, 2.55 mmol), phthalimide (450 mg, 3.06 mmol), and PPh3 (1 g, 3.83 mmol) under stirring at -10 °C. The resulting mixture was stirred at this temperature for 3 hours. The reaction was monitored by TLC. After concentration, the residue was purified by ISCO chromatography to give compound 55d (752 mg, yield: 75.6%). ESI-MS (m / z): 391.0 [M-1] + . Step 4: Compound 55d (752 mg, 1.93 mmol), Zn(CN)2 (680 mg, 5.79 mmol), Pd2(dba)3 (89 mg, 0.10 mmol), and 1,1'-bis(diphenylphosphine)ferrocenium (dppf) (105 mg, 0.19 mmol) were dissolved in DMAc (4 mL), degassed three times with N2, and stirred at 90 °C for 1 hour. The reaction was confirmed to be complete by TLC. The mixture was partitioned between water and ethyl acetate, and the separated organic phase was concentrated and purified by ISCO chromatography to give compound 55e (503 mg, yield: 90.1%). ESI-MS (m / z): 290.1 ​​[M+1] + . Step 5: Hydrazine hydrate (218 mg, 348 mmol) was added to a 2 mL THF solution of compound 55e (503 mg, 1.74 mmol) with stirring at room temperature. The resulting mixture was stirred at this temperature for 2 hours. The reaction was monitored by TLC to determine its completeness. The reaction mixture was concentrated and purified by ISCO chromatography to give compound 55f (236 mg, yield: 85.2%). ESI-MS (m / z): 160.1 [M+1] + . Step 6: Compound 55f (236 mg, 1.48 mmol), compound 41a (422 mg, 1.48 mmol), sodium tert-butoxide (426 mg, 4.44 mmol), and RuPhos Pd G3 (126 mg, 0.15 mmol) were dissolved in toluene (2 mL), degassed three times with N2, and stirred at 100 °C for 2 hours. The reaction was monitored by TLC. After concentration, the mixture was purified by ISCO chromatography to give compound 55 g (54 mg, yield: 11.5%). ESI-MS (m / z): 317.1 [M+1] + . Step 7: With stirring, add 50% sodium hydroxide aqueous solution (340 mg, 4.25 mmol) to a solution of 55 g (54 mg, 0.17 mmol) of compound in a mixed solvent of DMSO (0.3 mL) and ethylene glycol (0.3 mL). Stir the resulting mixture overnight at 100 °C. The reaction was monitored by TLC to confirm its completion. After cooling the mixture to room temperature, adjust the pH to 5 with 1 M hydrochloric acid (aqueous solution). Filter, collect the precipitate, and dry to give compound 55 h (25 mg, yield: 43.9%). ESI-MS (m / z): 334.1 [M⁻¹] - . Step 8: Compound 55h (25 mg, 0.075 mmol), 3-cyclopropylaniline (12 mg, 0.09 mmol), EDCI (29 mg, 0.15 mmol), and DMAP (1 mg, 0.008 mmol) were dissolved in DCM (0.1 mL) and stirred overnight at room temperature. The reaction was detected by TLC. After concentration, the mixture was purified by ISCO chromatography to give compound 55 (12 mg, yield: 35.5%). ESI-MS (m / z): 451.2 [M+1] + . 1 H NMR (400MHz, DMSO-) d 6) δ 10.12 (s, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.59–7.57 (d, J = 8.0Hz, 1H), 7.56–7.54 (d, J = 8.0Hz, 1H), 7.50 (s, 1H), 7.46–7.45 (d, J = 4.0Hz, 1H), 7.44–7.43 (d, J = 4.0Hz, 1H), 7.33–7.29 (dd, J =8.0, 8.0 Hz, 1H), 7.23–7.19 (dd, J = 8.0, 8.0Hz, 1H), 6.84–6.82 (d, J = 8.0Hz, 1H), 5.64–5.58 (dd, J = 14.4, 8.0Hz,1H), 3.88 (s, 3H), 3.28–3.22 (m, 1H), 3.11–3.00 (m, 1H), 2.61–2.55 (m, 1H),1.95–1.86 (m, 2H), 0.99–0.94 (m, 2H), 0.67–0.63 (m, 2H). Example 56 (S)-1-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-4-carboxamide

[0488] Compound 56 was prepared by the following steps:

[0489] Step 1: 60% NaH (303 mg, 7.6 mmol) was added to a dry DMF (7 mL) solution of compound 56a (1.0 g, 6.3 mmol) cooled to 0 °C. After stirring for 5 minutes, 2-bromo-4-fluoropyridine (1106 mg, 6.3 mmol) was added. The resulting mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC to confirm completion. The reaction was terminated by the slow addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (50 mL × 3), and the combined organic phases were washed with water (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give compound 56b (929 mg, yield: 46.8%). ESI-MS (m / z): 315.1 [M+H] + . Step 2: To a mixture of compound 56b (900 mg, 2.9 mmol), compound 1 g (891 mg, 4.3 mmol), K3PO4 (1819 mg, 8.6 mmol), and Pd(dppf)Cl2·CH2Cl2 (114 mg, 0.14 mmol), ethylene glycol dimethyl ether (4.0 mL) and water (1.5 mL) were added. The resulting mixture was degassed three times with N2 and refluxed at 90 °C for 1 hour. The reaction was detected by TLC. The reaction mixture was diluted with DCM (200 mL) and washed with water (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by gel column chromatography to give compound 56c (824 mg, yield: 91%). ESI-MS (m / z): 317.1 [M+H] + . Step 3: With stirring, 30% hydrogen peroxide (4.8 mL) was slowly added to a solution of compound 56c (824 mg, 2.6 mmol) and potassium carbonate in DMSO (9.6 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 4). The combined organic phases were washed with water (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography to give compound 56d (483 mg, yield: 55.6%). ESI-MS (m / z): 335.1 [M+H] + . Step 4: 1,4-Dioxane (1 mL) was added to a mixture of compound 56d (100 mg, 0.3 mmol), 4-iodotrifluorotoluene (98 mg, 0.36 mmol), K3PO4 (127 mg, 0.6 mmol), cuprous iodide (6 mg, 0.03 mmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (4.3 mg, 0.03 mmol). The mixture was stirred at 80 °C for 3 hours under nitrogen protection. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with ammonia (10 mL × 2) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography to give compound 56 (55 mg, yield: 38.3%) as a pale yellow solid. ESI-MS (m / z): 479.1 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 10.64 (s, 1H), 8.35 (d, J = 5.8 Hz, 1H), 8.29 (s, 1H), 8.02(s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.80–7.71 (m, 3H), 7.66 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 5.8, 2.4 Hz, 1H), 6.12 (dd, J = 6.6, 3.6 Hz, 1H), 3.88 (s, 3H), 3.35–3.26 (m, 1H), 3.17 (d, J = 5.2Hz, 1H), 2.72–2.60 (m, 1H), 2.16–2.03 (m, 1H). Example 57 (S)-N-(3-cyclopropylphenyl)-1-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0490] The synthetic route for compound 57 is as follows, and its preparation is based on the synthesis of compound 56 in Example 56:

[0491] The preparation method of compound 57 is the same as the synthesis steps of compound 56 in Example 56.

[0492] ESI-MS (m / z): 450.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H),8.23 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.36(t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.83 (d, J = 7.8 Hz,1H), 6.61–6.56 (m, 1H), 5.26 (q, J = 7.7 Hz, 1H), 3.89 (s, 3H), 3.31–3.18 (m,1H), 3.12–2.99 (m, 2H), 1.94–1.82 (m, 2H), 0.99–0.94 (m, 2H), 0.69–0.62 (m,2H). Example 58 (S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(4-(((4-(trifluoromethyl)phenyl)amino)methyl)-2,3-dihydro-1H-inden-1-yl)pyridin-3-amine

[0493] The synthetic route for compound 58 is as follows:

[0494] Step 1: Compound 13b (460 mg, 1.5 mmol) was dissolved in toluene (5 mL), degassed three times with nitrogen, and then DIBAL-H (1N toluene solution, 5 mL, 5.0 mmol) was added at -78 °C. The resulting mixture was stirred at this temperature for 2 hours. The reaction was monitored by TLC to indicate completion. The reaction was terminated by dropwise addition of water (10 mL). The separated organic phase was dried and concentrated to give compound 58a (552 mg, yield: 87%). ESI-MS (M / S): 319.2 [M+H] + . Step 2: With stirring, 4-aminotrifluorotoluene (242 mg, 1.5 mmol) and NaBH(OAc)3 (318 mg, 1.5 mmol) were added to a dichloromethane (1 mL) solution of compound 58a (159 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC to indicate completion. The reaction mixture was washed twice with saturated sodium bicarbonate aqueous solution. The separated organic phase was dried and concentrated, and the residue was purified by column chromatography to give compound 58 (178 mg, yield: 77%). ESI-MS (M / S): 464.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.16 (s, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.27 – 7.12 (m, 4H), 6.94 (t, J = 5.9 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 6.21 (d, J = 8.4Hz, 1H), 5.10 (q, J = 7.6 Hz, 1H), 4.33 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H), 3.06(ddd, J = 16.1, 8.8, 3.4 Hz, 1H), 2.85 (dt, J= 16.1, 8.1 Hz, 1H), 2.62 (dt, J =12.0, 5.7 Hz, 1H), 1.81 (dt, J = 12.5, 8.1 Hz, 1H). Example 59 The synthesis steps of compounds 59a-59f are as described in Example 58, which describes the synthesis of compound 58.

[0495] Table 16

[0496] Example 60 The synthesis steps of compounds 60a-60e are as described in step 2 (reductive amination) of Example 58.

[0497]

[0498]

[0499] Example 61 (1S)-N 4 -(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)-N 1 -(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0500] The synthetic route for compound 61 is as follows:

[0501] A mixture of 24e (150 mg, 0.5 mmol), 1-(3-chlorophenyl)-2,2,2-trifluoroethyl ketone, and p-toluenesulfonic acid (9 mg, 0.05 mmol) was heated to 100 °C and stirred for 12 hours. After cooling to room temperature, methanol (5 mL) and sodium borohydride (190 mg, 5.0 mmol) were added sequentially to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. TLC analysis indicated that the reaction was complete. Ethyl acetate (15 mL) was added to the reaction mixture, and the resulting mixture was washed with water (15 mL × 3), dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography to give product 61 (17 mg, yield: 7%). ESI-MS (m / z): 499.5 [M+H]+ . 1 H NMR (62 MHz, acetone- d 6) δ 8.24-7.89 (m, 3H), 7.88-7.58 (m, 3H), 7.58-7.34 (m, 2H), 7.16-6.55 (m, 3H), 6.44-6.31 (m, 1H), 5.83-5.52 (m, 3H), 3.92 (s, 3H), 3.61-2.90 (m, 2H), 2.74-2.43 (m, 1H), 1.29-1.20(m, 1H). Example 62 cyclohexyl(S)-1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate

[0502] The synthetic route for compound 62 is as follows:

[0503] EDCI (38 mg, 0.2 mmol) was added to a solution of dichloromethane (0.5 mL) containing 26a (33 mg, 0.1 mmol), cyclohexanol (20 mg, 0.2 mmol), DMAP (1 mg, 0.01 mmol), and triethylamine (20 mg, 0.2 mmol). The resulting mixture was stirred at room temperature until TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness, and the residue was purified by chromatography to give product 62 (37 mg, yield: 88%). ESI-MS (m / z): 417.2 [M+H] + . 1 H NMR (62MHz, acetone- d 6) δ 7.91 (dd, J = 12.3, 7.1 Hz, 5H), 7.67 – 7.10 (m, 3H), 5.58 (q, J =7.6 Hz, 1H), 4.82 (d, J = 8.2 Hz, 2H), 3.95 (s, 3H), 3.69 – 3.12 (m, 2H), 3.09– 2.00 (m, 2H), 1.95 (s, 2H), 1.55 (s, 8H). Example 63 (S)-N 1 -(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-N 4 -(3-phenyloxetan-3-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0504] The synthetic route for compound 63 is as follows:

[0505] To a DMSO (0.2 mL) solution containing 41b (74 mg, 0.2 mmol), 63a (74 mg, 0.4 mmol), potassium carbonate (260 mg, 0.8 mmol), BINAP (25 mg, 0.04 mmol), and Pd2(dba)3 (9 mg, 0.01 mmol) were added. The resulting mixture was degassed three times with N2, then heated to 90 °C and stirred until TLC analysis indicated completion. After natural cooling to room temperature, ethyl acetate (5 mL) was added to the reaction mixture. The mixture was washed with water (5 mL × 3), dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography to give product 63 (11 mg, yield: 13%). ESI-MS (m / z): 438.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.15 (s, 1H), 8.01 (s, 1H), 7.97–7.87(m, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.40–7.37 (m, 2H), 7.29–7.25 (m, 1H), 7.21 (s, 1H), 6.76 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.39 (s, 1H), 6.17 (d, J = 8.5 Hz, 1H), 5.44 (d, J= 8.0 Hz, 1H), 5.09–5.03 (m,1H), 4.92–7.91 (m, 2H), 4.86–7.84 (m, 2H), 3.87 (s, 3H), 3.03–2.97 (m, 1H), 2.82–2.74 (m, 1H), 2.62–2.58 (m, 1H), 1.90–1.76 (m, 1H). Example 64 (S)-3,3-dimethyl-N-(1-((6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-2-oxopyrrolidine-1-carboxamide

[0506] The synthetic route for compound 64 is as follows:

[0507] At 0 °C, a solution of triphosgene (88 mg, 0.296 mmol) dissolved in dichloromethane (1 mL) was added dropwise to a solution of 3,3-dimethyl-2-oxopyrrolidine (100 mg, 0.885 mmol) and pyridine (209 mg, 0.267 mmol) in dichloromethane (1 mL). After stirring for 0.5 hours, a solution of pyridine (20 mg) and 24e (75 mg, 0.245 mmol) in dichloromethane (2 mL) was added dropwise. The resulting mixture was stirred for another 2 hours and then washed twice with water. The organic layer was dried and concentrated, and the residue was purified by chromatography to give product 64 (57 mg, yield: 52%). ESI-MS (M / S): 446.1 [M+H] + . 1 HNMR (62 MHz, acetone- d 6) δ 10.65 (s, 1H), 8.34 – 7.66 (m, 5H), 7.15 (d, J = 6.6 Hz, 2H), 6.50 (d, J = 8.1 Hz, 1H), 5.92 – 5.54 (m, 1H), 3.92 (s, 3H), 3.83 – 2.93 (m, 4H), 2.75 –2.22 (m, 2H), 1.26 (s, 6H), 1.15 – 0.87 (m, 2H). Example 65 The synthetic routes for compounds 65a-65e are as follows:

[0508] Under nitrogen protection, p-nitrobenzene chloroformate (40 mg, 0.2 mmol) was added to a 1.0 mL solution of 24e (61 mg, 0.2 mmol) of dichloromethane cooled to -20 °C. After stirring at -20 °C for 30 minutes, an amine or alcohol was added to the mixture. The resulting mixture was stirred at room temperature for 15 minutes, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated to dryness, and the residue was purified by chromatography to obtain the target product.

[0509] Table 18

[0510] Example 66 (S)-N 4 -(5-(tert-butyl)isoxazol-3-yl)-N 1 -(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2,3-dihydro-1H-indene-1,4-diamine

[0511] Compound 66 was prepared by the following steps:

[0512] Step 1: Add 66a (116 mg, 0.5 mmol) to a solution of 24e (153 mg, 0.5 mmol) in dichloromethane (1 mL). Stir the resulting mixture at room temperature for 1 hour. Add water (30 mL) to the reaction mixture and extract with dichloromethane (30 mL × 3). Wash the combined organic layers with brine (30 mL), dry to dryness with sodium sulfate, and concentrate to dryness to give product 66b (170 mg, 97.6% yield). ESI-MS (m / z): 349.2 [M+H] + . Step 2: With stirring, LiHMDS (1 M THF solution, 0.75 mL) was added to a THF solution (0.5 mL) containing 3,3-dimethyl-2-butanone (75 mg, 0.75 mmol) cooled to 0°C. After 1 hour, a THF solution (0.5 mL) containing 66b (170 mg, 0.49 mmol) was added. The resulting mixture was stirred for another 4 hours. The reaction was terminated by adding saturated ammonium chloride aqueous solution (10 mL) and stirring for 30 minutes. The mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give a yellow solid product 66c (84 mg, yield 38.4%). ESI-MS (m / z): 449.3 [M+H] + . Step 3: Sodium hydroxide (72 mg, 1.8 mmol) was added to a stirred ethanol (2 mL) solution of 66c (80 mg, 0.18 mmol). The resulting mixture was cooled to -78°C, and iodomethane (26 mg, 0.18 mmol) was added. After stirring the mixture for 2 hours, hydroxylamine hydrochloride (25 mg, 0.36 mmol) was added. The reaction mixture was heated to 80°C and stirred for 1 hour. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give product 66 (32 mg, 41.4% yield). ESI-MS (m / z): 430.3 [M+H] + . 1 1H NMR (62 MHz, CDCl3) δ 8.13-7.76 (m, 2H), 7.41-6.91 (m, 4H), 6.38 (s,1H), 5.79-5.32 (m, 1H), 5.28-4.93 (m, 1H), 3.95 (s, 3H), 3.14-1.77 (m, 4H),1.29 (s, 9H). Example 67 (S)-N-(1-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-(tert-butyl)isoxazol-3-amine

[0513] The synthesis steps of compound 67 are as described in Example 66, which describes the synthesis of compound 66.

[0514] ESI-MS (M / S): 430.10 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 8.44 (s, 1H), 8.28 – 7.86 (m, 4H), 7.75 – 7.34 (m, 2H), 7.32 – 6.92 (m, 2H), 6.14 – 5.88 (m, 2H), 3.94 (s, 3H), 3.21 – 1.81 (m, 4H), 1.33 (s, 9H). Example 68 (S)-N-(1-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-(tert-butyl)isoxazol-3-amine

[0515] The synthesis steps of compound 68 are as described in Example 66, which describes the synthesis of compound 66.

[0516] ESI-MS (M / S): 445.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 8.14-7.78 (m,3H), 7.72 (s, 1H), 7.67-7.34 (m, 2H), 7.33-6.91 (m, 2H), 6.09-5.78 (m, 2H),5.19-4.92 (m, 1H), 3.89 (s, 3H), 3.28-1.81 (m, 4H), 1.33 (s, 9H). Example 69 4-fluoro-3-methoxy-N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-3-oxo-2,3-dihydro-1H-inden-4-yl)benzamide

[0517] Compound 69 was prepared by the following steps:

[0518] Step 1: NBS (1958 mg, 11 mmol) was added to a solution of 69a (2110 mg, 10 mmol) dissolved in carbon tetrachloride (25 mL). The mixture was degassed three times with nitrogen and then refluxed for 4 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was filtered through a diatomaceous earth filter, and the filtrate was transferred to a light-protected reaction flask (walled with aluminum foil). Triethylamine (5 mL) was added at 0 °C. The mixture was heated to room temperature and stirred for 1 hour. TLC analysis indicated that the reaction was complete. The mixture was concentrated and purified by column chromatography to give product 69b (1643 mg, 79% yield).

[0519] Step 2: Add 69b (731.5 mg, 3.5 mmol) to a methanol (30 mL) solution of 43a (1204 mg, 7 mmol). Heat the resulting mixture to 50 °C and stir for 48 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated and purified by column chromatography to give product 69c (1685 mg, 63% yield). ESI-MS (M / S): 383.2 [M+H] + . Step 3: To a 2 mL solution of 69c (191 mg, 0.5 mmol) in toluene, 4-fluoro-3-methoxybenzamide (328 mg, 1.5 mmol), cuprous iodide (9.6 mg, 0.05 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexanediamine (14.2 mg, 0.1 mmol), and potassium carbonate (212 mg, 1.5 mmol) were added. The resulting mixture was degassed three times with nitrogen, followed by reflux for 3 hours. TLC analysis indicated that the reaction was complete. The reaction mixture was washed twice with 5% ammonia, and the collected organic layer was dried, concentrated, and purified by column chromatography to give product 69 (121 mg, yield: 51%). ESI-MS (M / S): 472.2 [M+H] + . 1 H NMR (62 MHz, acetone- d 6) δ 11.26 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.19 – 7.26 (m, 10H), 6.44 (d, J= 8.4 Hz, 1H), 5.37 (s, 1H), 3.92 (d, J = 6.1 Hz, 6H), 2.63 (d, J = 8.5 Hz, 1H). Example 70 N-(1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-3-oxo-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)benzamide

[0520] The synthesis of compound 70 is described in Example 69, which describes the synthesis of compound 69.

[0521] ESI-MS (M / S): 492.2 [M+H] + . Example 71 N-(3-hydroxy-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)benzamide

[0522] N-(3-fluoro-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)benzamide

[0523] Compounds 71a and 71 were prepared by the following steps:

[0524] Step 1: Under stirring at 0°C, formic acid (0.1 mL) was added to a DCM solution of compound 70 (24.5 mg, 0.05 mmol), triethylamine (0.3 mL), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (3 mg, 0.005 mmol) (0.5 mL). The resulting mixture was stirred overnight at room temperature. The reaction was detected by TLC. After concentration, the reaction mixture was purified by ISCO chromatography to give compound 71a (a mixture of stereoisomers, 19.9 mg, yield: 79.0%). ESI-MS (M / S): 494.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 0.5H), 10.23 (s, 0.5H), 8.19–8.05 (m, 4H), 7.98–7.96 (m, 4H), 7.38–7.07 (m, 3H), 6.32 (d, J = 8.8 Hz, 0.5H), 6.18 (d, J 3.87 (d, J = 2.6Hz, 3H), 3.07–3.00 (m, 0.5H), 2.42–2.34 (m, 0.5H), 2.27–2.18 (m, 0.5H), 1.82–1.73 (m, 0.5H). Step 2: Under nitrogen protection, DAST (24.2 mg, 0.15 mmol) was added to a DCM (0.5 mL) solution of compound 71a (15.1 mg, 0.03 mmol). The resulting mixture was stirred at this temperature for 2 hours. The reaction was detected by TLC. After concentration, the mixture was purified by ISCO chromatography to give compound 71 as a mixture of stereoisomers (12.5 mg, yield: 84%). ESI-MS (M / S): 496.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.49–10.46 (m,1H), 8.20–8.15 (m, 3H), 8.07 (s, 1H), 7.96–7.87 (m, 4H), 7.60–7.45 (m, 2H),7.31–7.25 (m, 2H), 6.60–6.20 (m, 2H), 3.87 (s, 3H), 3.20–2.71 (m, 1H), 2.27–2.07 (m, 1H), 2.02–1.86 (m, 1H). Example 72 (S)-N-(1-((2-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)benzamide

[0525] The synthesis of compound 72 is described in reference to the synthesis of compound 15 in Example 15.

[0526] ESI-MS (M / S): 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.31–8.29 (m, 2H), 8.20–8.18 (m, 2H), 8.01 (s, 1H), 7.94–7.92 (m, 2H), 7.77–7.68 (m, 1H), 7.54–7.43 (m, 1H), 7.39–7.26 (m, 2H), 6.10–6.00 (m, 1H), 3.89(s, 3H), 3.12–3.05 (m, 1H), 2.98–2.86 (m, 1H), 2.73–2.65 (m, 1H), 2.28 (s,3H), 2.09–2.01 (m, 1H). Example 73 (S)-N-(3-cyclopropylphenyl)-1-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0527] Compound 73 was prepared by the following steps:

[0528] Step 1: Compound 73a (2000 mg, 9.43 mmol), compound 10b (1788 mg, 11.30 mmol), toluene (19 mL), sodium tert-butoxide (1267 mg, 13.22 mmol), and GPhos Pd G6 (888 mg, 0.94 mmol) were added sequentially to a 100 mL double-necked round-bottom flask. The resulting mixture was stirred thoroughly and degassed three times with N2, then heated to 90 °C and stirred for 3 hours. The reaction was monitored by TLC to confirm completion. After natural cooling to 30 °C, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was discarded, and the separated organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by ISCO chromatography to give compound 73b (2.3 g, yield: 84.6%). ESI-MS (M / S): 290.1 ​​[M+H] + . Step 2: Compound 73b (2.3 g, 7.96 mmol), DMSO (12 mL), ethylene glycol (12 mL), water (12 mL), and sodium hydroxide (6.0 g, 150.00 mmol) were added sequentially to a 100 mL flask. The resulting mixture was heated to 110 °C and stirred for 3 hours. The reaction was monitored by TLC to confirm its completion. After natural cooling to approximately 30 °C, the pH was adjusted to 6-7 with 3 M hydrochloric acid aqueous solution. A large amount of solid precipitate formed. The suspension was stirred briefly and then filtered under reduced pressure. The filter cake was washed with water (6 mL × 2) and dried under vacuum at approximately 50 °C to give compound 73c (2.3 g, yield: 93.1%). ESI-MS (M / S): 307.1 [MH] - . Step 3: Compound 73c (61 mg, 0.2 mmol), 3-cyclopropylaniline (53 mg, 0.4 mmol), DMAP (3 mg, 0.02 mmol), dichloromethane (0.5 mL), and EDCI (77 mg, 0.4 mmol) were added sequentially to a 4 mL vial. The resulting mixture was stirred at 25 °C for 3 hours. The reaction was monitored by TLC to confirm its completion. After concentration, the residue was purified by ISCO chromatography to give compound 73 (46 mg, yield: 55.3%). ESI-MS (M / S): 424.2 [M+H] + . 1 HNMR (62 MHz, Acetone- d6) δ 9.28 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.94 – 7.02(m, 8H), 6.98 – 6.65 (m, 1H), 6.06 – 5.68 (m, 1H), 5.46 – 4.89 (m, 1H), 3.96(s, 3H), 3.54 – 3.01 (m, 2H), 2.76 – 2.21 (m, 1H), 1.93 – 1.60 (m, 1H), 1.40 – 1.06 (m, 1H), 1.04 – 0.47 (m, 4H). Example 74 (S)-N-(4-cyclopropylthiazol-2-yl)-1-((2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide

[0529] Compound 74h was prepared by the following steps:

[0530] Step 1: Compound 74h-1 (2000 mg, 9.43 mmol), compound 10b (1788 mg, 11.30 mmol), toluene (19 mL), sodium tert-butoxide (1267 mg, 13.22 mmol), and GPhos Pd G6 (888 mg, 0.94 mmol) were added sequentially to a 100 mL double-necked round-bottom flask. The resulting mixture was stirred thoroughly and degassed three times with N2, followed by heating to 90 °C and stirring for 3 hours. The reaction was monitored by TLC to confirm its completion. After natural cooling to 30 °C, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was discarded, and the separated organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by ISCO chromatography to give compound 74h-2 (2.5 g, yield: 92%). ESI-MS (M / S): 290.1 ​​[M+H] + . Step 2: Compound 74h-2 (2.5 g, 8.65 mmol), DMSO (12 mL), ethylene glycol (12 mL), water (12 mL), and sodium hydroxide (6.0 g, 150.00 mmol) were added sequentially to a 100 mL flask. The resulting mixture was heated to 110 °C and stirred for 3 hours. The reaction was monitored by TLC to confirm its completion. After natural cooling to approximately 30 °C, the pH was adjusted to 6-7 with 3 M hydrochloric acid aqueous solution. A large amount of solid precipitate formed. The suspension was stirred briefly and then filtered under reduced pressure. The filter cake was washed with water (6 mL × 2) and dried under vacuum at approximately 50 °C to give compound 74h-3 (2.4 g, yield: 89.9%). ESI-MS (M / S): 307.1 [MH] - . Step 3: Compound 74h-3 (61 mg, 0.2 mmol), compound 74h-4 (56 mg, 0.4 mmol), DMAP (3 mg, 0.02 mmol), dichloromethane (0.5 mL), and EDCI (77 mg, 0.4 mmol) were added sequentially to a 4 mL vial. The resulting mixture was stirred at 25 °C for 3 hours. The reaction was monitored by TLC to determine its completeness. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by ISCO chromatography to give compound 74h (57.7 mg, yield: 67.0%).

[0531] The synthesis steps of compounds 74a-74i are the same as those of compound 73 in Example 73 or compound 74h in Example 74.

[0532] Table 19

[0533] Example 75 (S)-N-(2-fluoro-3-methylphenyl)-1-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-2,3-dihydro-1H-indene-4-carboxamide

[0534] Compound 75 was prepared by the following steps:

[0535] Step 1: Compound 73a (2360 mg, 10.0 mmol), 1,4-dioxane (27 mL), water (9 mL), potassium hydroxide (1680 mg, 30.0 mmol), Me4t-butylXPhos (674 mg, 1.4 mmol), and Pd2(dba)3 (229 mg, 0.25 mmol) were added sequentially to a 250 mL three-necked flask. The mixture was thoroughly stirred and degassed three times with N2, then heated to 90 °C and stirred for 3 hours. The reaction was monitored by TLC to confirm completion. After natural cooling to approximately 30 °C, the separated upper organic phase was discarded. The aqueous phase was diluted with distilled water (9 mL) and washed with dichloromethane (20 mL). The pH was adjusted to 8-9 with concentrated hydrochloric acid, and then further adjusted to 6-7 with 3 N hydrochloric acid aqueous solution. A large amount of solid precipitate formed. The suspension was stirred briefly and then filtered under reduced pressure. The filter cake was washed with distilled water (9 mL) and dried under vacuum at about 50 °C to give compound 75a (1495 mg, yield: 99.5%). ESI-MS (M / S): 150.1 [M+H] + . Step 2: Compound 75a (1490 mg, 10.0 mmol), compound 4b (1749 mg, 11.0 mmol), PPh3 (3935 mg, 15.0 mmol), and toluene (20 mL) were added sequentially to a 100 mL two-necked flask. The mixture was stirred thoroughly and degassed...

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof. in, X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Among them, W5 independently represents CR 1 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; wherein, L2 represents absent, -(CR a R b ) o -, -CR a R b O-, -OCR a R b -, -O-, -C(O)-, -NR a -, -S(O)2NR a -, -OC(O)-, -C(O)O-, -NR a S(O)2-, -CR a R b NR a -, -NR a CR a R b -, -NR a C(O)NR b -, -NR a C(O)NR b CR a R b -, -NR a C(O)O-, -NR a C(O)-, -C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O)R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C3-C6 heterocyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; and when R 1 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl, halogenated C3-C6 heterocyclic alkyl, C1-C6 alkyl-substituted C3-C6 heterocyclic alkyl, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 yuan heteroaryl); and when R 2 When it is a ring, two adjacent substituents on the ring can be linked together to form a ring. The ring can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring can also be arbitrarily replaced by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each of these can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, (CH3)2N-(C1-C6 alkyl), C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, or isotopic isomer, wherein, Where X1 represents O, S, NR a 、(CR L R L’ ) m C(O); Where X2 represents O, S, NR a 、(CR T R T’ ) n C(O); Where W1 independently represents CR W1 Or N; Where W2 independently represents CR W2 Or N; Where W3 independently represents CR W3 Or N; Where W4 independently represents CR W4 Or N; Among them, W5 independently represents CR 1 Or N; Where Y1 independently represents CR Y1 Or N; Where Y2 independently represents CR Y2 Or N; Where Y3 independently represents CR Y3 Or N; Among them, R W1 R W2 R W3 R W4 R Y1 R Y2 R Y3 Each can independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, nitro, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b -CR a R b NR a R b -NR a COR b -CONR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W1 and W2 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Alternatively, W1 and W4 together with the atoms attached to them can form a 5-6 saturated or unsaturated ring fused with ring A, which may also contain 0, 1, 2 or 3 heteroatoms selected from O, S or N. Where L1 represents non-existent, -(CR) a R b ) o -、-CR a R b O-、-OCR a R b -, -O-, -S-, -S(O)2-, -C(O)-, -NR a -、-S(O)2NR a -、-OC(O)-、-C(O)O-、-NR a S(O)2-、-CR a R b NR a -、-NR a CR a R b -; wherein, L2 represents absent, -(CR a R b ) o -, -CR a R b O-, -OCR a R b -, -O-, -C(O)-, -NR a -, -S(O)2NR a -, -OC(O)-, -C(O)O-, -NR a S(O)2-, -CR a R b NR a -, -NR a CR a R b -, -NR a C(O)NR b -, -NR a C(O)NR b CR a R b -, -NR a C(O)O-, -NR a C(O)-, -C(O)NR a -; Among them, R 1 Indicates hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a -SR a -P(O) R a R b -CN, -S(O)2R a -S(O)R a -SF5, -NR a R b Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, W5 and W2 together with the atoms attached thereto form a 5-6 member saturated or unsaturated ring fused with ring A, and may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; furthermore, the ring may also arbitrarily be replaced by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R 2 This indicates that the substituent is selected from 0-4 or fewer: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -S(O)2R a -S(O)R a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituted C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -CR a R b C6-C 10 Aryl, -CR a R b (5-10 membered heteroaryl); Among them, R 3 Indicates hydrogen, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and hydroxyl; Or, R 3 Together with W3 and the atoms attached thereto, they form a 5-7 member saturated or unsaturated ring fused with ring A. This ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N. Furthermore, this ring may be arbitrarily surrounded by 0, 1, or 2 heteroatoms selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and -OR atoms. a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced; Among them, R a R b Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R a R b Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R L R L’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R L R L’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Among them, R T R T’ Each can be independently represented as hydrogen, deuterium, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl or R T R T’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may contain 0, 1, or 2 heteroatoms selected from O, N, and S. Furthermore, the ring may be arbitrarily substituted by substituents selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. Where o, m, and n represent integers of 1, 2, or 3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, W1 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, W1 represents N.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, W2 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, CN(CH3)2, CCH2NHCH3, CCH2N(CH3)2, C(CN) or N.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, W3 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, W4 represents CH, CCH3, CF, CCF3, CCHF2, CCH2F, C(OCH3), CNH2, CNHCH3, C(CN), or N.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, Y1 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, Y2 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, Y3 represents CH, CCH3, CF, CCl, CCF3, CCHF2, CCH2F, C(OCH3), C(CN), or N.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, X1 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, X2 represents -CH2-, -CF2-, -CHF-, -O-, -S-, -CHOH-, -CH2CH2-, or -C(CH3)2-.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, L1 represents -CH2-, -CHF-, -CF2-, -O-, -NH-, or -NCH3-.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, L2 represents -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)O-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -NH-.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 It represents C1-C6 alkyl, halogen, hydroxyl, O (C1-C6 alkyl), or is selected from 0 to 4 substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a hydroxyl (C1-C6 alkyl), -CN, C3-C substituted with halogenated C1-C6 alkyl 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a 5-10 heteroaryl groups substituted with hydroxyl (C1-C6 alkyl), -CN, or halogenated C1-C6 alkyl groups.

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 Indicates 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, -OR a Hydroxyl (C1-C6 alkyl), -CN, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and imidazoleyl groups substituted by halogenated C1-C6 alkyl groups.

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 1 express .

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, W5 and W2 together form a ring that fused with ring A and has the following structure: , , , , , , , , , , , , , , , , The ring can be arbitrarily replaced by 0, 1, or 2 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b The substituents are replaced by the , where the wavy line indicates the site connected to L1.

23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, W5 and W2 together form a ring that fused with ring A and has the following structure: , , , , , , The wavy line represents the point connected to L1.

24. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted phenyl, pyridinyl, indazole, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothiophene, 1,2-benzisozolyl, benzo[D]isothiazolyl.

25. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 2 Indicates that it is selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl (C1-C6 alkyl), -NR a R b -CR a R b NR a R b -CN, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted .

27. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof, wherein, R 3 It represents hydrogen or CH3.

28. A compound having the following structure: 。 29. A pharmaceutical composition, wherein, The pharmaceutical composition comprises: the compound as described in claims 1-28, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

Images