KRAS inhibitors and their production and pharmaceutical applications

Abstract

The present invention relates to a KRAS inhibitor and its preparation and pharmaceutical application. In particular, the present invention relates to a KRas G12D inhibitor having the structure of formula (I), its preparation method, pharmaceutical composition containing it, its use as a KRas G12D inhibitor, and its use in treating and / or preventing cancer or tumor associated with KRas G12D. Each substituent in formula (I) is as defined in the specification. JPEG2024545620000128.jpg5794

Description

[Technical Field]

[0001] The present invention belongs to the field of drug synthesis, specifically to KRAS inhibitors and their preparation and application in pharmacy. [Background technology]

[0002] The RAS gene family includes HRAS, KRAS, and NRAS, which are oncogenes frequently mutated in cancer. Mutated RAS proteins are present in 20-30% of human tumors. Activated RAS proteins lead to malignant phenotypes in cancer cells, including dysregulation of cell proliferation and programmed cell death, increased invasiveness, and neovascularization. Due to their high affinity for GTP / GDP and the lack of a distinct binding pocket, drug development targeting RAS proteins has been slow.

[0003] Under normal conditions, RAS proteins function as molecular switches, converting between a GDP-bound, inactive state and a GTP-bound, active state. After stimulation with exogenous growth factors, facilitated by guanine nucleotide exchange factors (GEFs), RAS proteins convert from the inactive GDP-bound form to the activated GTP-bound form, allowing them to bind to and activate downstream signaling pathways. RAS then reverts to the inactive GDP-bound form with the aid of its intrinsic GTPase activity and GTPase-activating / accelerating proteins (GAPs).

[0004] Missense mutations at codons 12, 13, or 61 cause abnormal activation of RAS. These mutations prolong the time that RAS protein remains in the GTP state, leading to sustained activation of downstream signaling pathways. K-RAS is the most commonly mutated subtype of the RAS family in human cancers, including pancreatic cancer (71%), small intestine cancer (35%), colon cancer (35%), biliary tract cancer (26%), endometrial cancer (17%), and lung cancer (19%). Regarding mutation sites, G12D / G12V / G12C / G13D are the most common mutation types of K-RAS in pancreatic cancer, lung cancer, and colon cancer.

[0005] The lack of a distinct pocket in the protein makes the research and development of KRAS inhibitors difficult. Recent studies have revealed the presence of a previously undiscovered pocket in the KRAS-GDP bound state. Based on these new discoveries, covalent inhibitors targeting the mutant cysteine ​​at codon 12 have become a hotspot in KRAS inhibitor research and development, with some success. However, targeting other activating mutations in KRAS, in addition to the G12C mutation, particularly the KRAS G12D mutation, remains an urgent challenge. Therefore, there is a need to develop safe and effective KRAS G12D inhibitors for the treatment of KRAS-G12D-mediated cancers. Summary of the Invention

[0006] The present invention aims to provide a KRas G12D inhibitor, its preparation method and pharmaceutical application. The compounds of the present invention have strong inhibitory effects on KRas G12D and can be widely used in the preparation of drugs for treating and / or preventing KRas G12D-related cancers or tumors, which may lead to the development of a new generation of KRas G12D inhibitors.

[0007] A first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [ka] In the formula, R is hydrogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8Alkyl-OC(O)R 15 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 and optionally substituted with a substituent selected from the group consisting of: R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-8 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 and optionally substituted by one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups, said groups being independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium or halogen; Each R2 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R3 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R4 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5a represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16)-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-NH-S(O)R 13 , -C 0-8 Alkyl-NH-S(O)NR 16 R 17 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-S(O) r NR 16 R 17 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 and R 5d is defined as above, Or R 5b and R 5c together with the carbon atoms directly connected to them [ka] It forms R 5dis defined as above, Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them [ka] It forms R 5e , R 5f and R 5g are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-8 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 6a , R 6b , R 6c and R 6d are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 or R 6a and R 6b , R 6c and R 6d are one C together with the carbon atom directly connected to them. 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R7 and R8 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16)-C(O)R 15 or R7 and R8 together with the carbon atom directly connected thereto are selected from the group consisting of 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17)R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Each R9 is independently hydrogen, deuterium, halogen, cyano, nitro, azide, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 or two adjacent R9 together with the moiety directly linked thereto are selected from the group consisting of 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Each R 10 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 or -C 0-8 Alkyl-C(O)NR 16 R 17 and wherein said groups are optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 or -C 0-8 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of Each R 11 and R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 aryl group or 5-10 membered heteroaryl group, or R 11 and R 12 together with the sulfur atom to which they are directly attached form a 3-10 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, nitro group, azido group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 or -C 0-8 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of Each R 13 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 14 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, said groups independently optionally further containing deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 15 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 16 and R 17 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, and C 1-10 alkanoyl groups, which groups may independently optionally further comprise deuterium, halogen, hydroxyl, ═O, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; Or R 16 and R 17form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom directly linked thereto, and the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group may optionally further contain deuterium, halogen, a hydroxy group, ═O, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5, or 6, and Each r is independently 0, 1, or 2.

[0008] In a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Each R2 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R3 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R4 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5a represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-NH-S(O)R 13 , -C 0-4 Alkyl-NH-S(O)NR 16 R 17 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-S(O) r NR 16 R 17 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 and R 5d is defined as above, Or R 5b and R 5c together with the carbon atoms directly connected to them [ka] R 5d is defined as above, Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them [ka] It forms R 5e , R 5f and R 5g are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 6a , R 6b , R 6c and R 6d are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12, -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 or R 6a and R 6b , R 6c and R 6d are one C together with the carbon atom directly connected to them. 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R7 and R8 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-4 Alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 or R7 and R8 together with the carbon atom directly connected thereto are selected from the group consisting of3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Each R9 is independently hydrogen, deuterium, halogen, cyano, nitro, azide, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15, -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 selected from the group consisting of Two adjacent R9s, together with the moiety directly linked to them, form one C 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further include deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for compounds of formula (I).

[0009] In a preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, each R 10 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 or -C 0-4 Alkyl-C(O)NR 16 R 17and wherein said groups are optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 or -C 0-4 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of Each R 11 and R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl group or 5-8 membered heteroaryl group, or R 11 and R 12form a 3-6 membered heterocyclic group together with the sulfur atom to which they are directly attached, said group optionally further containing deuterium, halogen, cyano group, nitro group, azido group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 or -C 0-4 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of Each R 13 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups and -NR 16 R 17wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 14 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, said groups independently optionally further containing deuterium, halogen, hydroxyl groups, ═O, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 15 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 may be substituted by one or more substituents selected from the group consisting of Each R 16 and R 17 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5- to 8-membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, and C 1-4 alkanoyl groups, which groups may independently optionally further comprise deuterium, halogen, hydroxyl, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; Or R 16 and R 17 form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group together with the nitrogen atom directly linked thereto, and the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group may optionally further contain deuterium, halogen, a hydroxy group, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkanoyl groups.

[0010] In a preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (II): [ka] In the formula, R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, ═O, ═S, -SF5, -S(O)(═NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C0-4 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 2a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 2b is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 2c is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 2d is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14, -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 2e is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R3 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14, -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, ═O, ═S, -SF5, -S(O)(═NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-NH-S(O)R 13 , -C 0-4 Alkyl-NH-S(O)NR 16 R 17 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-S(O) r NR 16 R 17 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 and R 5d is defined as above, Or R 5b and R 5c together with the carbon atoms directly connected to them [ka] R 5d is as defined above, or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them [ka] It forms R5e , R 5f and R 5g are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of monotium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 6a , R 6b , R 6c and R 6d are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16)R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R 6a and R 6b , R 6c and R 6d are one C together with the carbon atom directly connected to them. 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R7 and R8 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R7 and R8 together with the carbon atom directly connected thereto are selected from the group consisting of 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8Aryl groups, 5-8 membered heteroaryl groups, ═O, ═S, -SF5, -S(O)(═NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 9a , R 9b , R 9c , R 9d and R 9e are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R 9d and R 9e are one C together with the carbon atom directly connected to them. 3-6 a cycloalkyl group and a 3- to 6-membered heterocyclic group, the other three being as defined above, 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group may independently optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, ═O, ═S, -SF5, -S(O)(═NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15, -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for compounds of formula (I).

[0011] In a preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (III): [ka] In the formula, R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 6-membered heterocyclic groups; R 2a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2c is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2d is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2e is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R3 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R 5a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5b and R 5c are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O) r R 13 and-OR 14 may be substituted by one or more substituents selected from the group consisting of R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-NH-S(O)R 13 , -C 0-4 Alkyl-NH-S(O)NR 16 R 17 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-S(O) r NR 16 R 17 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 )2, -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O) r R 13 , -OR 14 , -C(O)OR14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O) r R 13 and-OR 14 and R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c together with the carbon atoms directly connected to them [ka] R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them [ka] It forms R 5e , R 5f and R 5g are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R7 and R8 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 or R7 and R8 together with the carbon atom directly connected thereto form a C 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 9a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for compounds of formula (I).

[0012] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5b and R 5c are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5d are hydrogen, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, 5-8 membered heteroaryl groups, -NH-S(O)R 13 , -NH-S(O)NR 16 R 17 , -S(O) r R 13 , -S(O) r NR 16 R 17 , -OR 14 , -C(O)OR 14 , -C(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)R 15 and -C(O)NR 16 R 17 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, said groups independently optionally further containing deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 and R is optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, ═O, ═S, methylthio, ethylthio, methoxy, ethoxy, and isopropoxy, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; 5d is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, and isopropoxy; Or R 5b and R 5c together with the carbon atoms directly connected to them [ka] It forms R 5dis selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them [ka] It forms R 5e , R 5f and R 5g are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, and monodeuteromethyl; where R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined for compounds of formula (III).

[0013] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5ais selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy.

[0014] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15)2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined for compounds of formula (III).

[0015] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R1 is selected from the group consisting of hydrogen, deuterium, fluorine, and a methyl group; R 2a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2cis selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2d is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2e is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R3 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio.

[0016] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt thereof, R4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino.

[0017] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a trideuteromethyl group, a diduteromethyl group, a monodeuteromethyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, and an azetidinyl group; R 9a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

[0018] In a preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IV-a): [ka] In the formula, R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R 5a are hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5b and R 5c are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, said groups independently optionally further comprising deuterium, halogen, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 may be substituted by one or more substituents selected from the group consisting of R 5d1are hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 cycloalkyl groups or 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 and R 5d1 are hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; where R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for compounds of formula (I).

[0019] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16)-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for the compound of formula (IV-a).

[0020] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups independently optionally further include deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and —OC(O)R 15 may be substituted by one or more substituents selected from the group consisting of where R 14 and R 15 is as defined for the compound of formula (IV-a).

[0021] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt thereof, R4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino.

[0022] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt thereof, R4 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino.

[0023] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5ais selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy.

[0024] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5a is selected from the group consisting of hydrogen, deuterium, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, and trideuteroethoxy.

[0025] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5b and R 5care each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5d1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which groups are independently optionally further selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, ═O, ═S, —S(O) r R 13 and-OR 14 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, said groups independently optionally further containing deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 and R is optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, ═O, ═S, methylthio, ethylthio, methoxy, ethoxy, and isopropoxy, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen;5d1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; where R 13 , R 14 and r are as defined for the compound of formula (IV-a).

[0026] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 5b and R 5c are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, and trideuteroethoxy; R 5d1 is a methyl group, an ethyl group, an isopropyl group, or a trideuteromethyl group.

[0027] In a preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IV-b): [ka] In the formula, R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, =O, =S, -OS(O)2R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 )2, -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R5a are hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5h is selected from the group consisting of the following groups 1), 2) and 3): 1) is [ka] and R 5e and R 5f are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; 2) is [ka] and R 5g are hydrogen, deuterium, halogens and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; 3) is C 1-4 Alkyl group, C 3-6 is a cycloalkyl group or a 3- to 6-membered heterocyclic group, 1-4 The alkyl groups may independently optionally further comprise deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O) r R 13 and-OR 14 and wherein R 5h -OR 14 Substituted methyl group, C 3-6 provided that it is not a cycloalkyl group or a 3- to 6-membered heterocyclic group; where R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for compounds of formula (I).

[0028] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IV-b1): [ka] In the formula, R represents hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5e and R 5fare each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, and isopropyl, which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, or chlorine; where R 14 is as defined in formula (IV-b).

[0029] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, R is hydrogen, and R 5a is hydrogen and R 5e and R 5f are each independently selected from the group consisting of hydrogen, fluorine, and a methyl group.

[0030] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IV-b2): [ka] In the formula, R represents hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5g is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, and isopropyl, which groups independently and optionally may be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which groups independently and optionally may be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, or chlorine; where R 14 is as defined for compounds of formula (IV-b).

[0031] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, R is hydrogen, and R 5a is hydrogen and R 5g is selected from the group consisting of hydrogen, fluorine and a methyl group.

[0032] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IV-b3): [ka] In the formula, R represents hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, or —C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5h1 are methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl groups, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O) r R 13 and-OR 14 and wherein R 5h1 -OR 14 provided that the group is not a substituted methyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, or an azetidinyl group; where R 13 , R 14 and r are as defined for the compound of formula (IV-b).

[0033] In a more preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R is hydrogen, R is hydrogen, a methyl group, an ethyl group, a methoxy group, or a methylthio group, and R 5a is hydrogen or deuterium, R 5h1 is a methyl group, an ethyl group, a propyl group, or an isopropyl group, which groups independently optionally further contain deuterium, fluorine, chlorine, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O) r R 13 and-OR 14 and wherein R 5h1 -OR 14 provided that it is not a substituted methyl group, where R 13 , R 14 and r are as defined for the compound of formula (IV-b).

[0034] In the most preferred form, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes, but is not limited to, the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0035] A second aspect of the present invention provides a process for preparing a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] reacting a compound of formula (Ia) or an acid salt thereof with a compound of formula (Ib) or an acid salt thereof to form a compound of formula (I) or an acid salt thereof; or [ka] reacting a compound of formula (Ic) or an acid salt thereof with a compound of formula (Id) or an acid salt thereof to produce a compound of formula (I) or an acid salt thereof, wherein X is fluorine, chlorine or bromine, and R, R, R, R, R, R 5b , R 5c , R 5d , R 5e , R 6a , R 6b , R 6c , R 6d , R7, R8, R9, m and n are as defined for compounds of formula (I).

[0036] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] The present invention also relates to the use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing a cancer or tumor associated with KRas G12D.

[0038] The present invention also relates to KRas G12D-associated sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), pulmonary bubble (bronchiolar carcinoma) carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, nerve cell carcinoma), and pulmonary fibroblasts. fibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), kidney cancer (adenocarcinoma, nephroblastoma (Wilms' tumor), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, fetal cell carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, bile duct carcinoma, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, skull cancer (osteoma, hemangioma, granuloma, xanthomatosis, osteitis teratoma), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ventriculoma, blastoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma), uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified Cancer tumors), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tube (cancer tumor), blood cancer (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmarks, dysplastic nevi, lipoma, hemangioma, dermatofibroma,The present invention relates to use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing and / or treating keloids, psoriasis, adrenal tumors, and neuroblastoma.

[0039] The present invention also relates to the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, for use as a drug.

[0040] The present invention also relates to the use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof for treating and / or preventing cancers or tumors associated with KRas G12D.

[0041] The present invention also relates to KRas G12D-associated sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), pulmonary bubble (bronchiolar carcinoma) carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, nerve cell carcinoma), and pulmonary fibroblasts. fibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), kidney cancer (adenocarcinoma, nephroblastoma (Wilms' tumor), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, fetal cell carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, bile duct carcinoma, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, skull cancer (osteoma, hemangioma, granuloma, xanthomatosis, osteitis teratoma), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ventriculoma, blastoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma), uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified Cancer tumors), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tube (cancer tumor), blood cancer (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmarks, dysplastic nevi, lipoma, hemangioma, dermatofibroma,The present invention relates to a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof for preventing and / or treating keloids, psoriasis, adrenal tumors, and neuroblastoma.

[0042] The present invention also relates to a method for treating and / or preventing cancers or tumors associated with KRas G12D, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0043] The present invention also provides a method for treating KRas G12D-associated sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchial carcinoma (squamous, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), pulmonary bubble (bronchiolar carcinoma) carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma), which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. , leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), kidney cancer (adenocarcinoma, nephroblastoma (Wilms' tumor), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, fetal cell carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, bile duct carcinoma, osteogenic sarcoma (bone Sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, skull cancer (osteoma, hemangioma, granuloma, xanthomatosis, osteitis teratoma), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ventriculoma, blastoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord nerve fibroma, meningioma, glioma, sarcoma), uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma tumor), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (cancer tumor), blood cancer (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,The present invention relates to a method for preventing and / or treating non-Hodgkin's lymphoma (malignant lymphoma), malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmarks, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, adrenal tumors, and neuroblastomas. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present inventors have conducted extensive and in-depth research and have, for the first time, developed a KRas G12D inhibitor having the structure of the following formula (I): The series of compounds of the present invention can be widely applied to the manufacture of drugs for treating and / or preventing KRas G12D-associated cancers or tumors, and are expected to be developed as a new generation of KRas G12D inhibitors. Based on this, the present invention has been completed.

[0045] DETAILED DESCRIPTION: Unless stated to the contrary or otherwise explained, the following terms used in the specification and claims have the following meanings.

[0046] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear alkyl group or a branched alkyl group containing 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl ... a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methylpentyl group, a 2-methyl Examples of alkyl groups include, but are not limited to, octyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, and various branched isomers thereof. 1-10 The term "alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms, and "C 1-4 The term "alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 4 carbon atoms. 0-8 "Alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 0 to 8 carbon atoms, and "C 0-4 The term "alkyl group" refers to straight chain alkyl groups and branched chain alkyl groups containing 0 to 4 carbon atoms.

[0047] The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0048] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated π-electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, and is preferably a cycloalkyl group containing 3 to 12, 3 to 8, or 3 to 6 carbon atoms, such as "C 3-12 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 12 carbon atoms, and "C 3-10 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 10 carbon atoms, and "C 3-8 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 8 carbon atoms, and "C 3-6 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, including Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0049] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. A "spirocycloalkyl group" refers to a polycyclic group in which a single ring shares one carbon atom (called a spiro atom) between the rings. These groups may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, dispirocycloalkyl groups, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to, the following:

[0050] [ka]

[0051] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of which may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic groups, and fused cycloalkyl groups include, but are not limited to, the following:

[0052] [ka]

[0053] "Bridged cycloalkyl groups" refer to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected, and these groups may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged cycloalkyl groups include, but are not limited to, the following:

[0054] [ka]

[0055] The ring of the cycloalkyl group may be fused to the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like.

[0056] The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may be independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0057] The term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated π-electron system. One or more (preferably one, two, three, or four) ring atoms of the heterocyclic group are N, O, N·O, or S(O). r (where r is an integer of 0, 1, or 2), but does not include a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it is a heterocyclic group containing 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, a "3- to 6-membered heterocyclic group" refers to a heterocyclic group containing 3 to 6 ring atoms, a "3- to 8-membered heterocyclic group" refers to a heterocyclic group containing 3 to 8 ring atoms, a "4- to 8-membered heterocyclic group" refers to a heterocyclic group containing 4 to 8 ring atoms, a "4- to 10-membered heterocyclic group" refers to a heterocyclic group containing 4 to 10 ring atoms, a "5- to 8-membered heterocyclic group" refers to a heterocyclic group containing 5 to 8 ring atoms, and a "3- to 12-membered heterocyclic group" refers to a heterocyclic group containing 3 to 12 ring atoms.

[0058] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, homopiperazyl, oxetane, tetrahydrofuran, and the like.

[0059] Polycyclic heterocycles include spiro, fused, and bridged heterocyclic groups. A "spiro heterocyclic group" is a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the monocyclic rings, and one or more (preferably 1, 2, 3, or 4) of the ring atoms are N, O, N.O, or S(O). r (where r is an integer of 0, 1, or 2), with the remaining ring atoms being carbon. These groups may contain one or more double bonds (preferably 1, 2, or 3), but do not contain a ring with a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are classified as monospiroheterocyclic groups, dispiroheterocyclic groups, or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to:

[0060] [ka]

[0061] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more (preferably 1, 2, 3, or 4) rings optionally containing one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably 1, 2, 3, or 4) ring atoms are N, O, N.O, or S(O). r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, fused heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and fused heterocyclic groups include, but are not limited to, the following:

[0062] [ka]

[0063] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and these rings may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system, and one or more (preferably one, two, three, or four) ring atoms are N, O, N atoms, or S(O) atoms. r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged heterocyclic groups include, but are not limited to, the following:

[0064] [ka]

[0065] The ring of the heterocyclic group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to:

[0066] [ka]

[0067] The "heterocyclic group" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0068] The term "aryl group" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6-10 or 6-8 carbons, e.g., "C 6-10 "Aryl group" refers to an all-carbon aryl group containing 6-10 carbons, including, but not limited to, phenyl and naphthyl groups. 6-8 The term "aryl group" refers to an all-carbon aryl group containing 6-8 carbons. The ring of the aryl group may be fused to a heteroaryl group, heterocyclic group, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including, but not limited to:

[0069] [ka]

[0070] The "aryl group" may be substituted or unsubstituted, but in the case of a substituted group, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0071] The term "heteroaryl group" refers to a heteroaromatic group containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including N, O, N-, and S(O)r (where r is an integer of 0, 1, or 2), and is preferably a heteroaromatic group containing 5-10, 5-8, or 5-6 ring atoms. For example, a "5-8-membered heteroaryl group" refers to a heteroaromatic group containing 5-8 ring atoms, and a "5-10-membered heteroaryl group" refers to a heteroaromatic group containing 5-10 ring atoms, including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The ring of the heteroaryl group may be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including, but not limited to:

[0072] [ka]

[0073] The "heteroaryl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0074] The term "alkenyl group" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a straight-chain or branched-chain alkenyl group containing 2-10 or 2-4 carbon atoms. For example, "C 2-10 "Alkenyl group" refers to a straight or branched chain alkenyl group containing 2-10 carbon atoms, and "C 2-4The term "alkenyl group" refers to a straight or branched chain alkenyl group containing 2-4 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0075] The "alkenyl group" may be substituted or unsubstituted, but in the case of a substituted group, the substituents are independently selected from deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferred that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0076] The term "alkynyl group" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbon atoms. For example, "C 2-10 "Alkynyl group" refers to a straight or branched chain alkynyl group containing 2-10 carbon atoms, and "C 2-4 The term "alkynyl group" refers to a straight or branched chain alkynyl group containing 2-4 carbon atoms, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0077] The "alkynyl group" may be substituted or unsubstituted, and in the case of a substituted group, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0078] The term "alkoxy group" refers to an -O-alkyl group, the alkyl group being as defined above. For example, "C 1-10 An "alkoxy group" refers to an alkyloxy group containing 1-10 carbon atoms, and "C 1-4"Alkoxy group" refers to an alkyloxy containing 1-4 carbon atoms, and "C 1-2 The term "alkoxy group" refers to alkyloxy groups containing 1-2 carbons, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0079] The "alkoxy group" may be optionally substituted or unsubstituted, but when substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0080] The term "cycloalkoxy group" or "cycloalkyloxy group" refers to an -O-cycloalkyl group, the definition of which is as above. For example, "C 3-12 "Cycloalkoxy group" refers to a cycloalkyloxy group containing 3-12 carbon atoms, and "C 3-6 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3-6 carbons, including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0081] The "cycloalkoxy group" or "cycloalkyloxy group" may be optionally substituted or unsubstituted, but in the case of a substituted group, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0082] The term "heterocycleoxy" or "heterocyclyloxy" refers to an -O-heterocycle, where heterocycle is as defined above, and includes, but is not limited to, azetidinyloxy, oxetanyloxy, azacyclopentoxy, nitrogen, oxanyloxy, and the like.

[0083] The "heterocyclic oxy group" or "heterocyclyloxy group" may be optionally substituted or unsubstituted, but in the case of a substituted group, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 )2, -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 It is preferable that the number of the groups is one or more (preferably 1, 2, 3 or 4) selected from the group consisting of:

[0084] "C 1-10 "Alkanoyl group" means C 1-10 It refers to the monovalent atomic group remaining after removing the hydroxy group from an alkyl acid, and is usually expressed as "C0-9 alkyl-C(O)-". For example, "C1 alkyl-C(O)-" refers to an acetyl group, "C2 alkyl-C(O)-" refers to a propionyl group, and "C3 alkyl-C(O)-" refers to a butyryl group or an isobutyryl group.

[0085] "-C 0-8 Alkyl-S(O)(=NR 10 )R 11 " is -S(O)(=NR 10 )R 11 The sulfur atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0086] "-C 0-8 Alkyl-N=S(O)R 11 R 12 " is -N=S(O)R 11 R 12 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0087] "-C 0-8 Alkyl-N=SR 11 R 12 " is -N=SR 11 R 12 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group,0-8 The alkyl group is as defined above.

[0088] "-C 0-8 Alkyl-OS(O)R 13 " -OS(O)2R 13 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0089] "-C 0-8 Alkyl-S(O) r R 13 " is -S(O) r R 13 The sulfur atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0090] "-C 0-8 Alkyl-OR 14 " -OR 14 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0091] "-C 0-8 Alkyl-C(O)OR 14 " is -C(O)OR 14 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0092] "-C 0-8 Alkyl-C(O)SR 14 " is -C(O)SR 14 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0093] "-C 0-8Alkyl-SC(O)R 15 " - SC(O)R 15 The sulfur atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0094] "-C 0-8 Alkyl-C(O)R 15 " is -C(O)R 15 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0095] "-C 0-8 Alkyl-OC(O)R 15 " is -OC(O)R 15 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0096] "-C 0-8 Alkyl-P(O)(R 15 )2" is -P(O)(R 15 )2, the phosphorus atom is C 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0097] "-C 0-8 Alkyl-NR 16 R 17 " -NR 16 R 17 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0098] "-C 0-8 Alkyl-C(=NR 16 )R 15 " is -C(=NR 16 )R 15 The carbon atom in0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0099] "-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 " is -N(R 16 )-C(=NR 17 )R 15 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0100] "-C 0-8 Alkyl-C(O)NR 16 R 17 " is -C(O)NR 16 R 17 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0101] "-C 0-8 Alkyl-N(R 16 )-C(O)R 15 " is -N(R 16 )-C(O)R 15 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, 0-8 The alkyl group is as defined above.

[0102] Halogen-substituted C 1-10 The term "alkyl group" refers to a 1-10 carbon alkyl group in which a hydrogen atom in the alkyl group is optionally replaced with an atom of fluorine, chlorine, bromine, or iodine, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[0103] Halogen-substituted C 1-10The term "alkoxy group" refers to a 1-10 carbon alkoxy group in which a hydrogen atom in the alkyl group is optionally replaced by an atom of fluorine, chlorine, bromine, or iodine. Examples include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0104] Deuterium-substituted C 1-10 The term "alkyl group" refers to a 1-10 carbon alkyl group in which a hydrogen atom in the alkyl group is optionally replaced with a deuterium atom, including, but not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, and the like.

[0105] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0106] "Optional" or "optionally" means that a particular event or circumstance described below is possible, but does not necessarily occur, and the description includes cases where the particular event or circumstance occurs or does not occur, i.e., both substituted and unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be present, but is not necessarily present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0107] The term "substituted" means that one or more "hydrogen atoms" in a group may be independently replaced by a corresponding number of substituents. Of course, the substituents are only those that are chemically possible, and conform to the theory of chemical valence bonds. A person skilled in the art can confirm (experimentally or theoretically) whether or not substitution is possible without any special effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (e.g., an olefin).

[0108] "Stereoisomers" refer to isomers that arise due to differences in the spatial arrangement of atoms within a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or enantiomers and diastereoisomers. Stereoisomers that arise due to the rotation of a single bond are called conformational stereoisomers, also known as rotamers. Stereoisomers that arise due to bond length, bond angles, double bonds within a molecule, or the presence of rings are called configuration stereoisomers, and are divided into two types. Among them, isomers that arise due to the inability to freely rotate double bonds or single bonds of ring-forming carbon atoms are called geometric isomers, also known as cis-trans isomers, and are divided into two structures: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers with different optical properties resulting from the lack of antiaxial symmetry in the molecule are called optical isomers, and are divided into structures R and S. In the present invention, the term "stereoisomer" may be understood to include one or more of the enantiomers, structural stereoisomers, and conformational isomers, unless otherwise specified.

[0109] In the present invention, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0110] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, and other components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and contribute to the absorption of the active ingredients, thereby exerting their biological activity.

[0111] The present invention will be explained in more detail and comprehensively below with reference to examples, but the present invention is not limited to these examples alone.

[0112] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid phase mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 nuclear magnetic resonance instrument. The solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0113] Liquid-phase mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatography system (Sunfire C18 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatography system (Gimini C18 150 × 4.6 mm chromatography column).

[0114] The silica gel plates used for thin-layer chromatography were Yantai Yellow Sea HSGF254 or Qingdao GF254, with a diameter of 0.15 mm to 0.20 mm for TLC and 0.4 mm to 0.5 mm for thin-layer chromatography separation and purification. Column chromatography typically used Yantai Yellow Sea silica gel with a diameter of 200 to 300 mesh.

[0115] The starting materials in the examples of the present invention are known commercially available products or can be synthesized by methods known in the art.

[0116] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius (°C).

[0117] 1. Manufacturing of intermediates Preparation of Intermediate A1: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane [ka]

[0118] First step: Synthesis of (bromoethynyl)triisopropylsilane Ethynyltriisopropylsilane (15 g, 82.2 mmol) was dissolved in acetone (100 mL), and silver nitrate (1 g, 6.45 mmol) and N-bromosuccinimide (15 g, 86.3 mmol) were added. The reaction mixture was incubated at room temperature for 1 hour under nitrogen gas protection. The solvent was removed by concentration under reduced pressure, and 300 mL of petroleum ether was added to the residue. The mixture was then triturated and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, yielding (bromoethynyl)triisopropylsilane (21 g, 97.7% yield).

[0119] 1 H NMR (400MHz, CDCl3) δ 1.10 (m, 21H).

[0120] Second step: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol 7-Fluoronaphthalene-1,3-diol (5 g, 28.1 mmol) was dissolved in 1,4-dioxane (200 mL) and, under nitrogen gas protection, (bromoethynyl)triisopropylsilane (8.06 g, 30.8 mmol), ruthenium dichloride, 1-isopropyl-4-methylbenzene (1.2 g, 1.96 mmol), and potassium acetate (5.51 g, 56.2 mmol) were added. The reaction mixture was incubated at 110 °C for 18 hours under nitrogen gas protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (9.1 g, 90.4% yield). ESI-MS: 359 [M+1] + .

[0121] Third step: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (9 g, 25.1 mmol) was dissolved in anhydrous dichloromethane (200 mL), and N,N-diisopropylethylamine (12.4 mL, 75.4 mmol) and bromo(methoxy)methane (4.1 g, 32.6 mmol) were added dropwise. The reaction mixture was incubated at room temperature for 1 hour under nitrogen gas protection. The reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (7.5 g, 74.2% yield).

[0122] 1H NMR (400MHz, CDCl3) δ 9.12 (s, 1H), 7.65 (dd, J = 9.17, 5.62 Hz, 1H), 7.18 (t, J = 8.74 Hz, 1H), 6.96 (d, J = 2.45 Hz, 1H), 6.80 (d, J=1.83 Hz, 1H), 5.24 (s, 2H), 3.50 (s, 3H), 1.17 - 1.23 (m, 21H).

[0123] Fourth step: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonic acid 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4 g, 9.94 mmol) was dissolved in anhydrous dichloromethane (60 mL), and N,N-diisopropylethylamine (4.93 mL, 29.8 mmol) was added dropwise. The reaction solution was cooled to -40 °C under nitrogen gas protection. Trifluoromethanesulfonic anhydride (3.67 g, 14.9 mmol) was slowly added dropwise to the reaction solution. The reaction solution was reacted at -40 °C for 0.5 hours. TLC showed that a small amount of starting material remained. 200 mL of water was added to the reaction solution. The mixture was extracted with 100 mL of dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonic acid (3.05 g, yield 57.4%).

[0124] Fifth step: Synthesis of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonic acid (5.1 g, 9.54 mmol) was dissolved in anhydrous toluene (100 mL), and bis(pinacolato)diboron (4.84 g, 19.1 mmol), potassium acetate (2.81 g, 28.6 mmol), and Pd(dppf)Cl (349 mg, 0.48 mmol) were added. The reaction mixture was incubated at 130 °C under nitrogen gas protection for 3 h. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with saturated aqueous sodium chloride solution (100 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to obtain ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.6 g, yield 53.2%).

[0125] 1 H NMR (400MHz, CDCl3) δ 7.66 (dd, J = 8.91, 5.65 Hz, 1H), 7.50 (d, J = 2.26 Hz, 1H), 7.37 (d, J = 2.51 Hz, 1H), 7.22 (t, J = 8.78 Hz, 1H), 5.27 (s, 2H), 3.50 (s, 3H), 1.43 (s, 12H), 1.16-1.22 (m, 21H).

[0126] Intermediates A2 and A3 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate A1. [Table 1]

[0127] Preparation of Intermediate B: tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate [ka]

[0128] First step: Synthesis of tert-butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate At room temperature, tert-butyl 3,8-diazabicyclo[3.2.1]octo-8-carboxylate (7.0 g, 33.0 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (4.6 mL, 33.0 mmol) and (chloromethanetriyl)tribenzene (9.2 g, 33.0 mmol) were added successively. After stirring at room temperature for 24 hours, 2.8 g of (chloromethanetriyl)tribenzene was added. After stirring at room temperature for another 24 hours, the mixture was quenched by adding saturated aqueous sodium carbonate solution dropwise. The mixture was allowed to stand for layer separation, and the aqueous phase was extracted with dichloromethane (50 mL * 2). The combined organic phases were washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was separated on a high-performance silica gel column [eluent: petroleum ether: ethyl acetate = 1:1] to obtain tert-butyl 3,8-diazabicyclo[3.2.1]octo-8-carboxylate. 3-Triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (13.0 g, 86% yield) was obtained. ESI-MS: 243 [M+1] + .

[0129] Second step: Synthesis of tert-butyl 1-(methyl-d3)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate Under nitrogen gas protection, sec-butyllithium solution (3.6 mL, 4.6 mmol, 1.3 M) was added dropwise to a suspension of tert-butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (900.0 mg, 2.0 mmol) and N,N,N',N'-tetramethylethylenediamine (526 mg, 4.6 mmol) in anhydrous ether (20 mL). The temperature of the reaction mixture was maintained at around -30°C. After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours, and then methyl iodide (287 mg, 2.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 15 min. Saturated aqueous ammonium chloride (10 mL) was then added dropwise, and the mixture was allowed to stand for phase separation. The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified using a high-performance silica gel column [eluent: petroleum ether:ethyl acetate = 100:0 to 10:1] to give tert-butyl 1-(methyl-d3)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (888.0 mg, 77% yield). ESI-MS: 243 [M+1] + .

[0130] Third step: Synthesis of tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 1-(methyl-d3)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (880 mg, 1.87 mmol) was dissolved in dichloromethane (5 mL), 5 mL of acetic acid was added, and the solution was heated to 50 °C for 1 h. The mixture was then spun down and the resulting tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate was used directly in the next reaction. ESI-MS: 230.4 [M+1] + .

[0131] Preparation of Intermediate C1: tert-Butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate [ka]

[0132] First step: Synthesis of tert-butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate Under nitrogen gas protection, sec-butyllithium solution (14.4 mL, 18.7 mmol, 1.3 M) was added dropwise to a suspension of tert-butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (5.0 g, 11.0 mmol) and N,N,N',N'-tetramethylethylenediamine (2.2 g, 18.7 mmol) in anhydrous ether (40 mL). The temperature of the reaction mixture was maintained at around 0°C. After the addition was complete, the reaction mixture was stirred at 0°C for 1.5 hours. Ethyl formate (2.4 g, 33.0 mmol) was then added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 15 minutes. Saturated aqueous ammonium chloride (20 mL) was then added dropwise, and the mixture was allowed to stand for phase separation. The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified using a high-performance silica gel column [eluent: petroleum ether:ethyl acetate = 100:0 to 10:1] to give tert-butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (1.9 g, 36% yield). ESI-MS: 483.2 [M+1] + .

[0133] Second step: Synthesis of tert-butyl 1-(methylol)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (560.0 mg, 1.2 mmol) was dissolved in methanol (10 mL), sodium borohydride (78.0 mg, 2.3 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. Water (15 mL) and ethyl acetate (15 mL) were added to quench the reaction, and the mixture was stirred at room temperature for 5 minutes. The mixture was then allowed to stand for layer separation, and the aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phases were washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 1-(methylol)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (560.0 mg, 1.2 mmol). mg, yield 91%). ESI-MS: 485.2 [M+1] + .

[0134] Third step: Synthesis of tert-butyl 1-(methoxymethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 1-(methylol)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (700 mg, 1.444 mmol) was dissolved in DMF (10 mL) and sodium hydride (69.3 mg, 1.73 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, after which iodomethane (270 μL, 4.33 mmol) was added and the mixture was maintained at 0 °C for 2 hours. Upon completion of the reaction, the mixture was quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give tert-butyl 1-(methoxymethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (440 mg, yield 61.1%).

[0135] Fourth step: Synthesis of tert-butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 1-(methoxymethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (440 mg, 0.88 mmol) was dissolved in acetic acid (5 mL). The mixture was reacted at 25°C for 2 hours. The solvent was removed by concentration under reduced pressure to give tert-butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (220 mg, 97.3% yield). ESI-MS: 256 [M+1] + .

[0136] Intermediates C2 to C5 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate C1. [Table 2]

[0137] Preparation of Intermediate D1: tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0138] First step: Synthesis of tert-butyl 3-triphenylmethyl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Methyltriphenylphosphorane bromide cation (3.66 g, 10.3 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), potassium tert-butoxide (1.27 g, 11.3 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes. Then, a solution of tert-butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.65 g, 3.42 mmol) in tetrahydrofuran (10 mL) was slowly added. The mixture was reacted at 25 °C for 2 hours. TLC detection confirmed the reaction was complete. The reaction mixture was diluted with 30 mL of water and extracted twice with 30 mL of ethyl acetate. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance silica gel column chromatography to give tert-butyl 3-triphenylmethyl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.19 g, 72.4% yield).

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.50 (br s, 5H), 7.33-7.25 (m, 7H), 7.19-7.09 (m, 3H), 6.16 (dd, J =11.2, 17.9 Hz, 1H), 4.93 (d, J = 11.3 Hz, 1H), 4.81 (d, J = 18.1 Hz, 1H), 4.16 (d, J = 5.5 Hz, 1H), 3.19 (d, J = 11.0 Hz, 1H), 2.96 (d, J = 11.0 Hz, 1H), 2.58-2.46 (m, 1H), 2.36-2.22 (m, 1H), 2.13-1.89 (m, 2H), 1.92 (d, J = 11.0 Hz, 1H), 1.84 (d, J = 11.0 Hz, 1H), 1.15 (s, 9H).

[0140] Second step: Synthesis of tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-triphenylmethyl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 1.14 mmol) was dissolved in acetic acid (10 mL). The mixture was allowed to react overnight at 25 °C. The solvent was removed by concentration under reduced pressure to give tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (540 mg, crude product). The crude product could be used directly in the next reaction without isolation. ESI-MS: 183 [M+1-56] + .

[0141] Intermediates D2 to D5 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate D1. [Table 3]

[0142] Intermediate E1: tert-Butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0143] First step: Synthesis of tert-butyl 1-ethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-triphenylmethyl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 1.14 mmol) was dissolved in anhydrous methanol (20 mL) and wet Pd / C (200 mg, 10% purity) was added under nitrogen gas protection. The mixture was purged with hydrogen gas three times and reacted at 25°C under a hydrogen balloon atmosphere for 3 hours. TLC confirmed the reaction was complete. The filtrate was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent, affording tert-butyl 1-ethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 100% yield).

[0144] Second step: Synthesis of tert-butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-ethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 1.13 mmol) was dissolved in acetic acid (10 mL). The mixture was allowed to react overnight at 25 °C. The solvent was removed by concentration under reduced pressure to give tert-butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (540 mg, crude product). ESI-MS: 241 [M+1] + .

[0145] Intermediates E2 to E4 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate E1. [Table 4]

[0146] Preparation of Intermediate F: tert-Butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0147] First step: Synthesis of tert-butyl 1-methyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 11.0 mmol) was dissolved in tert-butyl methyl ether (50 mL). Tetramethylethylenediamine (4.15 mL, 27.5 mmol) was added to the mixture, and sec-butyllithium (21.1 mL, 27.5 mmol) was slowly added dropwise at -10°C. The mixture was reacted at 0°C for 2 hours. Iodomethane (1.87 g, 13.2 mmol) was added to the mixture at 0°C. The mixture was reacted at 0°C for 2 hours. TLC confirmed the reaction was complete. The reaction mixture was quenched by slowly adding water dropwise, extracted with water and ethyl acetate, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give tert-butyl 1-methyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, yield 97.1%).

[0148] 1 H NMR (400MHz, CDCl3) δ 7.49 (s, 6H), 7.30-7.23 (m, 8H), 7.18-7.11 (m, 3H), 4.16 (d, J = 5.1 Hz, 1H), 3.00-2.90 (m, 1H), 2.81 (d, J = 11.0 Hz, 1H), 2.54-2.46 (m, 1H), 2.41-2.31 (m, 1H), 2.27-2.18 (m, 1H), 1.87-1.81 (m, 1H), 1.38 (s, 3H), 1.18 (s, 9H).

[0149] Second step: Synthesis of tert-butyl 1,5-dimethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-methyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 5.33 mmol) was dissolved in anhydrous tert-butyl methyl ether (40 mL), and tetramethylethylenediamine (1.55 g, 13.3 mmol) was slowly added to the mixture under nitrogen gas protection at 0°C. sec-butyllithium (10.2 mL, 13.3 mmol) was slowly added to the mixture under nitrogen gas protection at -10°C, and the mixture was then cooled to -10°C. o The reaction was continued at RT for 1 hour, then iodomethane (0.91 g, 6.40 mmol) was slowly added under nitrogen gas protection at -10 to 0°C, and the reaction was continued for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was directly concentrated under reduced pressure to remove the solvent, and the resulting crude product, tert-butyl 1,5-dimethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 g), was used directly in the next reaction. ESI-MS: 483 [M+1] + .

[0150] Third step: Synthesis of tert-butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1,5-dimethyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.07 mmol) was dissolved in acetic acid (10 mL), and the mixture was reacted at 25 °C for 18 hours. LC-MS showed the reaction was complete. The reaction mixture was directly concentrated under reduced pressure to remove the solvent, and the resulting crude product, tert-butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (content: 500 mg), was used directly in the next reaction. ESI-MS: 241 [M+1] + .

[0151] Preparation of Intermediate G: tert-butyl 1-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0152] First step: Synthesis of tert-butyl 1-(1-hydroxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.29 mmol) was dissolved in tetrahydrofuran (40 mL), and methylmagnesium bromide (8.29 mL, 16.58 mmol) was slowly added at -78 °C. The mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed once with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was chromatographed on a high-performance silica gel column to give tert-butyl 1-(1-hydroxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.22 g, 78% yield) [ethyl acetate:petroleum ether = 0-50%]. ESI-MS: 499.29 [M+1] + .

[0153] Second step: Synthesis of tert-butyl 1-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-(1-hydroxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.22 g, 6.46 mmol) was dissolved in dichloromethane (20 mL) and acetic acid (20 mL) and reacted at 50°C for 18 hours. After the reaction was completed, the mixture was directly concentrated to give tert-butyl 1-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.66 g, 100% yield). ESI-MS: 257.18 [M+1] + .

[0154] Preparation of Intermediate H: tert-butyl 1-((methylthio)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0155] First step: Synthesis of tert-butyl 1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 11.0 mmol) was dissolved in ethyl ether (100 mL). Under the protection of nitrogen gas, N,N,N,N-tetramethylethylenediamine (3.20 g, 27.5 mmol) was added at -10 °C under stirring. Then, sec-butyllithium (1.3 M, 21.2 mL, 27.5 mmol) was slowly added dropwise. The mixture was stirred at -10 °C for 2 hours, and then chloromethyl methyl sulfide (2.12 g, 22.0 mmol) was added dropwise. The mixture was stirred at -10 °C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to obtain tert-butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 21.2% yield) was obtained.

[0156] 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 5H), 7.34-7.23 (m, 7H), 7.20-7.12 (m, 3H), 4.33 (s, 1H), 4.00 (d, J = 2.6 Hz, 1H), 3.24 - 3.05 (m, 1H), 2.86 (t, J = 12.4 Hz, 1H), 2.59-2.44 (m, 2H), 2.22-2.09 (m, 4H), 1.79-1.64 (m, 1H), 1.57 (s, 3H), 1.40 (s, 9H).

[0157] Second step: Synthesis of tert-butyl 1-((methylthio)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.97 mmol) was dissolved in acetic acid (10 mL) and stirred at 25 °C for 18 hours. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was crude tert-butyl 1-((methylthio)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 96.2% yield). ESI-MS: 273 [M+1] + .

[0158] Preparation of Intermediate I: tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0159] First step: Synthesis of tert-butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.28 mmol) was dissolved in dichloromethane (20 mL), and N-methylmorpholine oxide (751 mg, 6.41 mmol) and potassium osmate(VI) dihydrate (47.2 mg, 0.13 mmol) were added under nitrogen gas protection at -40 °C. The reaction was stirred at 25°C for 2 hours, quenched with saturated aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove the solvent, yielding tert-butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 85.6% yield) as the residue. The crude product was used directly in the next reaction.

[0160] Second step: Synthesis of tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.28 mmol) was dissolved in acetic acid (10 mL) and stirred at 25 °C for 18 hours. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was crude tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 89.8% yield). ESI-MS: 305 [M+1] + .

[0161] Preparation of Intermediate J: 8-(tert-butyl) 1-methyl 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate [ka]

[0162] First step: Synthesis of 8-(tert-butyl) 1-methyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate tert-Butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 11.0 mmol) was dissolved in tert-butyl methyl ether (60 mL). Tetramethylethylenediamine (4.15 mL, 27.5 mmol) was added to the mixture, and sec-butyllithium (21.2 mL, 27.5 mmol) was slowly added dropwise at -10°C. The mixture was reacted at 0°C for 2 hours. Diethylpyrocarbonate (2.95 g, 22.0 mmol) was added to the mixture at 0°C. The mixture was reacted at 0°C for 2 hours. TLC confirmed the reaction was complete. The reaction was quenched by slowly adding water dropwise, diluted with 50 mL of water, and extracted twice with 50 mL of ethyl acetate. The organic phase was washed once with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give 8-(tert-butyl) 1-methyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (3.2 g, 56.7% yield).

[0163] Second step: Synthesis of 8-(tert-butyl) 1-methyl 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate 8-(tert-butyl) 1-methyl (1S,5R)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (1.5 g, 2.93 mmol) was dissolved in acetic acid (15 mL). The mixture was reacted at 25°C for 2 hours. The solvent was removed by concentration under reduced pressure to obtain crude 8-(tert-butyl) 1-methyl 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (content 0.79 g, yield 99.9%).

[0164] Intermediate K1: Preparation of 1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane [ka]

[0165] First step: Synthesis of (3,8-diazabicyclo[3.2.1]octan-1-yl)methanol tert-Butyl 1-(methylol)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.25 mmol) was added to a solution of hydrochloric acid in ethyl acetate (100 mL, 4 M) and stirred at room temperature for 2 hours. A solid precipitated and was collected by filtration to give (3,8-diazabicyclo[3.2.1]octan-1-yl)methanol (1.78 g, hydrochloride salt, 100% yield). ESI-MS: 143 [M+1] + .

[0166] Second step: Synthesis of (3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methanol (3,8-Diazabicyclo[3.2.1]octan-1-yl)methanol (1.78 g, hydrochloride, 8.25 mmol) and potassium carbonate (3.43 g, 24.8 mmol) were added to acetonitrile (60 mL), and benzyl bromide (3.54 g, 20.7 mmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned and extracted with water (100 mL) and ethyl acetate (100 mL). The organic phase was adjusted to pH 1-2 with dilute hydrochloric acid and extracted with 2 M dilute hydrochloric acid (50 mL). The separated organic phase was discarded, and the aqueous phase was neutralized to a weak alkaline with 2 N aqueous sodium hydroxide and then extracted with ethyl acetate (100 mL). The extract was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent, yielding (3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methanol (2.5 g, 93.6% yield). ESI-MS: 323 [M+1] + .

[0167] Third step: Synthesis of 3,8-benzhydryl-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane (3,8-Benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methanol (0.5 g, 1.551 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (0.04 g, 60% purity, 0.931 mmol) was slowly added at 0°C under nitrogen gas protection. The mixture was reacted at 0°C for 2 hours. Ethyl iodide (0.12 mL, 1.55 mmol) was added at 0°C. The mixture was reacted at 0°C for 2 hours. TLC confirmed the reaction was complete. The reaction was quenched by slowly adding water dropwise, diluted with 30 mL of water, and extracted twice with 20 mL of ethyl acetate. The organic phase was washed once with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give 3,8-benzhydryl-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane (510 mg, yield 93.8%).

[0168] Fourth step: Synthesis of 1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane 3,8-Benzhydryl-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane (500 mg, 1.45 mmol) was dissolved in methanol (25 mL), and concentrated hydrochloric acid (1 mL) and wet palladium-carbon (200 mg, 10% purity) were added to the mixture. The mixture was reacted at 50°C under hydrogen gas (50 psi) for 18 hours. The palladium-carbon was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane (240 mg, 96.9% yield). ESI-MS: 171 [M+1] + .

[0169] Intermediates K2 to K3 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate K1. [Table 5]

[0170] Preparation of Intermediate L: tert-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0171] First step: Synthesis of tert-butyl 1-((E)-2-methoxyvinyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Methoxymethyl)triphenylphosphonium bromide (2.13 g, 6.21 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and potassium tert-butoxide (0.77 g, 6.83 mmol) was slowly added under nitrogen gas protection at 0°C. The mixture was reacted at 0°C for 10 minutes. Then, tert-butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.07 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and slowly added to the reaction solution. The reaction solution was reacted at 0°C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted twice with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give tert-butyl 1-((E)-2-methoxyvinyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900 mg, yield 84.9%).

[0172] Second step: Synthesis of tert-butyl 1-(2-methoxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((E)-2-methoxyvinyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 0.98 mmol) was dissolved in anhydrous methanol (10 mL). Under argon gas protection, 10% wet palladium on carbon (1.04 g, 0.98 mmol) was slowly added, and the atmosphere was purged with hydrogen gas three times. The mixture was reacted at 25 °C overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the product, tert-butyl 1-(2-methoxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, crude product).

[0173] Third step: Synthesis of tert-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-(2-methoxyethyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.88 mmol) was dissolved in acetic acid (5 mL), and the mixture was reacted overnight at 25° C. The reaction solution was concentrated under reduced pressure to remove the solvent, and tert-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (content 200 mg, crude product) was obtained.

[0174] Preparation of Intermediate M1: tert-butyl 1-((N-methylacetylamino)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0175] First step: Synthesis of tert-butyl 1-((methylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-formyl-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.24 mmol) was dissolved in MeOH (30 mL) and stirred at room temperature while adding methylamine hydrochloride (251.83 mg, 3.73 mmol), diisopropylethylamine (0.62 mL, 3.73 mmol), and acetic acid (0.07 mL, 1.24 mmol). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, and then sodium cyanoborohydride (234.37 mg, 3.73 mmol) was added. The reaction mixture was heated to 60°C and stirred for 1 hour. LCMS monitoring indicated complete reaction of the starting material and the formation of product. The reaction mixture was cooled to room temperature, aqueous sodium bicarbonate (25 mL) was added, and the mixture was concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted with ethyl acetate. The extracted organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was separated on a high-performance silica gel column [silicon dioxide, 0-100% ethyl acetate in petroleum ether] to give tert-butyl 1-((methylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.90 mmol, 67.14% yield). ESI-MS: 498.4 [M+1] + .

[0176] Second step: Synthesis of tert-butyl 1-((N-methylacetylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.90 mmol) was dissolved in DCM (5 mL) and stirred under ice-water cooling. Diisopropylethylamine (0.30 mL, 1.81 mmol) and acetyl chloride (0.08 mL, 1.09 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at 0°C under the protection of a nitrogen balloon for 1 hour. TLC showed that the starting materials had completely reacted. The reaction was quenched by adding 10 mL of water to the reaction solution, and the aqueous phase was extracted with dichloromethane. The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was separated on a high-performance silica gel column [silicon dioxide, 50% ethyl acetate in petroleum ether] to give tert-butyl 1-((N-methylacetylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.83 mmol, 92.21% yield). ESI-MS 562.3 [M+23] + .

[0177] Third step: Synthesis of tert-butyl 1-((N-methylacetylamino)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((N-methylacetylamino)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.83 mmol) was dissolved in 5 mL of dichloromethane, and acetic acid (5 mL, 87.26 mmol) was added. The reaction mixture was heated to 50°C under the protection of a nitrogen balloon and stirred for 3 hours. TLC monitoring indicated complete reaction of the starting materials. The reaction mixture was concentrated to give tert-butyl 1-((N-methylacetylamino)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.824 mmol, 98.81% yield). The crude product was used directly in the next step. ESI-MS: 298.3 [M+1] + .

[0178] Intermediates M2 and M3 can be produced by selecting corresponding raw materials with reference to all or part of the synthesis method for intermediate M1. [Table 6]

[0179] Preparation of Intermediate N: Methyl 2-(3,8-diazabicyclo[3.2.1]octan-1-yl)acetate [ka]

[0180] First step: Synthesis of (3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methyl methanesulfonate (3,8-Benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methanol (1.6 g, 4.96 mmol) and triethylamine (2.76 mL, 20.0 mmol) were dissolved in dichloromethane (50 mL). Methanesulfonic anhydride (0.95 mL, 7.44 mmol) was slowly added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was separated with water (100 mL) and dichloromethane (100 mL *3). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated using a high-performance silica gel column. The organic phase was concentrated under reduced pressure to remove the solvent, yielding (3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methyl methanesulfonate (1.8 g, 90.5% yield). ESI-MS:401 [M+1] + .

[0181] Second step: Synthesis of 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetonitrile (3,8-Benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)methyl methanesulfonate (4.3 g, 10.7 mmol), potassium carbonate (2.97 g, 21.5 mmol), trimethylsilyl cyanide (5.73 mL, 42.9 mmol), and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 42.9 mL, 42.9 mmol) were dissolved in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was then partitioned and extracted with water (400 mL) and ethyl acetate (400 mL *3). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated using a high-performance silica gel column, and the organic phase was concentrated under reduced pressure to remove the solvent, yielding 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetonitrile (1.9 g, 53.4% ​​yield). ESI-MS: 332 [M+1] + .

[0182] Third step: Synthesis of 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetic acid 2-(3,8-Benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetonitrile (1.9 g, 5.73 mmol) was dissolved in a mixture of acetic acid (10 mL) and concentrated hydrochloric acid (3 mL). The reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent, yielding 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetic acid (2 g, 99.6% yield). ESI-MS: 351 [M+1] + .

[0183] Fourth step: Synthesis of methyl 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetate 2-(3,8-Benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetic acid (1.3 g, 3.71 mmol) was dissolved in a mixture of methanol (20 mL) and concentrated sulfuric acid (0.36 g, 3.71 mmol). The reaction mixture was stirred at 70 °C for 18 hours. The organic phase was concentrated under reduced pressure to remove the solvent, and the mixture was separated and extracted with water (30 mL) and ethyl acetate (30 mL *3). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated using a high-performance silica gel column. The organic phase was concentrated under reduced pressure to remove the solvent, yielding methyl 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetate (1.3 g, 96.2% yield). ESI-MS: 365 [M+1] + .

[0184] Fifth step: Synthesis of methyl 2-(3,8-diazabicyclo[3.2.1]octan-1-yl)acetate Methyl 2-(3,8-benzhydryl-3,8-diazabicyclo[3.2.1]octan-1-yl)acetate (1.4 g, 3.84 mmol), palladium hydroxide on carbon (0.8 g, 10% purity), and a catalytic amount of hydrochloric acid were dissolved in methanol (20 mL). The reaction mixture was stirred under hydrogen gas (50 Psi) at 50 °C for 24 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting methyl 2-(3,8-diazabicyclo[3.2.1]octan-1-yl)acetate (707 mg, 99.9% yield) was used directly in the next step. ESI-MS: 185 [M+1] + .

[0185] Preparation of Intermediate O: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine [ka]

[0186] First step: Synthesis of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate 2-Chloro-3-fluoroisonicotinic acid (90 g, 513 mmol) was dissolved in toluene (675 mL) and tert-butyl alcohol (675 mL), and triethylamine (142 mL, 1.03 mol), diphenylphosphoryl azide (116 mL, 538 mmol), and Boc anhydride (11.0 mL, 51.3 mmol) were added. The reaction mixture was incubated at room temperature under nitrogen gas protection for 0.5 h, then at 80 °C for 6 h. Upon completion, the mixture was cooled to room temperature, diluted with 800 mL of water, and extracted with ethyl acetate (500 mL * 2). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (105 g, 83.0% yield). ESI-MS: 247 [M+1] + .

[0187] Second step: Synthesis of 3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione tert-Butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (30 g, 122 mmol) was dissolved in tetrahydrofuran (300 mL) and n-butyllithium (121 mL, 304 mmol) was added dropwise at -78 °C under nitrogen gas protection. After the addition was complete, the reaction mixture was slowly warmed to -20 °C and reacted at this temperature for 1 hour. Then, tert-butyl isocyanate (14.3 mL, 243 mmol) was added dropwise to the reaction mixture at -20 °C. The reaction mixture was slowly warmed to room temperature and reacted for 1 hour, then heated to 70 °C and reacted overnight. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (500 mL * 2). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give 3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (248 g, yield 72.6%).

[0188] Third step: Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 3-(tert-Butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (24 g, 88.3 mmol) was slowly added in portions to phosphorus oxychloride (300 mL), and N,N-diisopropylethylamine (43.8 mL, 265 mmol) was slowly added dropwise. The reaction was allowed to proceed at 110 °C overnight. Most of the phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly poured into ice-cold saturated aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was triturated with 200 mL of petroleum ether, filtered, and the filter cake was dried to give 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (14.8 g, 66.6% yield).

[0189] 1 H NMR (400MHz, DMSO-d6) δ 8.94 (s, 1 H).

[0190] Preparation of Intermediate P: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one [ka]

[0191] First step: Synthesis of 2,6-dichloro-3-fluoropyridin-4-amine 2,6-Dichloropyridin-4-amine (50 g, 306 mmol) was dissolved in methanol (1.25 L) and water (250 mL), followed by the addition of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (245 g, 690 mmol). The mixture was reacted at 45 °C for 18 hours, and LC-MS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was rotary evaporated and extracted with ethyl acetate (500 mL) and water (300 mL). The organic phase was washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 2,6-dichloro-3-fluoropyridin-4-amine (18.2 g, 32.4% yield). ESI-MS: 181 [M+1] + .

[0192] Second step: Synthesis of tert-butyl (tert-butoxycarbonyl) (2,6-dichloro-3-fluoropyridin-4-yl)carbamate 2,6-Dichloro-3-fluoropyridin-4-amine (18.2 g, 101 mmol) was dissolved in tetrahydrofuran (250 mL), and 4-dimethylaminopyridine (0.62 g, 5.04 mmol) and di-tert-butyl dicarbonate (53.9 mL, 251 mmol) were added. The mixture was reacted at 60 °C for 2 hours, and TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then methanol (200 mL) was added and the mixture was triturated for 30 minutes. The resulting mixture was collected by filtration to give tert-butyl (tert-butoxycarbonyl) (2,6-dichloro-3-fluoropyridin-4-yl)carbamate (24.3 g, 63.2% yield).

[0193] 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 4.3 Hz, 1H), 1.49 (s, 18H).

[0194] Third step: Synthesis of tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate Lithium diisopropylamide (105 mL, 210 mmol) was slowly added dropwise to anhydrous tetrahydrofuran (200 mL) at -78°C and stirred for 10 minutes. tert-Butyl (tert-butoxycarbonyl) (2,6-dichloro-3-fluoropyridin-4-yl)carbamate (24.3 g, 63.7 mmol) was dissolved in tetrahydrofuran (200 mL) and slowly added dropwise to the solution at -78°C. After the addition was complete, the reaction was allowed to proceed for 1 hour. TLC showed the reaction was complete. The reaction was quenched by slowly adding acetic acid (20 mL) to the reaction mixture. The reaction mixture was extracted with ethyl acetate (400 mL) and water (300 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent, thereby obtaining tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (26.6 g, yield 99.9%).

[0195] Fourth step: Synthesis of 4-amino-2,6-dichloro-5-fluoronicotinic acid tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (26.6 g, 69.6 mmol) was dissolved in dioxane (80 mL), concentrated hydrochloric acid (30 mL) was added, and the mixture was reacted at 65 °C for 3 hours, at which point LCMS showed the reaction was complete. The solvent was removed by concentration under reduced pressure to give 4-amino-2,6-dichloro-5-fluoronicotinic acid (15 g, 95.7% yield). ESI-MS: 225 [M+1] + .

[0196] Fifth step: Synthesis of 4-amino-2,6-dichloro-5-fluoronicotinoyl chloride 4-Amino-2,6-dichloro-5-fluoronicotinic acid (15 g, 66.7 mmol) was dissolved in thionyl chloride (40 mL), and the mixture was reacted at 60 °C for 3 h, at which point LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to remove the solvent, yielding 4-amino-2,6-dichloro-5-fluoronicotinoyl chloride (16 g, 98.6% yield).

[0197] Sixth step: Synthesis of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one 4-Amino-2,6-dichloro-5-fluoronicotinoyl chloride (16 g, 65.7 mmol) was dissolved in anhydrous acetone (80 mL), and NHSCN (15 g, 197 mmol) was dissolved in anhydrous acetone (80 mL) and slowly added to the solution. The mixture was reacted at 50 °C for 1 hour, and TLC showed the reaction was complete. The reaction mixture was poured into 400 mL of water and stirred for 10 minutes. A solid precipitated, which was filtered. The filter cake was rinsed with water and dried to give 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (15.9 g, 90.7% yield).

[0198] Seventh step: Synthesis of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 5,7-Dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (15.9 g, 59.6 mmol) was dissolved in methanol (130 mL), followed by the addition of iodomethane (12.7 g, 894 mmol) and 100 mL of 1 M aqueous sodium hydroxide. The mixture was reacted at 25 °C for 3 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into 400 mL of water, and the pH was adjusted to ~6 with dilute hydrochloric acid. The solid precipitated, filtered, and the filter cake was rinsed with water and dried to give 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (15 g, 80.6% yield).

[0199] 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (br s, 1H), 2.60 (s, 3H).

[0200] Preparation of Intermediate Q: ((2-fluoro-6-(methoxymethoxy)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane [ka]

[0201] First step: Synthesis of 7-fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol 6-Chloro-7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (2 g, 4.576 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.15 g, 9.153 mmol) were dissolved in ethylene glycol dimethyl ether (15 mL), potassium carbonate (1.89 g, 13.73 mmol), and Pd(dppf)Cl (0.33 g, 0.458 mmol) were added, and the mixture was reacted at 100 °C for 18 h. After the reaction was complete, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed once with saturated brine. The organic phase was dried and filtered. The filtrate was concentrated. The residue was purified by high-performance silica gel column chromatography [0-50% ethyl acetate:petroleum ether] to give 7-fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (715 mg, 37.4% yield). ESI-MS: 417.2 [M+1] + .

[0202] Second step: Synthesis of 7-fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonic acid 7-Fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.43 g, 3.432 mmol) and N,N-diisopropylethylamine (2.21 g, 17.16 mmol) were dissolved in dichloromethane (20 mL), and trifluoromethanesulfonic anhydride (1.45 g, 5.149 mmol) was added at 0 °C. The mixture was then reacted at 0 °C for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed once with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was purified by high-performance silica gel column chromatography [0-50% ethyl acetate:petroleum ether] to obtain 7-fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonic acid (1.04 g, 55.3% yield). ESI-MS:549.2 [M+1] + .

[0203] Third step: Synthesis of ((2-fluoro-6-(methoxymethoxy)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 7-Fluoro-3-(methoxymethoxy)-6-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.04 g, 1.896 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.44 g, 5.687 mmol), and potassium acetate (560 mg, 5.687 mmol) were dissolved in toluene (20 mL), Pd(dppf)Cl (140 mg, 0.19 mmol) was added, and the mixture was purged with nitrogen gas three times and reacted at 135 °C for 18 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed once with saturated brine. The organic phase was dried and filtered. The filtrate was concentrated. The resulting residue was purified by high-performance silica gel column chromatography [0-50% ethyl acetate:petroleum ether] to give ((2-fluoro-6-(methoxymethoxy)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (564 mg, 56.5% yield). ESI-MS: 527.3 [M+1] + .

[0204] Preparation of Intermediate R: 1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [ka]

[0205] First step: Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (5000 mg, 9.76 mmol) was added to a solution of hydrochloric acid in ethyl acetate (24.4 mL). The mixture was reacted at 25°C for 5 hours. The mixture was concentrated. The crude product was separated using a high-performance silica gel column to obtain 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (1500 mg, 32.8% yield).

[0206] 1 H NMR (400MHz, DMSO-d6) δ 9.88 (s, 1H), 7.83 (dd, J = 5.9, 9.1 Hz, 1H), 7.85-7.76(m, 1H), 7.40 (t, J = 9.0 Hz, 1H),7.32 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 1.34 (s, 12H), 1.14-1.08 (m, 21H).

[0207] Second step: Synthesis of 1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol Under a nitrogen atmosphere, 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (500 mg, 1.07 mmol) was dissolved in acetonitrile (10 mL). 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (416 mg, 1.17 mmol) was added to the solution and reacted at 25 °C for 5 hours. The reaction mixture was separated and extracted with water (20 mL) and ethyl acetate (20 mL *3). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated on a high-performance silica gel column to obtain 1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (250 mg, yield 48.2%).

[0208] 1 H NMR (400MHz, CDCl3) δ 7.85 (dd, J = 5.6, 9.2 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.25-7.20 (m, 1H), 5.33 (br d, J = 3.0 Hz, 1H), 1.35 (s, 12H), 1.10-1.05 (m, 21H).

[0209] Preparation of Intermediate S: tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0210] First step: Synthesis of tert-butyl 1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 11.0 mmol) was dissolved in ethyl ether (100 mL). Under nitrogen gas protection, N,N,N,N-tetramethylethylenediamine (3.20 g, 27.5 mmol) was added at -10°C. Sec-butyllithium (1.3 M, 21.2 mL, 27.5 mmol) was slowly added dropwise and reacted at -10°C for 2 hours. Then, chloromethyl methyl sulfide (2.12 g, 22.0 mmol) was added dropwise and reacted at -10°C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to obtain tert-butyl 3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. (1R,5S)-1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 21.2% yield) was obtained.

[0211] 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 5H), 7.34 - 7.23 (m, 7H), 7.20-7.12 (m, 3H), 4.33 (s, 1H), 4.00 (d, J = 2.6 Hz, 1H), 3.24-3.05 (m, 1H), 2.86 (t, J = 12.4 Hz, 1H), 2.59-2.44 (m, 2H), 2.22-2.09 (m, 4H), 1.79-1.64 (m, 1H), 1.57 (s, 3H), 1.40 (s, 9H).

[0212] Second step: Synthesis of tert-butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methylthio)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.28 mmol) was dissolved in dichloromethane (20 mL) and, under nitrogen gas protection, N-methylmorpholine oxide (751 mg, 6.41 mmol) and potassium osmate(VI) dihydrate (47.2 mg, 0.13 mmol) were added at -40 °C. The reaction mixture was allowed to react at 25 °C for 2 hours, quenched with saturated aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent, yielding tert-butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 85.6% yield). The crude product was used directly in the next reaction.

[0213] Third step: Synthesis of tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 1-((methanesulfonyl)methyl)-3-triphenylmethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.28 mmol) was dissolved in acetic acid (10 mL) and reacted at 25 °C for 18 hours. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was crude tert-butyl 1-((methanesulfonyl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 89.8% yield). ESI-MS: 305 [M+1] + .

[0214] II. Manufacture of specific embodiments Example 1 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0215] First step: Synthesis of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (220 mg, 0.87 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (223 mg, 0.87 mmol) were dissolved in anhydrous dichloromethane (10 mL). DIEA (0.72 mL, 4.35 mmol) was added slowly under nitrogen gas protection at -40 °C, and the reaction was continued under nitrogen gas protection at -40 °C for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL * 2), washed with saturated aqueous sodium chloride (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (370 mg, 89.9% yield). ESI-MS: 472 [M+1] + .

[0216] Second step: Synthesis of tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (370 mg, 0.78 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methanol (124 mg, 0.78 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (150 mg, 1.56 mmol) was slowly added under nitrogen gas protection at 0°C. After the addition was complete, the mixture was maintained at 0°C and allowed to react for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL * 2), washed with saturated aqueous sodium chloride (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the solvent was removed. The residue was purified using a high-performance silica gel column to give tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (200 mg, 42.9% yield). ESI-MS: 595 [M+1] + .

[0217] Third step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate tert-Butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (200 mg, 0.34 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189 mg, 0.37 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dissolved in anhydrous dioxane (5 mL) and water (1 mL). Adamantane-based second-generation palladium chloride (11.2 mg, 0.02 mmol) was slowly added under nitrogen gas protection at 25°C, and the reaction was carried out at 85°C for 1 hour under nitrogen gas protection. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL * 2), washed with saturated aqueous sodium chloride (20 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solvent was removed. The residue was purified using a high-performance silica gel column to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (260 mg, 81.8% yield). ESI-MS: 945 [M+1] + .

[0218] Fourth step: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octo-8-carboxylate (250 mg, 0.26 mmol) was dissolved in acetonitrile (2 mL), and hydrochloric acid / dioxane (2 mL) was slowly added dropwise at 25°C. The mixture was allowed to react at 0°C for 1 hour. The solvent was removed by concentration under reduced pressure to give 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (180 mg, 0.23 mmol, 85.0% yield). ESI-MS: 801 [M+1] + .

[0219] Fifth step: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (170 mg, 0.21 mmol) was dissolved in DMF (10 mL) and cesium fluoride (1.61 g, 10.6 mmol) was added at 25 ° C. The reaction was carried out at 25 ° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated using a reverse-phase column to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (22.4 mg, 11.94% yield, 98.471% purity). ESI-MS: 645 [M+1] + .

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 10.47-9.95 (m, 1H), 9.04 (s, 1H), 7.98 (dd, J = 5.9, 9.1 Hz, 1H), 7.58-7.34 (m, 2H), 7.27-7.15 (m, 1H), 5.43-5.16 (m, 1H), 4.62-4.25 (m, 2H), 4.20-3.84 (m, 3H), 3.67-3.51 (m, 2H), 3.49-3.38 (m, 4H), 3.34 (s, 3H), 3.09 (d, J = 7.3 Hz, 2H), 3.02 (s, 1H), 2.88-2.76 (m, 1H), 2.17-1.97 (m, 3H), 1.89-1.73 (m, 4H), 1.70-1.63 (m, 2H), 1.39-1.39 (m, 1H).

[0221] Examples 2 to 31 can be produced by referring to all or part of the synthesis method of Example 1 and selecting corresponding raw materials. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0222] The nuclear magnetic data of the compounds prepared in the above examples are as follows: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0223] Example 32 Preparation of 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0224] First step: Synthesis of 2,7-dichloro-4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine 1-(Ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane (240 mg, 1.41 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (355 mg, 1.41 mmol) were dissolved in anhydrous dichloromethane (5 mL). N,N-Diisopropylethylamine (0.93 mL, 5.63 mmol) was slowly added under nitrogen gas protection at -40 °C, and the reaction was continued under nitrogen gas protection at -40 °C for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL * 2), washed with saturated aqueous sodium chloride (10 mL), and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give 2,7-dichloro-4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine (510 mg, 93.6% yield). ESI-MS: 386 [M+1] + .

[0225] Second step: Synthesis of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 2,7-Dichloro-4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine (510 mg, 1.32 mmol) was dissolved in ethanol (10 mL), and BOC anhydride (0.28 mL, 1.32 mmol) was added to the mixture. The mixture was reacted at 80°C for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated on a high-performance silica gel column to give tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 37.3% yield). ESI-MS: 486 [M+1] + .

[0226] Third step: Synthesis of tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.95 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (150 mg, 0.95 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Sodium tert-butoxide (181 mg, 1.89 mmol) was slowly added under nitrogen gas protection at 0 °C, and the reaction was continued under nitrogen gas protection at 0 °C for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 2), washed with saturated aqueous sodium chloride (10 mL), and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 46.87% yield). ESI-MS: 609 [M+1] + .

[0227] Fourth step: Synthesis of tert-butyl 1-(ethoxymethyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 0.44 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (272 mg, 0.53 mmol), and potassium phosphate (282 mg, 1.33 mmol) were dissolved in anhydrous dioxane (5 mL) and water (0.5 mL). Adamantane-based second-generation palladium catalyst (14.8 mg, 0.02 mmol) was slowly added under nitrogen gas protection at 25°C, and the reaction was continued for 1 hour at 85°C under nitrogen gas protection. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (10 mL*2), washed with saturated aqueous sodium chloride solution (10 mL), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was separated using a high-performance silica gel column to obtain tert-butyl ether. 1-(ethoxymethyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 79.9% yield). ESI-MS: 959 [M+1] + .

[0228] Fifth step: Synthesis of 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol tert-Butyl 1-(ethoxymethyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.35 mmol) was dissolved in acetonitrile (6 mL), and hydrochloric acid / dioxane (2 mL) was slowly added dropwise at 25°C. The mixture was allowed to react at 0°C for 1 hour. The solvent was removed by concentration under reduced pressure to give 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (280 mg, 96.9% yield). ESI-MS: 815 [M+1] + .

[0229] Sixth step: Synthesis of 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (280 mg, 0.344 mmol) was dissolved in DMF (10 mL) and cesium fluoride (2.61 g, 17.2 mmol) was added at 25 °C. The reaction was allowed to proceed for 1 hour at 25 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated using a reverse-phase column to give 4-(4-(1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (87 mg, yield 37.49%, purity 97.51%). ESI-MS: 659 [M+1] + .

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 10.25-10.09 (m, 1H), 9.03 (d, J = 3.3 Hz, 1H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.53-7.34 (m, 2H), 7.19 (s, 1H), 5.41-5.14 (m, 1H), 4.63-4.26 (m, 2H), 4.19-3.98 (m, 2H), 3.97-3.82 (m, 1H), 3.68-3.56 (m, 2H), 3.55-3.49 (m, 3H), 3.48 (s, 3H), 3.13-3.07 (m, 2H), 3.04-3.00 (m, 1H), 2.89-2.78 (m, 1H), 2.00 (s, 3H), 1.89-1.73 (m, 4H), 1.72-1.63 (m, 2H), 1.53-1.40 (m, 1H), 1.15 (dt, J = 3.7, 6.9 Hz, 3H).

[0231] Examples 33 to 35 can be produced by referring to all or part of the synthesis method of Example 32 and selecting corresponding raw materials. [Table 9]

[0232] The nuclear magnetic data of the compounds prepared in the above examples are as follows: [Table 10]

[0233] Example 36 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0234] First step: Synthesis of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (3 g, 10.7 mmol) was dissolved in N,N-dimethylacetamide (30 mL) and sodium methoxide in methanol (3.86 g, 21.4 mmol) was added. The mixture was stirred at 50 °C for 2 hours, the pH was adjusted to 3, water was added, and the mixture was filtered. The filter cake was collected and dried to give 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (2.69 g, 91.1% yield). ESI-MS: 276 [M+1] + .

[0235] Second step: Synthesis of 4,7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (900 mg, 3.26 mmol) was dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (3128 mg, 24.2 mmol) and phosphorus oxychloride (6580 mg, 42.9 mmol) were added. The mixture was stirred at 80 °C for 1 hour, and the reaction mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The remaining mixture was slowly poured into water, extracted with ethyl acetate and saturated sodium bicarbonate solution, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give 4,7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (900 mg, 93.7% yield). ESI-MS: 295 [M+1] + .

[0236] Third step: Synthesis of tert-butyl 3-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 4,7-Dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (900 mg, 3.06 mmol) was dissolved in dichloromethane (20 mL), and under nitrogen gas protection, tert-butyl 1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.31 mmol) and N,N-diisopropylethylamine (664 mg, 5.14 mmol) were added at -40 °C. The mixture was stirred at -40°C for 1 hour, extracted with water and dichloromethane, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was separated using a high-performance silica gel column to give tert-butyl 3-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (520 mg, 39.1% yield). ESI-MS 517 [M] +

[0237] Fourth step: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine tert-Butyl 3-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 0.812 mmol) was dissolved in dioxane (9 mL), and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (624 mg, 1.22 mmol), potassium phosphate (689 mg, 3.24 mmol), and 3 mL of water were added. Under nitrogen gas protection, [(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)palladium(II) chloride was added, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was then slowly poured into 20 mL of water, extracted with ethyl acetate (50 mL), and washed with saturated aqueous sodium chloride (30 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine (750 mg). ESI-MS: 867 [M+1] + .

[0238] 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 5.6, 8.9 Hz, 1H), 7.49 (d, J = 1.3 Hz, 1H), 7.37 (dd, J = 2.5, 18.6 Hz, 1H), 7.31-7.26 (m, 1H), 5.29 (d, J = 2.3 Hz, 2H), 4.96-4.64 (m, 1H), 4.43-4.29 (m, 1H), 4.03-3.87 (m, 4H), 3.77-3.69 (m, 1H), 3.61-3.49 (m, 5H), 3.25-3.06 (m, 1H), 2.60 (d, J = 3.8 Hz, 3H), 1.99-1.88 (m, 2H), 1.81-1.58 (m, 5H), 1.51 (s, 9H), 0.90-0.84 (m, 18H).

[0239] Fifth step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine (650 mg, 0.750 mmol) was dissolved in dichloromethane (5 mL), metachloroperbenzoic acid (0.40 mL, 1.12 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous magnesium sulfate. After that, it was concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to obtain tert-butyl ether. 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, crude product). ESI-MS: 883 [M+1] + .

[0240] Sixth step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.82 mmol) was dissolved in tetrahydrofuran (10 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (194 mg, 1.22 mmol) was added. Under the protection of nitrogen gas, lithium bis(trimethylsilyl)amide (0.98 mL, 0.98 mmol) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was slowly poured into 30 mL of water, extracted with ethyl acetate (80 mL), washed with saturated aqueous sodium chloride solution (30 mL), and the organic phase was dried over anhydrous magnesium sulfate. The organic phase was then concentrated under reduced pressure to remove the solvent. The residue was separated on a high-performance silica gel column to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (580 mL). mg, yield 52.2%). ESI-MS: 979 [M+1] + .

[0241] Seventh step: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.51 mmol) was dissolved in acetonitrile (3 mL) and hydrochloric acid / dioxane (3 mL, 4 M) was added. The reaction was stirred at 25°C for 1 hour, and then concentrated under reduced pressure to remove the solvent. The residue was 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (500 mg, 93.0% yield). The crude product was used directly in the next reaction. ESI-MS: 834 [M+1] + .

[0242] Eighth step: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.430 g, 0.52 mmol) was dissolved in N,N-dimethylformamide (15 mL) and cesium fluoride (15.7 g, 103 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour, filtered, and the organic phase was concentrated under reduced pressure to remove the solvent. The residue was separated using a reverse-phase column to obtain 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 26.2% yield, 95.44% purity). ESI-MS: 678 [M+1] + .

[0243] 1H NMR (400 MHz, DMSO-d6) δ 10.56-9.78 (m, 1H), 8.18-8.16 (m, 1H), 7.98 (dd, J = 5.9, 9.1 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 5.39-5.19 (m, 1H), 4.28-4.17 (m, 1H), 4.16-4.09 (m, 1H), 4.06-3.99 (m, 1H), 3.89 (d, J = 1.3 Hz, 3H), 3.54 (s, 2H), 3.42 (d, J = 4.9 Hz, 2H), 3.21 (d, J = 12.1 Hz, 2H), 3.09 (d, J = 6.5 Hz, 2H), 3.02 (s, 1H), 2.88-2.78 (m, 1H), 2.53 (s, 1H), 2.13 (s, 1H), 2.07-1.97 (m, 2H), 1.91-1.62 (m, 6H), 1.57-1.37 (m, 2H).

[0244] Examples 37 and 38 can be produced by referring to all or part of the synthesis method of Example 36 and selecting corresponding raw materials. [Table 11]

[0245] The nuclear magnetic data of the compounds prepared in the above examples are as follows: [Table 12]

[0246] Example 39 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0247] First step: Synthesis of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 3.57 mmol) was dissolved in anhydrous acetonitrile (10 mL), and N,N-diisopropylethylamine (2.36 mL, 14.3 mmol) and phosphorus oxychloride (0.67 mL, 7.14 mmol) were added. The mixture was reacted at 80 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.9 g, 84.1% yield). ESI-MS: 298 [M+1] + .

[0248] Second step: Synthesis of tert-butyl 3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.9 g, 3.0 mmol) and N,N-diisopropylethylamine (2.0 mL, 12.1 mmol) were dissolved in anhydrous acetonitrile (15 mL), and tert-butyl 1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 2.67 mmol) was added at -10 °C. The mixture was reacted at -10 °C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give tert-butyl 3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.78 g, 50% yield). ESI-MS: 521 [M+1] + .

[0249] Third step: Synthesis of tert-butyl 3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.53 g, 1.02 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (64 mg, 0.51 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). Potassium phosphate (647 mg, 3.05 mmol) and adamantane second-generation palladium catalyst (68 mg, 0.102 mmol) were added, and the mixture was heated at 100 °C for 3 h. LC-MS showed the reaction was complete. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride (50 mL), and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a high-performance silica gel column to give tert-butyl 3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (261 mg, 51.8% yield). ESI-MS: 501 [M+1] + .

[0250] Fourth step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.21 g, 0.42 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (322 mg, 0.63 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL) and water (3 mL). Potassium phosphate (356 mg, 1.68 mmol) and adamantane second-generation palladium catalyst (56 mg, 0.09 mmol) were added, and the mixture was reacted at 100 °C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride (50 mL), and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 29.2% yield). ESI-MS: 851 [M+1] + .

[0251] Fifth step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 0.123 mmol) was dissolved in anhydrous dichloromethane (10 mL), m-CPBA (32 mg, 0.186 mmol) was added, and the mixture was reacted at 25 °C for 3 hours. LC-MS showed the reaction was complete. 50 mL of water was poured into the reaction mixture, which was then extracted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent, yielding tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.1 g, 90.9% yield). ESI-MS: 867 [M+1] + .

[0252] Sixth step: Synthesis of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylsulfinyl(sulfinyl))pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.1 g, 0.115 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (24 mg, 0.15 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), and LHMDS (0.14 mL, 0.14 mmol) was added at 0 °C. The mixture was reacted at 0 °C for 1 hour. LC-MS showed the reaction was complete. 50 mL of water was poured into the reaction mixture, which was then extracted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent, yielding tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (106 mg, 95.5% yield). ESI-MS: 963 [M+1] + .

[0253] Seventh step: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), and a hydrochloric acid / 1,4-dioxane solution (3 mL, 4 M) was added. The mixture was reacted at 25° C. for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent and give 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (90 mg, crude product). ESI-MS: 818 [M+1] + .

[0254] Eighth step: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (90 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (6 mL) and cesium fluoride (3.34 g, 22 mmol) was added. The reaction was allowed to proceed at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated using a reverse-phase column to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (5 mg, yield 6.68%, purity 97.2%). ESI-MS: 662 [M+1] + .

[0255] 1 H NMR (400MHz, DMSO-d6) δ 10.14 (s, 1H), 8.05-7.92 (m, 1H), 7.51-7.35 (m, 2H), 7.23 (s, 1H), 5.41-5.17 (m, 1H), 4.23-3.95 (m, 2H), 3.75-3.47 (m, 3H), 3.47-3.40 (m, 2H), 3.36 (m, 3H), 3.15-2.97 (m, 3H), 2.84 (s, 1H), 2.68 (s, 1H), 2.34 (s, 2H), 2.19-1.93 (m, 4H), 1.78 (s, 4H), 1.72-1.48 (m, 1H), 1.43-1.19 (m, 1H), 0.86 (s, 1H).

[0256] Example 40 can be produced by referring to all or part of the synthesis method of Example 39 and selecting corresponding raw materials. [Table 13]

[0257] The nuclear magnetic data of the compounds prepared in the above examples are as follows: [Table 14]

[0258] Examples 41 and 42: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol and 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (1.9 g, 2.93 mmol) was subjected to chiral separation (Column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 um), Condition: 0.1% aqueous ammonia in IPA), to give Example 41 and Example 42, respectively.

[0259] Example 41, (663 mg, yield 34.3%), ESI-MS: 648[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.78 (dd, J = 6.0, 9.1, Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 7.19-7.06 (m, 2H), 5.37-5.17 (m, 1H), 4.57-4.29 (m, 2H), 4.12 (d, J = 10.4 Hz, 1 H), 3.99 (d, J = 10.4 Hz, 1 H), 3.88-3.74 (m, 1H), 3.63-3.51 (m, 5H), 3.14-2.97 (m, 3H), 2.87-2.75 (m, 1H), 2.13 (d, J = 3.6 Hz, 1H), 2.07-1.93 (m, 2H), 1.90-1.56 (m, 7H), 1.45 (d, J = 8.8 Hz, 1H).

[0260] Example 42, (767 mg, yield 39.5%), ESI-MS: 648[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.79 (dd, J = 6.1, 9.1 Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1 H), 7.11 (d, J = 2.3 Hz, 1H), 5.37-5.17 (m, 1H), 4.56-4.30 (m, 2H), 4.13-3.99 (m, 2H), 3.86-3.76 (m, 1H), 3.61-3.53 (m, 5H) 3.14-2.98 (m, 3H), 2.86-2.77 (m, 1H), 2.12 (s, 1H), 2.06-1.96 (m, 2H), 1.90-1.55 (m, 7H), 1.45 (d, J = 10.0 Hz, 1H).

[0261] Examples 43 and 44: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5S)-1-(methyl-d3)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5R)-1-(methyl-d3)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-(methyl-d3)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol was chiral separated (Column: DAICEL CHIRALPAK OX (250mm*50mm, 10 um), Condition: CO2 / MeOH (0.2% NH3) = 45 / 55) to give Example 43 and Example 44, respectively.

[0262] Example 43, ESI-MS:618[M+1] + . 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 5.28 (d, J = 52 Hz, 1H), 4.55 - 4.31 (m, 2H), 4.14 - 4.00 (m, 2H), 3.89 (d, J = 27.6 Hz, 1H), 3.64 - 3.36 (m, 6H), 3.13 - 3.06 (m, 2H), 3.01 (s, 1H), 2.86 - 2.77 (m, 1H), 2.14 - 1.95 (m, 4H), 1.88 - 1.40 (m, 7H).

[0263] Example 44, ESI-MS: 618 [M+1] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 2.7 Hz, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J = 2.9 Hz, 1H), 5.27 (d, J = 54.2 Hz, 1H), 4.57 - 4.28 (m, 2H), 4.19 - 3.97 (m, 2H), 3.89 (d, J = 28.9 Hz, 1H), 3.66 - 3.37 (m, 5H), 3.15 - 2.97 (m, 4H), 2.86 - 2.76 (m, 一1H), 2.19 - 1.93 (m, 4H), 1.88 - 1.39 (m, 7H).

[0264] Examples 45 and 46: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0265] Examples 45 and 46 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0266] Example 45: ESI-MS:645 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.96 (dd, J = 5.9, 9.2 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 5.38-5.17 (m, 1H), 4.57-4.28 (m, 2H), 4.15-4.00 (m, 2H), 3.95-3.84 (m, 1H), 3.67-3.49 (m, 3H), 3.49-3.38 (m, 5H), 3.13-2.99 (m, 3H), 2.87-2.78 (m, 1H), 2.15-1.95 (m, 3H), 1.91-1.58 (m, 7H), 1.46 (d, J = 8.8 Hz, 1H).

[0267] Example 46: ESI-MS:645 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 5.8, 9.0 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.21-7.16 (m, 1H), 5.37-5.17 (m, 1H), 4.58-4.29 (m, 2H), 4.14 (dd, J = 3.9, 10.4 Hz, 1H), 4.01 (dd, J = 3.3, 10.3 Hz, 1H), 3.96-3.86 (m, 1H), 3.65-3.51 (m, 2H), 3.49-3.37 (m, 5H), 3.14-2.99 (m, 3H), 2.87-2.78 (m, 1H), 2.13 (br s, 1H), 2.08-1.95 (m, 2H), 1.89-1.60 (m, 7H), 1.46 (d, J = 9.0 Hz, 1H).

[0268] Examples 47 and 48: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5R)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl-5-d)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5S)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl-5-d)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0269] Examples 47 and 48 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0270] Example 47: 1 H NMR (400 MHz, DMSO-d6) δ 10.22-10.07 (m, 1H), 9.01 (s, 1H), 7.95 (dd, J = 6.0, 9.1 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.19-7.13 (m, 1H), 5.43-5.14 (m, 1H), 4.56-4.26 (m, 2H), 4.12 (dd, J = 3.8, 10.4 Hz, 1H), 4.17-3.95 (m, 1H), 3.99 (dd, J = 3.2, 10.3 Hz, 1H), 3.93-3.81 (m, 1H), 3.64-3.48 (m, 1H), 3.46-3.42 (m, 1H), 3.41-3.35 (m, 2H), 3.13-2.96 (m, 3H), 2.86-2.74 (m, 1H), 2.13-1.94 (m, 3H), 1.89-1.57 (m, 7H), 1.51-1.35 (m, 1H).

[0271] Example 48: 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.1 Hz, 1H), 7.47 (t, J = 9.1 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 5.39-5.17 (m, 1H), 4.58-4.29 (m, 2H), 4.15-4.00 (m, 2H), 3.97-3.85 (m, 1H), 3.65-3.50 (m, 1H), 3.49-3.45 (m, 1H), 3.45-3.37 (m, 2H), 3.18-2.99 (m, 3H), 2.88-2.79 (m, 1H), 2.16-1.98 (m, 3H), 1.93-1.55 (m, 7H), 1.51-1.42 (m, 1H).

[0272] Examples 49 and 50: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-((1S,5R)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-((1R,5S)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0273] Examples 49 and 50 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0274] Example 49: 11H NMR (400 MHz, DMSO-d6) δ 10.47 - 9.89 (m, 1H), 7.98 (dd, J = 5.9, 9.1 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.23 (t, J = 2.9 Hz, 1H), 5.36 - 5.20 (m, 1H), 4.26 - 4.18 (m, 1H), 4.12 - 4.08 (m, 1H), 4.05 - 4.02 (m, 1H), 3.89 (s, 3H), 3.09 (d, J = 5.0 Hz, 3H), 3.01 (s, 1H), 2.88 - 2.78 (m, 2H), 2.51 (s, 3H), 2.12 (s, 1H), 2.06 - 1.97 (m, 3H), 1.85 - 1.65 (m, 7H), 1.42 (d, J = 12.1 Hz, 2H).

[0275] Example 50: 1 1H NMR (400 MHz, DMSO-d6) δ 11.45 - 9.14 (m, 1H), 7.97 (dd, J = 6.1, 8.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.28 - 7.19 (m, 1H), 5.36 - 5.20 (m, 1H), 4.20 (d, J = 16.4 Hz, 1H), 4.14 (d, J = 10.4 Hz, 1H), 3.99 (dd, J = 2.6, 10.3 Hz, 1H), 3.89 (s, 3H), 3.52 (s, 2H), 3.08 (d, J = 6.9 Hz, 3H), 3.01 (s, 1H), 2.86 - 2.79 (m, 1H), 2.51 (s, 2H), 2.13 - 1.96 (m, 4H), 1.87 - 1.63 (m, 7H), 1.47 - 1.35 (m, 2H).

[0276] Examples 51 and 52: 4-(5-ethoxy-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5R)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- Preparation of 4-(5-ethoxy-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5S)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0277] Examples 51 and 52 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0278] Example 51: 11H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.01 - 7.94 (m, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.22 (s, 1H), 5.39 - 5.16 (m, 1H), 4.48 - 4.26 (m, 2H), 4.13 - 4.07 (m, 1H), 4.06 - 4.01 (m, 1H), 3.90 - 3.76 (m, 1H), 3.52 (s, 1H), 3.45 - 3.39 (m, 4H), 3.32 - 3.31 (m, 1H), 3.09 (d, J = 4.4 Hz, 2H), 3.04 - 3.00 (m, 1H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.12 (s, 1H), 2.07 - 1.97 (m, 2H), 1.89 - 1.74 (m, 3H), 1.72 - 1.46 (m, 3H), 1.42 - 1.29 (m, 5H).

[0279] Example 52: 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 2.4, 4.9 Hz, 1H), 5.38-5.18 (m, 1H), 4.50-4.26 (m, 2H), 4.14 (d, J = 10.4 Hz, 1H), 3.99 (dd, J = 3.3, 10.3 Hz, 1H), 3.90-3.75 (m, 1H), 3.52 (s, 1H), 3.45-3.39 (m, 3H), 3.30-3.25 (m, 2H), 3.09 (d, J = 6.5 Hz, 2H), 3.01 (s, 1H), 2.88-2.79 (m, 1H), 2.12 (s, 1H), 2.09-2.07 (m, 1H), 2.09-2.03 (m, 1H), 1.99 (br s, 1H), 1.90-1.75 (m, 3H), 1.72-1.57 (m, 2H), 1.51 (s, 1H), 1.43-1.28 (m, 5H).

[0280] Examples 53 and 54: Preparation of 4-(4-((1S,5R)-1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0281] Examples 53 and 54 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0282] Example 53: 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1 H), 7.76 (dd, J = 5.9, 9.2 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 7.11 (d, J = 9.9 Hz, 2H), 5.44-5.14 (m, 1H), 4.54-4.24 (m, 2H), 4.17-4.00 (m, 2H), 3.80 (d, J = 15.9 Hz, 2H), 3.58-3.53 (m, 2H), 3.34-3.29 (m, 1H), 3.09 (d, J = 8.4 Hz, 2H), 3.01 (s, 1H), 2.90-2.75 (m, 1H), 2.16-2.11 (m, 1H), 2.07-1.98 (m, 2H), 1.88-1.74 (m, 4H), 1.68-1.53 ​​(m, 4H), 1.33 (d, J = 7.3 Hz, 1H), 0.94 (dt, J = 3.5, 7.5 Hz, 3H).

[0283] Example 54: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.80 (dd, J = 6.1, 9.1 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.12 (t, J = 2.6 Hz, 1H), 5.38-5.16 (m, 1H), 4.53-4.27 (m, 2H), 4.13 (dd, J = 2.1, 10.2 Hz, 1H), 4.01 (d, J = 10.3 Hz, 1H), 3.82 (d, J = 19.1 Hz, 1H), 3.63-3.51 (m, 2H), 3.31 (t, J = 12.9 Hz, 2H), 3.11-2.99 (m, 3H), 2.88-2.75 (m, 1H), 2.19-1.96 (m, 3H), 1.90-1.50 (m, 8H), 1.34 (dd, J = 6.2, 11.2 Hz, 1H), 0.94 (dt, J = 3.7, 7.5 Hz, 3H).

[0284] Examples 55 and 56: 5-ethynyl-6-fluoro-4-(8-fluoro-4-((1R,5R)-1-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((1S,5S)-1-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0285] Examples 55 and 56 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0286] Example 55: 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.99-7.95 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 (s, 1H), 7.19 (s, 1H), 5.35-5.21 (m, 1H), 4.73 (d, J = 4.6 Hz, 1H), 4.62-4.57 (m, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.31 (d, J = 11.9 Hz, 1H), 4.16-4.09 (m, 2H), 4.08-4.01 (m, 2H), 3.90 (d, J = 16.3 Hz, 2H), 3.57 (s, 3H), 3.10-3.03 (m, 3H), 2.83 (d, J = 6.6 Hz, 1H), 2.05 (s, 5H), 1.77 (s, 7H), 分 1.46 (s, 1H).

[0287] Example 56: 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.0 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.18 (s, 1H), 分 5.36-5.20 (m, 1H), 4.73 (dd, J = 3.1, 6.4 Hz, 1H), 4.65-4.59 (m, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 11.4 Hz, 1H), 4.14 (dd, J = 5.0, 10.2 Hz, 2H), 4.02 (dd, J = 4.4, 10.3 Hz, 2H), 3.91 (d, J = 17.9 Hz, 分 2H), 3.61-3.53 (m, 3H), 3.09 (d, J = 9.3 Hz, 2H), 3.02 (s, 1H), 2.83 (d, J = 6.5 Hz, 1H), 2.12-1.96 (m, <5H), 1.83-1.63 (m, 7H), 1.45 (d, J = 4.9 Hz, 1H). It should be noted that there seems to be some unclear or incorrect notations in the original text (such as "分" in the translated content), which may need to be further verified in the original source to ensure accurate translation.

[0288] Examples 57 and 58: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5R)-1-vinyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol and 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5S)-1-vinyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0289] Examples 57 and 58 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0290] Example 57: 11H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.93 (dd, J = 6.1, 9.1 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.09 (dd, J = 10.9, 17.5 Hz, 1H), 5.41-5.31 (m, 1H), 5.30-5.12 (m, 2H), 4.56 (d, J = 12.0 Hz, 1H), 4.44 (br dd, J = 6.1, 11.4 Hz, 1H), 4.33 (d, J = 11.9 Hz, 1H), 4.15 (dd, J = 3.1, 10.4 Hz, 1H), 4.03 (d, J = 10.4 Hz, 1H), 3.90 (d, J = 10.0 Hz, 1H), 3.69-3.54 (m, 2H), 3.09 (d, J = 10.1 Hz, 2H), 3.02 (s, 1H), 2.91-2.77 (m, 1H), 2.68 (s, 1H), 2.20-2.11 (m, 1H), 2.09-1.98 (m, 2H), 1.94-1.60 (m, 7H), 1.48 (t, J = 10.6 Hz, 1H), 1.04 (d, J = 6.1 Hz, 1H).

[0291] Example 58: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.93 (dd, J = 6.1, 9.1 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.17 (s, 1H), 6.09 (dd, J = 10.9, 17.6 Hz, 1H), 5.38-5.31 (m, 1H), 5.30-5.12 (m, 2H), 4.55 (d, J = 12.6 Hz, 1H), 4.49-4.39 (m, 1H), 4.31 (s, 1H), 4.17-4.09 (m, 1H), 4.08-4.00 (m, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.68-3.54 (m, 2H), 3.09 (d, J = 9.5 Hz, 2H), 3.02 (s, 1H), 2.83 (d, J = 6.4 Hz, 1H), 2.68 (s, 1H), 2.14 (d, J = 4.8 Hz, 1H), 2.07-1.99 (m, 2H), 1.91-1.61 (m, 7H), 1.53-1.44 (m, 1H).

[0292] Examples 59 and 60: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5R)-1-((Z)-2-fluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5S)-1-((Z)-2-fluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0293] Examples 59 and 60 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0294] Example 59: 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.03 (d, J = 0.7 Hz, 1H), 7.98 (dd, J = 6.0, 9.2 Hz, 1H), 7.51-7.36 (m, 2H), 7.19 (dd, J = 2.5, 7.2 Hz, 1H), 6.89-6.59 (m, 1H), 5.40-5.00 (m, 2H), 4.83-4.56 (m, 1H), 4.46-4.19 (m, 1H), 4.15 (dd, J = 5.5, 10.4 Hz, 1H), 4.03 (dd, J = 6.5, 10.3 Hz, 1H), 3.97-3.81 (m, 1H), 3.71-3.39 (m, 4H), 3.14 (d, J = 2.7 Hz, 2H), 3.02 (s, 1H), 2.88-2.79 (m, 1H), 2.19-2.04 (m, 3H), 1.99 (s, 1H), 1.89-1.74 (m, 4H), 1.70-1.56 (m, 2H).

[0295] Example 60: 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.04(s, 1H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.53-7.36 (m, 2H), 7.25-7.15 (m, 1H), 6.91-6.62 (m, 1H), 5.33-5.09 (m, 1H), 4.81-4.58 (m, 1H), 4.54 (t, J = 6.9 Hz, 1H), 4.33-4.19 (m, 1H), 4.17-4.04 (m, 2H), 3.98-3.80 (m, 1H), 3.73-3.55 (m, 3H), 3.12 (d, J = 5.5 Hz, 2H), 3.06-3.01 (m, 1H), 2.92-2.77 (m, 1H), 2.18-2.05 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.74 (m, 4H), 1.70-1.57 (m, 2H).

[0296] Examples 61 and 62: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1R,5R)-1-((E)-2-fluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1S,5S)-1-((E)-2-fluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka]

[0297] Examples 61 and 62 can be produced by selecting appropriate conditions with reference to the methods of Examples 41 and 42.

[0298] Example 61: 1 1H NMR (400 MHz, DMSO-d6) δ10.18 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 6.0, 9.2 Hz, 1H), 7.55 - 7.35 (m, 2H), 7.19 (t, J = 2.8 Hz, 1H), 7.13 (dd, J = 2.6, 11.3 Hz, 1H), 5.86 - 5.68 (m, 1H), 5.40 - 5.17 (m, 1H), 4.57 - 4.28 (m, 2H), 4.19 - 3.88 (m, 3H), 3.65 - 3.53 (m, 2H), 3.13 - 3.00 (m, 3H), 2.89 - 2.78 (m, 2H), 2.16 - 2.05 (m, 2H), 2.01 (s, 1H), 1.92 - 1.81 (m, 3H), 1.81 - 1.71 (m, 3H), 1.51 (d, J = 4.3 Hz, 2H).

[0299] Example 62: 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1 H), 9.06 (d, J = 2.2 Hz, 1 H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.56 - 7.35 (m, 2H), 7.26 - 7.05 (m, 2H), 6.92 (dd, J = 2.6, 11.3 Hz,1H), 5.87 - 5.69 (m, 1H), 5.40 - 5.14 (m, 1H), 4.57 - 4.27 (m, 2H), 4.15 - 4.01 (m, 2H), 3.94 (dd, J = 0.7, 2.7 Hz, 1H), 3.66 - 3.51 (m, 2H), 3.09 (d, J = 8.1 Hz, 2H), 3.02 (s, 1H), 2.83 (d, J = 6.2 Hz, 1H), 2.16 - 2.11 (m, 1H), 2.08 - 1.98 (m, 2H), 1.91 - 1.75 (m, 6H), 1.72 - 1.61 (m, 1 H), 1.57 - 1.44 (m, 1H).

[0300] Biological Measurement and Evaluation 1.KRAS G12D / cRAF binding assay 1. Compound production Compounds were dissolved in 100% DMSO at a starting concentration of 5 mM and diluted 3-fold into DMSO for a total of eight concentration points. 1 μL of compound or DMSO from each concentration point was added to 99 μL of experimental buffer to give a 10X stock solution.

[0301] 2. Test procedure 1) 4 μL of His-tagged KRAS in a 384-well plate G12D and the working mixture solution of GMPPNP was added. 2) 10X compound stock solution or 1% DMSO was added to a 384-well plate. 3) The plate was centrifuged at 1000 rpm for 1 minute. 4) 4 μL of GST-tagged cRAF solution was added to a 384-well plate. 5) The plate was centrifuged at 1000 rpm for 1 minute. 6) The plate was incubated at room temperature for 15 minutes. 7) 10 μL of detection working solution was added to a 384-well plate. 8) The plate was centrifuged at 1000 rpm for 1 minute. 9) The plate was incubated at room temperature for 60 minutes. 10) The 384-well plate was placed in Envision and measurement data was acquired.

[0302] 3. Data processing Ratios were calculated for each compound concentration based on the DMSO control signal and the Alphalisa signal in each compound well. A four-parameter log dose-response equation was used to calculate the 50% (IC) concentration of the test compound versus the ratio. 50 As a quality control measure, the endpoint value (IC) of a reference compound was measured in each experiment. 50 ) was evaluated. If the endpoint value was within three times the expected value, the experiment was considered successful.

[0303] [Table 15]

[0304] The "positive compound" used in the biological test evaluation of this application is Example 252 in WO2021041671A1 (the positive compound used in the following antiproliferative 2D CTG test and mouse pharmacokinetic experiment is the same), and its chemical structure is as follows: [ka]

[0305] II. Antiproliferative 2D CTG test 1. Experimental procedure: 1.1 Day 0: Laying the plate When the cells reached approximately 80% confluence, they were detached with 0.25% trypsin. The detached cells were resuspended in 5 mL of fresh cell culture medium and centrifuged to collect the cells. The cell count was then calculated. The cells were then suspended in medium-concentration medium. The cells were plated in a 96-well plate at 1,000 cells / well for AGS and 1,000 cells / well for GP2D. The 96-well plate was placed in a 37°C incubator and incubated overnight.

[0306] 1.2 Day 1 Compound treatment A 10-point serial dilution was performed at a 1:5 ratio from a 10 mM stock solution. 10X compound-containing medium was transferred to the corresponding wells of a 96-well plate. The final peak compound concentration was 10 μM, and the final DMSO concentration was 0.1%. The 96-well plate was placed in a 37°C incubator and incubated for 3 days for AGS cells and 4 days for GP2D cells.

[0307] 1.3 Day 4 Baseline reading 1.4 Reading signals 50 μL / well of detection reagent (CTG) was added to the AGS cells and the signal was read on the Envision instrument.

[0308] 1.5 Day 5: Reading the signal 50 μL / well of detection reagent (CTG) was added to the GP2D cells and the signal was read on the Envision instrument.

[0309] 2. Data processing Percent inhibition (%) at each compound concentration was calculated based on the signals from the HPE and ZPE control wells and the fluorescence signal from each compound well contained in each assay plate. ZPE control wells containing enzyme and substrate had 0% inhibition, while HPE control wells containing substrate only had 100% inhibition. A four-parameter log dose-response equation was used to calculate the 50% (IC) inhibition value from the test compound concentration and percent inhibition value. 50 As a quality control measure, the endpoint value (IC) of a reference compound was measured in each experiment. 50 ) was evaluated. If the endpoint value was within three times the expected value, the experiment was considered successful.

[0310] [Table 16]

[0311] From the activity data of the compounds in the specific examples, it can be seen that a series of compounds of the present invention have strong inhibitory effects on KRAS cell activity. Under the same test conditions, the cell inhibitory activity of some example compounds is comparable to or even improved to some extent compared with positive compounds.

[0312] 3. Pharmacokinetics experiments in mice 1. Test Drug The compounds used in this study were derived from specific example compounds of the present invention.

[0313] 2. Test animals ICR mice, male, N=3. Source: Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.

[0314] 3. Drug preparation and administration Single oral (PO) administration to ICR mice: Compounds were weighed and added to a 0.5% CMC + 1% Tween 80 solvent, followed by shaking and sonication to obtain a pale yellow suspension. Three mice were fasted overnight and then orally administered with a 10 mg / kg dose.

[0315] Single intravenous (IV) injection to ICR mice: Compounds were weighed and added to 20% HP-β-CD in 50 mM pH 4.7 acetate buffer, followed by shaking and sonication to obtain a pale yellow suspension. After overnight fasting, three mice were administered IV at a dose of 2 mg / kg via tail vein injection.

[0316] 4. Sample Collection: Approximately 90 μL of blood was collected from the orbit at each time point, anticoagulated with sodium heparin, placed on ice, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). The collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a refrigerator at -20°C.

[0317] A 40 μL plasma sample was added to 160 μL of ice-cold acetonitrile containing an internal standard, vortexed for 1 minute, and centrifuged at 18,000 rpm for 10 minutes. The supernatant was transferred to a 96-well plate, and 5 μL was injected into an LC-MS / MS for analysis.

[0318] [Table 17]

[0319] From the pharmacokinetic data of the compounds of the above specific examples, it can be seen that a series of compounds of the present invention can be absorbed into mouse body by IV or oral absorption, and have very good PK data.Compared with positive compounds, the IV and oral AUC of a series of compounds of the present invention are significantly improved, especially the oral AUC of some example compounds is improved by more than ten times, even several tens of times, and has obviously improved bioavailability.Through testing, it has been proved that a series of compounds of the present invention has very good development prospects, and it is expected to solve the problem that positive compounds cannot be administered orally, and can only be administered by IV.

[0320] All documents related to the present invention are incorporated by reference in this application as if each document were individually incorporated by reference. Furthermore, after reading the above disclosure of the present invention, one skilled in the art will be able to make various variations and modifications to the present invention, and it will be understood that equivalents thereof are also within the scope of the claims of the present invention. Furthermore, the present invention includes the following aspects. [Aspect 1] Formula (I): [ka] [Wherein: R is hydrogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, -C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-8 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, said groups independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Each R 2 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 3 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 4 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5a represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; R 5b 、R 5c and R 5d are independently hydrogen, deuterium, halogen, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-NH-S(O) 2 R 13 、-C 0-8 Alkyl-NH-S(O) 2 NR 16 R 17 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-S(O) r NR 16 R 17 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium or halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-10 forming a cycloalkyl group or a 3- to 10-membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-10 Alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, ═O, ═S, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O) 2 R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 ) 2 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 and R 5d is defined as above, Or R 5b and R 5c together with the carbon atoms directly connected to them

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Claims

1. Formula (II): 【Chemistry 1】 [In the formula: R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 2a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 2b is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 2c is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 2d is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 2e is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 3 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 5a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-NH-S(O) 2 R 13 , -C 0-4 Alkyl-NH-S(O) 2 NR 16 R 17 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-S(O) r NR 16 R 17 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 and R 5d is defined as above, Or R 5b and R 5c together with the carbon atoms directly connected to them 【Chemistry 2】 R 5d is as defined above, or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them 【Transformation 3】 It forms R 5e , R 5f and R 5g are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -NR 16 R 17 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 6a , R 6b , R 6c and R 6d are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R 6a and R 6b , R 6c and R 6d are one C together with the carbon atom directly connected to them. 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 7 and R 8 are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R 7 and R 8 are one C together with the carbon atom directly connected to them. 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 9a , R 9b , R 9c , R 9d and R 9e are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 or R 9d and R 9e are one C together with the carbon atom directly connected to them. 3-6 a cycloalkyl group and a 3- to 6-membered heterocyclic group, the other three being as defined above, 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group may independently optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; each R 10 is independently selected from the group consisting of hydrogen, deuterium, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C 6-8 aryl group, a 5- to 8-membered heteroaryl group, —C 0-4 alkyl-S(O) r R 13 , —C 0-4 alkyl-C(O)OR 14 , —C 0-4 alkyl-C(O)R 15 and —C 0-4 alkyl-C(O)NR 16 R 17 , which groups may optionally be further selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, halogen-substituted C 1-4 alkyl group, deuterium-substituted C 1-4 alkyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, a C6-8 aryl group, a 5- to 8-membered heteroaryl group, —C0-4 alkyl-S(O)rR13, —C0-4 alkyl-OR14, —C0-4 alkyl-C(O)OR14, —C0-4 alkyl-C(O)R15, —C0-4 alkyl-OC(O)R15, —C0-4 alkyl-NR16R17, —C0-4 alkyl-C(═NR16)R15, —C0-4 alkyl-N(R16)-C(═NR17)R15, —C0-4 alkyl-C(O)NR16R17 and —C0-4 alkyl-N(R16)-C(O)R 15, optionally substituted by one or more substituents selected from the group consisting of each R 11 and R 12 is independently selected from the group consisting of hydrogen, deuterium, a hydroxy group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C 6-8 aryl group, and a 5- to 8-membered heteroaryl group; or R 11 and R 12 together with the sulfur atom to which they are directly linked form a 3- to 6-membered heterocyclic group, which optionally further comprises deuterium, a halogen, a cyano group, a nitro group, an azido group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halogen-substituted C 1-4 alkyl group, a deuterium-substituted C 1-4 alkyl group, a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C 6-8 aryl group, a 5- to 8-membered heteroaryl group, -C 0-4 optionally substituted by one or more substituents selected from the group consisting of alkyl-S(O)rR13, -C0-4alkyl-OR14, -C0-4alkyl-C(O)OR14, -C0-4alkyl-C(O)R15, -C0-4alkyl-OC(O)R15, -C0-4alkyl-NR16R17, -C0-4alkyl-C(=NR16)R15, -C0-4alkyl-N(R16)-C(=NR17)R15, -C0-4alkyl-C(O)NR16R17 and -C0-4alkyl-N(R16)-C(O)R15; each R13 is independently selected from the group consisting of hydrogen, deuterium, a hydroxy group, a C1-4 alkyl group, a C2-4 alkenyl group, a C3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C6-8 aryl group, a 5- to 8-membered heteroaryl group, and -NR16R17, which groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, a halogen, a hydroxy group, =O, a C1-4 alkyl group, a C1-4 alkoxy group, a C3-6 cycloalkyl group, a C3-6 cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclic oxy group, a C6-8 aryl group, a C6-8 aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, and -NR16R17; each R14 is independently selected from the group consisting of hydrogen, deuterium, a C1-4 alkyl group, a C2-4 alkenyl group, a C3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C6-8 aryl group, and a 5- to 8-membered heteroaryl group, which groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy group, =O, cyano group, a C1-4 alkyl group, a C1-4 alkoxy group, a C3-6 cycloalkyl group, a C3-6 cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclic oxy group, a C6-8 aryl group, a C6-8 aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, and -NR16R17; each R 15 is independently selected from the group consisting of hydrogen, deuterium, a hydroxy group, a C 1-4 alkyl group, a C 1-4 alkoxy group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclyloxy group, a C 6-8 aryl group, a C 6-8 aryloxy group, a 5-8 membered heteroaryl group, a 5-8 membered heteroaryloxy group and -NR 16 R 17 , which groups are independently optionally further selected from deuterium, halogen, hydroxy group, ═O, a cyano group, a C 1-4 alkyl group, a C 1-4 alkoxy group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclyloxy group, a C 6-8 aryl group, a C 6-8 optionally substituted by one or more substituents selected from the group consisting of an aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, and —NR 16 R 17 ; each R 16 and R 17 is independently selected from the group consisting of hydrogen, deuterium, a hydroxy group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C 6-8 aryl group, a 5- to 8-membered heteroaryl group, a sulfinyl group, a sulfonyl group, a methylsulfonyl group, an isopropylsulfonyl group, a cyclopropylsulfonyl group, a p-toluenesulfonyl group, an aminosulfonyl group, a dimethylaminosulfonyl group, and a C 1-4 alkanoyl group, which groups are independently optionally further selected from the group consisting of deuterium, a halogen, a hydroxy group, ═O, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halogen-substituted C 1-4 alkyl group, a deuterium-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a C 3-6 cycloalkyl group, a C 3-6 optionally substituted by one or more substituents selected from the group consisting of a cycloalkoxy group, a 3- to 6-membered heterocyclic group, a 3- to 6-membered heterocyclyloxy group, a C6-8 aryl group, a C6-8 aryloxy group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryloxy group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group and a C1-4 alkanoyl group; Alternatively, R 16 and R 17 together with the nitrogen atom directly bonded thereto form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group, and the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group optionally further contains deuterium, halogen, a hydroxy group, ═O, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halogen-substituted C 1-4 alkyl group, a deuterium-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclyloxy group, a C 6-8 aryl group, a C 6-8 aryloxy group, a 5-8 membered heteroaryl group, a 5-8 membered heteroaryloxy group, an amino group, a mono-C 1-4 alkylamino group, a di-C 1-4 alkylamino group, and a C 1-4 and optionally substituted with one or more substituents selected from the group consisting of alkanoyl groups. each r is independently 0, 1, or 2. A compound represented by the formula:

2. The compound of formula (II) is a compound of formula (III): 【Chemistry 4】 [In the formula: R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 6-membered heterocyclic groups; R 2a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2c is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2d is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 2e is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 3 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 and -SR 13 selected from the group consisting of R 4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R 5a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5b and R 5c are independently hydrogen, deuterium, halogen, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, =S, -SF 5 , -S(O) r R 13 and-OR 14 may be substituted by one or more substituents selected from the group consisting of R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-NH-S(O) 2 R 13 , -C 0-4 Alkyl-NH-S(O) 2 NR 16 R 17 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-S(O) r NR 16 R 17 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, =S, -SF 5 , -S(O) r R 13 and-OR 14 and R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c together with the carbon atoms directly connected to them 【Transformation 5】 R 5d are hydrogen, deuterium, halogens, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 wherein said groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them 【Transformation 6】 It forms R 5e , R 5f and R 5g are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 7 and R 8 are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 R is selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 7 and R 8 are one C together with the carbon atom directly connected to them. 3-6 forming cycloalkyl groups and 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 9a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined in claim 1.

2. The compound of formula (II) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the formula (II):

3. R 5b and R 5c are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5d However, hydrogen, deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, 5-8 membered heteroaryl groups, -NH-S(O) 2 R 13 , -NH-S(O) 2 NR 16 R 17 , -S(O) r R 13 , -S(O) r NR 16 R 17 , -OR 14 , -C(O)OR 14 , -C(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)R 15 and -C(O)NR 16 R 17 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c However, together with the carbon atoms directly connected to them, one C(O), C 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, said groups independently optionally further containing deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 and R is optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, ═O, ═S, methylthio, ethylthio, methoxy, ethoxy, and isopropoxy, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; 5d is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, and isopropoxy; Or R 5b and R 5c together with the carbon atoms directly connected to them 【Transformation 7】 It forms R 5d is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; Or R 5b , R 5c and R 5d together with the carbon atoms directly connected to them 【Transformation 8】 It forms R 5e , R 5f and R 5g are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, and monodeuteromethyl; where R 13 , R 14 , R 15 , R 16 , R 17 3. The compound of formula (II) according to claim 2, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: and r is as defined in claim 2.

4. R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy.

5. R is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, or -C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined in claim 2, a compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof.

6. R 1 is selected from the group consisting of hydrogen, deuterium, fluorine and a methyl group; R 2a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2c is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2d is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 2e is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; R 3 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio.

7. R 4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino.

8. R 7 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; R 9a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

9. The compound of formula (II) is represented by formula (IV-a): 【Chemistry 9】 [In the formula: R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R 5a are hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5b and R 5c are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, said groups independently optionally further comprising deuterium, halogen, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 may be substituted by one or more substituents selected from the group consisting of R 5d1 are hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 cycloalkyl groups or 3-6 membered heterocyclic groups, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c are one C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, and -OR 14 and R 5d1 are hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; where R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined in claim 1.

2. The compound of formula (II) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the formula (II):

10. R is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, oxetanyl group, azetidinyl group, or -C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 10. The compound of formula (II) according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: and r is as defined in claim 9.

11. R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and -C(O)OR 14 , which may independently be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and -OC(O)R 15 ; The compound of formula (II) according to claim 9, its stereoisomer or its pharmaceutically acceptable salt, characterized in that R 14 and R 15 are as defined in claim 9.

12. R 4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino.

13. A compound of formula (II) according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R 4 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino and dimethylamino.

14. R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy.

15. A compound of formula (II) according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R 5a is selected from the group consisting of hydrogen, deuterium, cyano group, hydroxy group, methyl group, ethyl group, propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, trideuteromethyl group, dideuteromethyl group, monodeuteromethyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, trifluoromethoxy group, difluoromethoxy group, trideuteromethoxy group, dideuteromethoxy group, trifluoroethoxy group and trideuteroethoxy group.

16. R 5b and R 5c are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5d1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which groups are independently optionally further selected from the group consisting of deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, ═O, ═S, —S(O) r R 13 and-OR 14 wherein said groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; Or R 5b and R 5c However, together with the carbon atoms directly connected to them, one C 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, said groups independently optionally further containing deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 and R is optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, ═O, ═S, methylthio, ethylthio, methoxy, ethoxy, and isopropoxy, which groups are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; 5d1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; where R 13 , R 14 10. The compound of formula (II) according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: and r is as defined in claim 9.

17. R 5b and R 5c are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, and trideuteroethoxy; 10. The compound of formula (II) according to claim 9, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R 5d1 is a methyl group, an ethyl group, an isopropyl group or a trideuteromethyl group.

18. The compound of formula (II) is represented by formula (IV-b): 【Chemistry 10】 [In the formula: R is hydrogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, ═S, -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 may be substituted by one or more substituents selected from the group consisting of R 4 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -OR 14 , -SR 13 and -NR 16 R 17 selected from the group consisting of R 5a are hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups and -C 0-4 Alkyl-OR 14 selected from the group consisting of R 5h is selected from the group consisting of the following groups 1), 2) and 3): 1) is 【Chemistry 11】 and R 5e and R 5f are independently hydrogen, deuterium, halogen and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups being independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; 2) is 【Chemistry 12】 and R 5g is hydrogen, deuterium, halogen and C 1-4 alkyl groups, which groups may independently optionally further comprise deuterium, halogen, cyano groups, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 and optionally substituted with one or more substituents selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups, said groups independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; 3) is C 1-4 Alkyl group, C 3-6 is a cycloalkyl group or a 3- to 6-membered heterocyclic group, 1-4 The alkyl groups may independently optionally further comprise deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, =S, -SF 5 , -S(O) r R 13 and-OR 14 and wherein R 5h But, -OR 14 Substituted methyl group, C 3-6 provided that it is not a cycloalkyl group or a 3- to 6-membered heterocyclic group; where R 13 , R 14 , R 15 , R 16 , R 17 and r is as defined in claim 1.

2. The compound of formula (II) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the formula (II):

19. The compound of formula (II) is represented by formula (IV-b1): 【Chemistry 13】 [In the formula: R is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, or -C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R 4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5e and R 5f are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, and isopropyl, which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, and chlorine; where R 14 is as defined in claim 18] 19. The compound of formula (II) according to claim 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by the formula (II):

20. A compound of formula (II) according to claim 18, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R is hydrogen, R 4 is hydrogen, R 5a is hydrogen, and R 5e and R 5f are each independently selected from the group consisting of hydrogen, fluorine and a methyl group.

21. The compound of formula (II) is represented by formula (IV-b2): 【Chemistry 14】 [In the formula: R is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, or -C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R 4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5g is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, and isopropyl, which may independently and optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, which may independently and optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, and chlorine; where R 14 is as defined in claim 18] 19. The compound of formula (II) according to claim 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by the formula (II):

22. A compound of formula (II) according to claim 18, its stereoisomer or its pharmaceutically acceptable salt, characterized in that R is hydrogen, R 4 is hydrogen, R 5a is hydrogen and R 5g is selected from the group consisting of hydrogen, fluorine and a methyl group.

23. The compound of formula (II) is represented by formula (IV-b3): 【Chemistry 15】 [In the formula: R is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, or -C(O)OR 14 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R 4 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; R 5a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, and cyclobutoxy; R 5h1 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, or an azetidinyl group, which groups independently optionally further contain deuterium, halogen, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, =S, -SF 5 , -S(O) r R 13 and-OR 14 and wherein R 5h1 But, -OR 14 provided that the group is not a substituted methyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, or an azetidinyl group; where R 13 , R 14 and r is as defined in claim 18.

19. The compound of formula (II) according to claim 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by the formula (II):

24. R is hydrogen, R 4 is hydrogen, a methyl group, an ethyl group, a methoxy group, or a methylthio group, R 5a is hydrogen or deuterium, R 5h1 is a methyl group, an ethyl group, a propyl group, or an isopropyl group, which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, ═O, ═S, —SF 5 , —S(O) r R 13 , and —OR 14 , which are independently and optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen, provided that R 5h1 is not an —OR 14 substituted methyl group; 19. The compound of formula (II) according to claim 18, its stereoisomer or its pharmaceutically acceptable salt, characterized in that R 13 , R 14 and r are as defined in claim 18. 【Request Item 25】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 2. The compound of formula (II) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

26. 26. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1 to 25, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. 27. The pharmaceutical composition of claim 26 for treating and / or preventing cancers or tumors associated with KRas G12D.

28. KRas G12D-related sarcomas, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchial carcinoma, pulmonary foam carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder and urethral cancer, prostate cancer, testicular cancer, liver cancer, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, bile duct carcinoma, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma 27. The pharmaceutical composition according to claim 26, for preventing and / or treating malignant giant cell tumor, chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, skull cancer, meningeal cancer, brain cancer, uterine cancer, vulvar cancer, vaginal cancer, fallopian tube cancer, blood cancer, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, birthmark, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis and adrenal tumor, neuroblastoma.

29. The sarcoma is angiosarcoma, fibrosarcoma, rhabdomyosarcoma, or liposarcoma; The bronchogenic carcinoma is squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, or adenocarcinoma; Bubonic pulmonary carcinoma is bronchiolar carcinoma; The esophageal cancer is squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, or lymphoma; The gastric cancer is lymphoma or leiomyosarcoma; the pancreatic cancer is ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, or vasoactive intestinal polypeptide tumor; The small intestine cancer is adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, or fibroma; The colorectal cancer is adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma; The kidney cancer is adenocarcinoma, Wilms' tumor, lymphoma, or leukemia; the bladder and urethral cancer is squamous cell carcinoma, transitional cell carcinoma, or adenocarcinoma; the prostate cancer is adenocarcinoma or sarcoma; The testicular cancer is seminoma, teratoma, embryonal carcinoma, fetal epithelial carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; the liver cancer is hepatocellular carcinoma; The osteogenic sarcoma is osteosarcoma; The malignant lymphoma is reticulum cell sarcoma; The osteochondroma is an osteochondral exostosis; The skull cancer is osteoma, hemangioma, granuloma, xanthomas, or osteitis deformans; The meningeal cancer is meningioma, meningeal sarcoma, or gliomatosis; the brain cancer is astrocytoma, medulloblastoma, glioma, ventriculoma, blastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, or sarcoma; The uterine cancer is endometrial cancer, granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, or malignant teratoma; the vulvar cancer is squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, or melanoma; the vaginal cancer is clear cell carcinoma, squamous cell carcinoma, or sarcoma botryoides; The fallopian tube is a cancerous tumor; The blood cancer is myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, or myelodysplastic syndrome; Non-Hodgkin's lymphoma is a malignant lymphoma, 29. The pharmaceutical composition of claim 28.

30. The Wilms tumor is nephroblastoma; the blastoma is a pinealoma; the endometrial cancer is a serous cystadenocarcinoma, a mucinous cystadenocarcinoma, or an unclassified cancer tumor; Botryoid sarcoma is embryonal rhabdomyosarcoma; The myeloid leukemia is acute or chronic, 30. The pharmaceutical composition of claim 29.

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