TW202409032A - Fused ring compound, and preparation method therefor and use thereof - Google Patents

Abstract

Disclosed in the present invention are a fused ring compound, and a preparation method therefor and a use thereof. The present invention provides the fused ring compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The fused ring compound represented by formula I of the present invention has good inhibitory activity on SOS1, and is expected to treat and/or prevent diseases related to SOS1 activity or expression quantity.

Description

A condensed ring compound, its preparation method and application

This application claims the priority of Chinese Patent Application No. 2022109369139 with a filing date of August 5, 2022, Chinese Patent Application No. 202211294374X with a filing date of October 21, 2022, Chinese Patent Application No. 2022115292859 with a filing date of November 30, 2022, and Chinese Patent Application No. 2023109135728 with a filing date of July 24, 2023. This application cites the full text of the above Chinese patent applications.

The present invention relates to a condensed ring compound, a preparation method thereof and an application thereof.

RAS protein is a guanine trinucleotide phosphate (GTP) binding protein with a molecular weight of 21kDa located on the cell membrane, composed of 188 or 189 amino acids. The activity of RAS protein is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When bound to GDP, it is in an "inactive" state, and when bound to GTP, it is in an "activated" state. RAS protein itself has a relatively weak GTPase hydrolysis function and a slow nucleotide exchange rate. Binding to GTPase activating proteins (GAP) can enhance the GTP hydrolysis function of RAS protein, while guanine nucleotide exchange factor (GEF) can catalyze the exchange of nucleotides (GTP exchange GDP). SOS1 (Son of Sevenless 1) is a RAS-specific GEF. SOS1 binds to RAS to promote RAS to release GDP and bind to GTP, thereby activating RAS. After RAS is activated, it can activate multiple downstream signaling pathways, including the MAPK signaling pathway and the PI3K signaling pathway. These signaling pathways play an important role in promoting cell differentiation, proliferation, and survival. RAS mutations are genetic drivers of many cancers, and RAS mutations are found in 20%-30% of human tumors, such as lung cancer, colorectal cancer, and pancreatic cancer.

The RAS gene family includes KRAS, NRAS, and HRAS. KRAS mutations exist in many tumors, such as lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%). The most common KRAS mutation is the G12 mutation at codon 12. For example, in KRAS-mutated lung adenocarcinoma, colorectal cancer, and pancreatic cancer, G12 mutations account for 85%, 68%, and 91%, respectively; HRAS and NRAS mutations are relatively rare and mainly occur in cancer types such as melanoma, leukemia, and thyroid cancer. In addition, abnormal activation of RAS proteins (such as gene mutations, amplification, and overexpression) is also closely related to resistance to some anti-tumor drugs, such as EGFR monoclonal antibodies and EGFR small molecule inhibitors. Therefore, RAS-related signaling pathways have become important anti-tumor targets.

The guanine nucleotide exchange factor of the RAS family involved in cancer-related signaling pathways is mainly SOS1. Reducing the expression of SOS1 can significantly inhibit the proliferation and survival of KRAS-mutated cancer cells. Since SOS1 is a common node for multiple activated RAS signaling pathways, and almost all growth factor receptors activate RAS signaling pathways through SOS1, SOS1 inhibitors have the potential to become broad-spectrum anti-cancer drugs. The signaling pathways involved in activation of SOS1 also play an important role in other mutated types of cancer. SOS1 can interact with the adapter protein Grb2 to form a SOS1/Grb2 complex, which binds to activated receptor tyrosine kinases (such as EGFR, HER2, Erbb4, TRKA, TRKB, TRKC, RET and AXL, etc.). SOS1 can also be recruited to phosphorylated cell surface receptors, such as T cell receptors, B cell receptors, and monocyte lineage stimulating factor receptors. The localization of SOS1 on the cell membrane allows SOS1 to better promote the activation of RAS family proteins and activate downstream signaling pathways. SOS1 is also involved in the activation of other GTP hydrolases, such as RAC1, etc. RAC1 is also related to the pathogenesis of various human cancers and other diseases. In addition, SOS1 mutations have been found in lung adenocarcinoma, embryonal rhabdomyosarcoma, and cutaneous granulosa cell tumors, and overexpression of SOS1 has been found in bladder cancer and prostate cancer. In addition to cancer, inherited SOS1 mutations are also related to the pathogenesis of RAS lesions, including Noonan syndrome, cardio-facial-cutaneous syndrome, and hereditary gingival fibroma type 1.

There are currently no SOS1 inhibitors approved for marketing, so new SOS1 inhibitors with good efficacy need to be developed to meet clinical needs.

The technical problem to be solved by the present invention is the defects of existing SOS1 inhibitors such as single structure. The present invention provides a fused ring compound, its preparation method and its application. This type of compound has good inhibitory activity against SOS1.

The present invention provides a fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt; Wherein, Ring A is C _6-12 aryl, 5-10 membered heteroaryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; each R ¹ is independently It is deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , cyano, oxo (=O), nitro, C _1-6 alkyl, C _1-6 alkyl -O-, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a , C _1-6 alkyl-O- substituted by one or more R ^1b , substituted by one Or C _2-6 alkenyl substituted by one or more R ^1c , C _2-6 alkynyl substituted by one or more R ^1d , C _3-7 cycloalkyl, C _3- substituted by one or more R ^1e ₇ -cycloalkyl, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl substituted by one or more R ^1f , C _6-12 aryl, C _6-12 substituted by one or more R ^1g Aryl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R ^1h , C _3-7 cycloalkenyl, C _3-7 ring substituted by one or more R ¹ⁱ Alkenyl, -C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ , or two R ¹ together with the attached ring atoms form a C _3-7 cycloalkyl group, surrounded by one or more C _3-7 cycloalkyl, 3-7-membered heterocyclyl substituted by R ^1e , 3-7-membered heterocyclyl substituted by one or more R ^1f , C _3-7 cycloalkenyl or one or more C _3-7 cycloalkenyl substituted by R ¹ⁱ ; when there are multiple substituents, they may be the same or different; each R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h and R ¹ⁱ are each independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , nitro, cyano, C _1-6 alkyl, C _1-6 alkyl-O-, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1-a , C _1-6 alkyl-O- substituted by one or more R ^1-b , C _2-6 alkenyl substituted by one or more R ^1-c , C _2-6 alkynyl substituted by one or more R ^1-d , C _3-7 cycloalkyl, C _3-7 ring Alkyl-O-, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl-O-, C _3-7 cycloalkyl substituted by one or more R ^1-e , substituted by one or more R C _3-7 cycloalkyl-O- substituted with ^1-e , 3-7-membered heterocyclyl substituted with one or more R ^1-f , 3-7-membered heterocyclyl substituted with one or more R ^1-f Heterocyclyl-O-, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^1-g , 5-10 membered heteroaryl, substituted by one or more R ^1-h 5-10 membered heteroaryl, C _3-7 cycloalkenyl, C _3-7 cycloalkenyl-O-, C _3-7 cycloalkenyl substituted by one or more R ^1-i , substituted by one or Multiple R ^1-i substituted C _3-7 cycloalkenyl -O-, -C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ - N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O)- N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ ; when there are multiple substituents, they are the same or different; each R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h and R ^1-i respectively Independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , nitro, cyano, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl , C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclic group; Ring D is C _6-12 aryl, 5-6 membered heteroaryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; R ² is absent, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo, nitro, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 One-membered heterocyclic group; L is the connecting bond, -C(=O)-, -C(=O)O-, -C(=O)NR ⁸ -, -NR ⁸ -, -S-, -O-, -S(O)-, -S(O) ₂ - or -(CH ₂ ) _p -; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is hydrogen, deuterium, C _1-6 Alkyl, C _1-6 alkyl substituted by one or more R ^3a , C _2-6 alkenyl, C _2-6 alkenyl substituted by one or more R ^3b , C _2-6 alkynyl, C _2-6 alkynyl substituted by one or more R ^3c , C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl, substituted by one or multiple R ^3e -substituted 3-7-membered heterocyclyl, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3f , 5-10-membered heteroaryl, substituted by one or more R 3f A 5-10-membered heteroaryl group substituted by R ^3g , a C _3-7 cycloalkenyl group, or a C _3-7 cycloalkenyl group substituted by one or more R ^3h ; when there are multiple substituents, they may be the same or different; Each of R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h is independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, nitro, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl substituted by one or more R ^3-b Base -O-, C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 alkenyl substituted by one or more R ^3-c , C ₂ substituted by one or more R ^3-d _-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3-e , 3-7 membered heterocyclyl, substituted by one or more R ^3-f 3-7 membered heterocyclyl, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3-g , 5-10 membered heteroaryl, substituted by one or more R ^{3- h} -substituted 5-10-membered heteroaryl, C _3-7 cycloalkenyl, C _3-7 cycloalkenyl substituted by one or more R ^3-i , C _3-7 cycloalkyl-O-, One or more R ^3-j substituted C _3-7 cycloalkyl -O-, -SR ⁹ , -C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O )-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , - S(O) ₂ -N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ , or two R ^3d , two R ^3e , two R ^3f , two R ^3g or two R ^3h together with the attached ring atoms form a C _3-7 cycloalkyl, C substituted by one or more R ^3-e _3-7 cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^3-f , C _3-7 cycloalkenyl or substituted by one or more R ^{3- i} -substituted C _3-7 cycloalkenyl; when there are multiple substituents, they may be the same or different; each R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i and R ^3-j are each independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , nitro, cyano, C _{1 -6} alkyl, C _1-6 alkyl-O-, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 3-7 membered heterocyclyl, -SR ⁹ , -C(=O)- OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)- R ⁹ or -NR ⁸ C(=O)-OR ⁹ ; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene) -, -(C ₂ -C ₄ alkenylene)-or -(C ₂ -C ₆ alkynylene)-; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, Cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or substituted by one Or C _3-7 cycloalkyl substituted by multiple R ^4b ; when there are multiple substituents, they are the same or different; each R ^4a and R ^4b are independently hydrogen, deuterium, hydroxyl, halogen, amine group, cyanide base, nitro, amino protecting group, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is absent, oxo, hydrogen, deuterium, hydroxyl, halogen, Amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^5a , C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^5b , 3-7 membered heterocyclyl, 3- substituted by one or more R ^5c 7-membered heterocyclyl, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^5d ; when there are multiple substituents, they are the same or different; each R ^5a , R ^5b and R ^5c are each independently deuterium, C _1-6 alkyl, hydroxyl, halogen, amine or cyano; R ⁶ is hydrogen, deuterium, hydroxyl, halogen, amine, cyano, oxo (=O), C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl or absent; each R ⁷ is independently hydrogen, C _1-6 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or amino protecting group substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom Forming a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^7a ; when there are multiple substituents, they are the same or different; each R ^7a and R ^7b are independently deuterium , C _1-6 alkyl, halogen, hydroxyl, amine, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl or C _2-6 alkynyl; each R ⁸ and R ⁹ respectively Independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; R ¹⁰ is hydrogen, deuterium, hydroxyl, halogen, amine, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl or C _1-6 alkyl; R ¹¹ is cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^11a ; when there are multiple substituents, they are the same or different; each R ^11a is independently deuterium, halogen or Hydroxy; m is 0, 1, 2, 3, 4 or 5; p is 1, 2, 3, 4, 5 or 6; the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent Each of the 3-7-membered heterocyclic groups in the ring group is independently "a 3-7-membered heterocyclic group whose heteroatom species is independently selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3."; The 5-10-membered heteroaryl group in the 5-10-membered heteroaryl group and the 5-10-membered heteroaryl group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, and the heteroatom species is independently selected from N, O and S. "5-10-membered heteroaryl group with 1, 2 or 3 atoms"; the 5-6-membered heteroaryl group is "the heteroatom species is independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-6 membered heteroaryl groups"; the amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, phthalate Formyl, benzyl, p-methoxybenzyl, trityl or p-toluenesulfonyl group; When the carbon atom of * has chirality, the fused ring compound shown in formula I is , or mixtures thereof.

In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (the content of this paragraph is hereinafter referred to as "in a certain embodiment").

In one embodiment, when X is a connecting bond, R ⁴ is C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; when there are multiple substituents, they may be the same or different.

In one embodiment, X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)-, or -(C ₂ -C ₆ alkynylene)-; when X is a connecting bond, R ⁴ is cyano, or .

In one embodiment, R ⁶ is oxo; L is a connecting bond, -C(=O)-, -C(=O)O-, -C(=O)NR ⁸ -, -NR ⁸ -, -O-, -S-, -S(O)-, -S(O) ₂ - or -(CH ₂ ) _p -; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, nitro, C 1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl substituted by one or more R ^3-b C _1-6 alkyl-O-, C _2-6 alkenyl, C _{2-6 alkynyl, C 2-6 alkenyl} substituted by one or more R ^3-c , C _2-6 alkynyl substituted by one or more R ^3-d , C 3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3-e , _3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R ^3-f , C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3-g , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R ^3-h , C _3-7 cycloalkenyl, C _3-7 cycloalkenyl substituted by one or more R ^3-i , C -S(O ⁾ -R 9, -NR 8 -S(O) 2 -R ⁹ , -NR ₈ -S(O) 2 -N(R 7 ) 2, _-S (O) 2 ^-N (R ^{7 )} ₂ , -S(O) _-R ⁹ , -NR ⁸ -S(O) _-R ⁹ , -NR 8 -S(O) _{-R 9} ^, -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -S(O) _-R ⁹ , ^{-NR 8} -S(O)-R ⁹ , -NR ⁸ -S(O) _-N (R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ , or -NR ⁸ C(=O)-OR ⁹ ; when there are multiple substituents, they may be the same or different.

In a certain scheme, R ⁶ is oxo; L is a connecting bond; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is a 3-7-membered heterogeneous compound substituted by one or more R ^3e Ring group; when there are multiple substituents, they may be the same or different; each R ^3e is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano group, C _1-6 alkyl, substituted by one or more C _1-6 alkyl substituted by R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl -O-, C _3-7 cycloalkyl -O-, C _2-6 alkynyl or -C(=O)-R ⁹ substituted by one or more R ^3-j ; when the substituent is multiple time, the same or different.

In a certain plan, Not hydrogen.

In one embodiment, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^{3e, R 3f ,} R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i , R In ^R3-j , ^R4 , ^{R4a, R4b ,} R5, ^R5a , ^R5b , ^R5c , ^R6 , ^R7 , ^R7a , ^R7b , ^R8 , ^R9 , ^R10 and ^R11 , the _C1-6 alkyl group _{and the C1-6} ^alkyl _group substituted with a substituent are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl, for example, methyl or ethyl.

In a certain scheme, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^{1h , R 1i ,} R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^{3 -i} , R ^3-j , R ⁴ , R ^4a , R ^4b , R ⁵ , R ^5a , R ^{5b, R 5c ,} R ⁶ , R ^7a , R ^7b , R ¹⁰ and R ^11a , the halogens are each independent Ground is F, Cl, Br or I, for example F.

In one embodiment, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i , R ^3-j , R In ^R4 , ^R5 , ^R6 , ^R7a , ^R7b and ^R10 , the _C1-6 alkyl-O- and _{the C1-6 alkyl} -O- substituted by a substituent are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

In a certain scheme, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^{1h , R 1i ,} R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R Among ^3e , R ^3f , R ^3g , R ^3h , R ⁵ , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ and R ¹⁰ , the C _2-6 alkenyl group, C _2- substituted by a substituent The C _2-6 alkenyl groups in the _6- alkenyl group are each independently vinyl (-CH=CH ₂ ), propenyl (-CH=CH-CH ₃ ), or allyl (-CH ₂ -CH=CH ₂ ). , isopropenyl (-C(CH ₃ )=CH ₂ ), -CH=CH-CH ₂ -CH ₃ , -CH ₂ -CH=CH-CH ₃ , -CH=CH-CH ₂ -CH ₂ -CH _3. -CH ₂ -CH=CH-CH ₂ -CH ₃ , -CH=CH-CH(CH ₃ ) ₂ , -CH ₂ -CH=C(CH ₃ ) ₂ or -CH=CH-(CH ₂ ) ₃ -CH ₃ .

In a certain scheme, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^{1h , R 1i ,} R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R Among ^3e , R ^3f , R ^3g , R ^3h , R ⁵ , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ and R ¹⁰ , the C _2-6 alkynyl group, C _2- substituted by a substituent The C _2-6 alkynyl groups in the _6- alkynyl group are each independently ethynyl (-C≡CH), propynyl (-C≡C-CH ₃ ), -C≡C-CH ₂ -CH ₃ , -CH ₂ C≡C-CH ₃ , -C≡C-CH ₂ -CH ₂ -CH ₃ , -CH ₂ C≡C-CH ₂ -CH ₃ , -C≡C-CH ₂ -CH ₂ -CH ₂ -CH _3. -C≡C-CH ₂ -CH(CH ₃ ) ₂ , -C≡CC(CH ₃ ) ₃ , -C≡C-CH(CH ₃ ) ₂ or -CH ₂ C≡C-CH ₂ -CH ₂ -CH ₃ .

In one embodiment, the C _3-7 cycloalkyl in ring A, the C _3-7 cycloalkyl in R ¹ , the C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, two R ^1s together with the ring atom to which they are attached form a C _3-7 cycloalkyl, two R ^1s together with the ring atom to which they are attached form a C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, the C 3-7 cycloalkyl in R ^1a , R ^1b , R ^1c , R 1d , R ^1e , R ^1f , R ^1g , R ^1h and R ¹ⁱ , the C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, ^the C _3-7 cycloalkyl in C _3-7 cycloalkyl-O-, the C _3-7 cycloalkyl substituted by a substituent _{the C 3-7 cycloalkyl} in R ^1-a , R ^1-b , R ^{1-c, R 1-d} , R ^{1-e ,} R ^1-f , R ^1-g , R ^1-h , R ^1-i and R ² , the C _3-7 cycloalkyl in R ³ , the C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, the C _3-7 cycloalkyl in R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , the C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, the C _3-7 cycloalkyl in the C _3-7 cycloalkyl-O- R _{3 -a} , R ^{3-b, R 3-c} , R ^3-d , R 3 ^{-e, R 3-f, R 3-g} _, ^{R 3-h} , R ^{3 -i} and R ^{3-j are} substituted with a substituent; R _3-4 , R 3-5, R ^3-6 , R 3-7, R 3-8, R 3-9, _{R 3-10} , R 3-11, R 3-12, R 3-13, R 3-14, R 3-15, R 3-16, R 3-17, R 3-18, R _3-19 , R ⁴⁰ , R ⁴¹ , R 42, R ^43, R 44, R ⁴⁵ , R ⁴⁶ , R 47, R ⁴⁸ , R 49, R50, R51, R52, R53, R54, ^R55 , R56, R57, R58, ^R59 , ^{R60, R61, R62,} _R63 ^{, R64, R65} in the embodiment of the present invention, the C _3-7 cycloalkyl in R ⁵ , _the C _3-7 cycloalkyl in the C _3-7 cycloalkyl substituted by a substituent, _the C _3-7 cycloalkyl in R ⁷ , and _{the C 3-7 cycloalkyl} in R ⁸ and R ⁹ are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or , for example, cyclopropyl.

In one embodiment, the C _3-7 cycloalkenyl in ring A, the C _3-7 cycloalkenyl in R ¹ , the C _3-7 cycloalkenyl in the C _3-7 cycloalkenyl substituted by a substituent, two R ^1s together with the ring atom to which they are attached form a C _3-7 cycloalkenyl, two R ^1s together with the ring atom to which they are attached form a C 3-7 cycloalkenyl in the C _3-7 cycloalkenyl substituted by a substituent, the C _3-7 cycloalkenyl in R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h and R ¹ⁱ , the C _3-7 cycloalkenyl in the C _3-7 cycloalkenyl substituted by a substituent, and the C _3-7 cycloalkenyl in the C _3-7 cycloalkenyl-O- C _3-7 cycloalkenyl in R ₁ ^-a , R ^{1-b, R 1-} _c , R ^{1-d, R 1-e} , R ¹ - ^f , R ^{1 -g} , R ^1-h , R ^1-i and R ² , C _3-7 cycloalkenyl in R ³ , C _3-7 cycloalkenyl in C _3-7 cycloalkenyl substituted with a substituent, C _3-7 cycloalkenyl in R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , C _3-7 cycloalkenyl in C _3-7 cycloalkenyl substituted with _a substituent, two R R ^3-a , R ^{3 -} b, R ³ -c, R 3-d, R ^3-e , R ³ -f, R ^{3-g ,} R ^{3 -h} , R ^{3 -i} and R ^{3 - j, the} C _3-7 cycloalkenyl in R ⁵ , _{the C 3-7 cycloalkenyl} in the C _3-7 cycloalkenyl substituted by a ^substituent , and _{the C 3-7} ^cycloalkenyl in _{the C 3-7} ^cycloalkenyl substituted by a substituent ^. The C _3-7 cycloalkenyl group in R ⁷ , R ⁸ and R ⁹ is a C _3-7 cycloalkenyl group, wherein each of the C _3-7 cycloalkenyl groups is independently a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group or a cycloheptenyl group.

In a certain scheme, ring A, ring D, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R 1f , R ^1g , R ^1h , R ¹ⁱ , R ^{1 -a} , R ^{1- b} , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^{3- g} , R ^3-h , R ^3-i , R ^3-j , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ , the 3-7 membered heterocyclic group, the 3-7-membered heterocyclic group substituted by a substituent 3-7-membered heterocyclyl group among 7-membered heterocyclyl group, 3-7-membered heterocyclyl group among 3-7-membered heterocyclyl group-O-, 3-7-membered heterocyclyl group-O- substituted by a substituent Each of the 3-7 membered heterocyclic groups in the Ring system) heterocyclyl, specifically, the monocyclic heterocyclyl can be pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, piperazinyl, Azetidinyl, 1,2-dihydropyridyl, tetrahydropyridyl, etc.

In a certain solution, in R ³ , the number of heteroatoms of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group or the 3-7-membered heterocyclic group substituted by one or more R ^3e Independently 1 or 2; the heteroatom species of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^3e are independently selected from One or two of N and O; the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^3e are each independently " The heteroatom type is independently selected from one or two types of N and O, and the number of heteroatoms is 1 or 2 3-7-membered heterocyclic groups"; further, the 3-7-membered heterocyclic groups are Each of the 3-7-membered heterocyclyl groups in one or more R ^3e -substituted 3-7-membered heterocyclyl groups is independently "the number of heteroatoms is 1 or 2, and the heteroatom type is independently selected from N and O" The 4-7 membered heterocyclyl group; the 4-7 membered heterocyclyl group can be a 4-7 membered monocyclic heterocyclyl group, a 5-7 membered bridged ring heterocyclyl group or a 5-7 membered spirocyclic heterocyclyl group ; Specifically, when R ³ is a 4-7-membered monocyclic heterocyclyl group, the 4-7-membered monocyclic heterocyclyl group can be piperidinyl, tetrahydropyranyl, piperazinyl, azetidine base, morpholinyl or pyrrolidinyl; when R ³ is a 5-7-membered bridged ring heterocyclyl group, the 5-7-membered bridged ring heterocyclyl group can be , , or ; When R ³ is a 5-7-membered spirocyclic heterocyclyl group, the 5-7-membered spirocyclic heterocyclyl group can be ; for example , , , , , , , , , , or .

In a certain solution, in R ⁴ , the number of heteroatoms of the 3-7-membered heterocyclyl in the 3-7-membered heterocyclyl or the 3-7-membered heterocyclyl substituted by one or more R ^4a Independently 1, 2 or 3; the heteroatom species of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^4a Independently selected from one or more of N, O and S; each of the 3-7-membered heterocyclyl groups in the 3-7-membered heterocyclyl group and the 3-7-membered heterocyclyl group substituted by one or more R ^4a Independently is "a 3-7-membered heterocyclic group whose heteroatom species is independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; further, the 3-7-membered heterocyclic group The number of heteroatoms of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R ^4a is independently 1 or 2; the 3-7-membered heterocyclic group, The heteroatom species of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R ^4a are independently selected from one or two types of N and O; the 3-7-membered heterocyclic group The 3-7-membered heterocyclyl groups in the 3-7-membered heterocyclyl group substituted by one or more R ^4a are each independently "the heteroatom species is independently selected from one or two types of N and O, and the heteroatom The number of 4-7-membered heterocyclic groups is 1 or 2; for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl or morpholinyl; and for example , , , , , , , , or ;Another example , , , or .

In a certain scheme, in R ⁷ , the two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclyl group, a 3-7 membered heterocyclyl group substituted by one or more R ^7a The number of heteroatoms of the 3-7-membered heterocyclic group is independently 1 or 2; the two R ⁷ together with the connected nitrogen atoms form a 3-7-membered heterocyclic group, which is substituted by one or more R ^7a The heteroatom species of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group are independently selected from one or two types of N and O; the two R ⁷ together with the connected nitrogen atom form 3- The 3-7-membered heterocyclyl groups in the 7-membered heterocyclyl group and the 3-7-membered heterocyclyl group substituted by one or more R ^7a are each independently "heteroatom species independently selected from one or both N and O species.""Species, 4-7-membered heterocyclic group with 1 or 2 heteroatoms"; for example: pyrrolidinyl, another example ; In a certain scheme, in ring D, the 3-7-membered heterocyclic group is "a 6-membered heterocyclic group with N heteroatom type and 1 or 2 heteroatoms", for example, 1, 2-Dihydropyridyl, another example is or , "c" means that the atom is located in the meta position of the N atom of the B ring.

In a certain scheme, Ring A, Ring D, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^{1f , R 1g ,} R ^1h , R ¹ⁱ , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , the C _6-12 aryl group and the C _{6-12 aryl group in the C 6-12 aryl} group substituted by a substituent are each independently Ground is phenyl or naphthyl; for example: phenyl.

In one embodiment, in Ring A, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^{1e , R 1f ,} R ^1g , R ^1h , R ¹ⁱ , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , the 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group substituted with a substituent are each independently “a 5-8 membered heteroaryl group having 1, 2 or 3 heteroatoms, the types of which are independently selected from N, O and S”.

In _a certain embodiment, in X, the -(C ₁ -C ₄ alkylene)- and -O-(C _{1 -C 4} alkylene)- are each independently methylene, ethylene, n-propylene or isopropylene, for example: -CH ₂ -, -CH 2 CH 2 -, -CH(CH ₃ )-, -CH 2 CH ₂ CH _{2 -, -CH(CH 3 )CH 2 -, -CH(CH 2 CH 3 ) - or -C (} CH ₃ ) ₂ -, preferably -CH ₂ -, -CH ₂ CH ₂ -, -CH( _{CH 3 )} - or -CH ₂ CH ₂ CH ₂ -; further, the "C ₁ -C ₄ alkylene" in "-O-(C ₁ -C ₄ alkylene)-" is connected to R ⁴ .

In one embodiment, in X, the -(C ₂ -C ₄ alkenylene)- is independently vinylene, propenylene, allylene or butenylene, such as -CH=CH-, -CH=CH-CH ₂ -; further, the -(C ₂ -C ₄ alkenylene)- can be , , or , where the f end is connected to R ⁴ .

In _{one embodiment} , in -C≡C-, -CH ₂ -C≡CH, -C≡C-CH ₂ -, -C≡C-CH ₂ -CH ₂ -, -C≡C-CH(CH ₃ )-CH ₂ -, -C≡CC(CH ₃ ) ₂ -, preferably -C≡C-, -C≡C-CH ₂ - or -C≡CC(CH ₃ ) ₂ -; further, the -(C ₂ -C _6Alkynylene )- can be -C≡C-*, -C≡C-CH ₂ -* or -C≡CC(CH ₃ ) ₂ -*, where the * end is connected to R ⁴ .

In one embodiment, Ring A is C _6-12 aryl; preferably, Ring A is phenyl.

In one embodiment, each R ¹ is independently halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl-O-, C _2-6 alkene group, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a or C _1-6 alkyl-O- substituted by one or more R ^1b ; preferably, each R ¹ is independently halogen, C _1-6 alkyl, cyano or C _1-6 alkyl substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different.

In one embodiment, each R ^1a and R ^1b is independently halogen; preferably, each R ^1a and R ^1b is independently F or Cl.

In a certain embodiment, m is 0, 1, 2 or 3; preferably, m is 2.

In one embodiment, R ² is hydrogen, hydroxyl, halogen, amine, cyano, C _1-6 alkyl or C _1-6 alkyl-O-; preferably, R ² is hydrogen.

In one embodiment, L is a connecting key.

In a certain embodiment, R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl, substituted by one or more R ^3e 3-7 membered heterocyclyl, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; preferably, R ³ is C _3-7 cycloalkyl, substituted by one or C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl substituted by one or more R ^3e , C _3-7 cycloalkenyl or C substituted by one or more R ^3h _3-7 cycloalkenyl; more preferably, R ³ is a 3-7 membered heterocyclyl substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different.

In a certain embodiment, each R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, substituted by one or more R ^{3- a} -substituted C _1-6 alkyl, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O -, C _3-7 cycloalkyl-O-, C _2-6 alkynyl or -C(=O)-R ⁹ substituted by one or more R ^3-j ; further, each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _{1 -6} alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _2-6 alkynyl or -C(=O)-R ⁹ ; preferably, Each R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1- substituted with one or more R ^3-b ₆ alkyl-O-, C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; Preferably, each R ^3d , R ^3e and R ^3h are independently hydroxyl, -N( R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O- or -C( =O)-R ⁹ ; further preferably, each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, C _1-6 alkyl-O-, substituted by one or more R ^3-b C _1-6 alkyl-O-, C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl-O- or -C(=O)- substituted by one or more R ^3-j R ⁹ ; more preferably, each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, C _1-6 alkyl-O-, C _1-6 substituted by one or more R ^3-b Alkyl -O- or -C(=O)-R ⁹ ; when there are multiple substituents, they may be the same or different.

In a certain embodiment, each R ^3-a , R ^3-b and R ^3-j are each independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; further, each R ^3-a and Each R ^3-b is independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; further, each R ^3-b is independently deuterium, hydroxyl or halogen.

_{In a certain embodiment , ​} Alkenylene)-or -(C ₂ -C ₆ alkynylene)-; preferably, "C ₁ -C ₄ alkylene" and R in -O-(C ₁ -C ₄ alkylene)- ⁴ connected; further, X is a connecting bond, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene) - or -(C ₂ -C ₆ alkynylene)-; preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ ; preferably _{Where , ​ ​ ​ ​} (C ₂ -C ₆ alkynylene)-; preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ .

In a certain embodiment, R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl , 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; Preferably, R ⁴ is hydrogen , C _1-6 alkyl, cyano group, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R 4a or substituted by one or more R ^4a C _3-7 cycloalkyl substituted by R ^4b ; more preferably, R ⁴ is hydrogen, C _1-6 alkyl, cyano, hydroxyl, -N(R ⁷ ) ₂ , substituted by one or more R ^4a 3-7 membered heterocyclyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; further preferably, R ⁴ is -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, substituted by one or more R 4b 3-7 membered heterocyclyl, C _3-7 cycloalkyl substituted by one or more R ^4a , or C _3-7 cycloalkyl substituted by one or more R ^4b ; most preferably, R ⁴ is -N (R ⁷ ) ₂ , a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^4a ; when there are multiple substituents, they may be the same or different.

In a certain embodiment, each R ^4a and R ^4b is each independently hydroxyl, halogen, amine, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuteriums; preferably, each R ^4a and R ^4b is each independently amine, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuteriums; more preferably, each R ^4a and R ^4b is each independently C _1-6 alkyl or amine; further preferably, each R ^4a is each independently C _1-6 alkyl.

In one embodiment, R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; preferably, R ⁵ is hydrogen or C _1-6 alkyl; more preferably, R ⁵ is C _1-6 alkyl.

In one embodiment, R ⁶ is oxo (=O).

In a certain embodiment, each R ⁷ is independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R ^7a ; further, each R ⁷ is independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic group; further, each R ⁷ is independently hydrogen or C _1-6 alkyl; when there are multiple substituents, they may be the same or different.

In a certain embodiment, each R ^7b is independently deuterium, halogen, hydroxyl or cyano; preferably, each R ^7b is independently deuterium or hydroxyl; more preferably, each R ^7b is independently deuterium.

In a certain embodiment, each R ⁹ is independently hydrogen or C _1-6 alkyl; preferably, each R ⁹ is independently C _1-6 alkyl.

In one embodiment, ring D is a 3-7 membered heterocyclic group.

In a certain embodiment, R ¹⁰ is C _1-6 alkyl; preferably, R ¹⁰ is methyl.

In one embodiment, R ¹¹ is C _1-6 alkyl; preferably, R ¹¹ is methyl.

In a certain embodiment, in the fused ring compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, Ring A is a C _6-12 aryl group; each R ¹ is independently a halogen, a hydroxyl, -N(R ⁷ ) ₂ , a C _1-6 alkyl, a cyano, a C _1-6 alkyl-O-, a C _2-6 alkenyl, a C _{2-6 alkynyl, a C 1-6 alkyl} substituted by one or more R ^1a , or a C _1-6 alkyl-O- substituted by one or more R ^1b ; when there are multiple substituents, they are the same or different; each R ^1a and R ^1b is independently a halogen; m is 0, 1, 2 or 3; R ² is hydrogen, a hydroxyl, a halogen, an amine, a cyano, a C _1-6 alkyl or a C _1-6 alkyl-O-; L is a connecting bond; R ^{R 3} is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they may be the same or different; each of R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _{1-6 alkyl, C 1-6} alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O-, C _1-6 alkyl substituted by one or more R ^3-j wherein the substituents are substituted _with -C(=O)-R ⁹ ; when there are multiple substituents, they are the same or different; each of R ^3-a , R ^3-b and R ^3-j is independently deuterium, hydroxyl, _halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₄ alkynylene)-; preferably, in -O-(C ₁ -C ₄ alkylene)-, "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R ^4a , a C _3-7 cycloalkyl group, or a C _3-7 cycloalkyl group substituted by one or more R ^4b ; when there are multiple substituents, they are the same or different; each R ^4a and R ^4b are independently hydroxyl, halogen, amino, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen, hydroxyl, halogen, amino, cyano, or C _1-6 alkyl; R ⁶ is oxo (=O); each R ⁷ is independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more R ^7b , or two R ^R7 together with the nitrogen atom to which it is attached forms a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more ^R7a ; when there are multiple substituents, they are the same or different; each ^R7a and ^R7b is independently deuterium, halogen, hydroxyl or cyano; each ^R9 is independently hydrogen or _C1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; ^R10 is _C1-6 alkyl; ^R11 is _C1-6 alkyl; wherein, is not hydrogen; the 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by a substituent are each independently a "3-7 membered heterocyclic group in which the heteroatom type is independently selected from N, O and S, and the number of the heteroatom is 1, 2 or 3".

In a certain embodiment, in the fused ring compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, Ring A is a C _6-12 aryl group; each R ¹ is independently a halogen, a hydroxyl, -N(R ⁷ ) ₂ , a C _1-6 alkyl, a cyano, a C _1-6 alkyl-O-, a C _2-6 alkenyl, a C _{2-6 alkynyl, a C 1-6 alkyl} substituted by one or more R ^1a , or a C _1-6 alkyl-O- substituted by one or more R ^1b ; when there are multiple substituents, they are the same or different; each R ^1a and R ^1b is independently a halogen; m is 0, 1, 2 or 3; R ² is hydrogen, a hydroxyl, a halogen, an amine, a cyano, a C _1-6 alkyl or a C _1-6 alkyl-O-; L is a connecting bond; R ^{R 3} is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they may be the same or different; each of R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _{1-6 alkyl, C 1-6 alkyl} substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents, they are the same or different; each R ^3-a and R ^3-b is independently deuterium, hydroxyl or halogen; X is a connecting bond, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₄ alkynylene)-; preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R ^4a , C _wherein ^the substituents are _3-7 membered heterocyclic groups; ^{R 10} _is ^C _1-6 ^{alkyl ;} _and ^{R 11} _is ^C _{1-6 alkyl .}

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group; each R ¹ is independently is halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, by one or C _1-6 alkyl substituted by multiple R ^1a or C _1-6 alkyl-O- substituted by one or more R ^1b ; when the substituents are multiple, the same or different; each R ^1a and R ^1b is each independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, amine, cyano, C _1-6 alkyl or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl, 3 substituted by one or more R ^3e -7-membered heterocyclyl, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they are the same or different; each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _{1 -6} alkyl-O-, C _1-6 alkyl-O- substituted with one or more R ^3-b , C _3-7 cycloalkyl-O-, substituted with one or more R ^3-j C _3-7 cycloalkyl-O-, C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents, the same or different; each R ^3-a , R ^{3 -b} and R ^3-j are each independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O- (C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, -O-(C ₁ -C ₄ alkylene) - "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl , -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl, or substituted by one or more R ^4b C _3-7 cycloalkyl; when there are multiple substituents, they may be the same or different; each R ^4a and R ^4b are independently hydroxyl, halogen, amino, C _1-6 alkyl or substituted by one or more deuterium-substituted C _1-6 alkyl; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo (=O); each R ⁷ is independently Hydrogen, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclyl or substituted by one or more R 7b Each R ^7a -substituted 3-7-membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R ^7a and R ^7b is independently deuterium, halogen, hydroxyl or cyano; each R ⁹ is independently is hydrogen or C _1-6 alkyl; Ring D is 3-7 membered heterocyclyl; R ¹⁰ is C _1-6 alkyl; R ¹¹ is C _1-6 alkyl; wherein, Not hydrogen; The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, a 3-7-membered heterocyclic group with 1, 2 or 3 heteroatoms."

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group; each R ¹ is independently is halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, by one or C _1-6 alkyl substituted by multiple R ^1a or C _1-6 alkyl-O- substituted by one or more R ^1b ; when the substituents are multiple, the same or different; each R ^1a and R ^1b is each independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, amine, cyano, C _1-6 alkyl or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they are the same or different; each R ^3d , R ^3e and R ^3h are independently Hydroxy, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl substituted by one or more R ^3-j -O-, C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents, they may be the same or different; each R ^3-a , R ^3-b and R ^3-j respectively Independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene base)-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, -O-(C ₁ -C ₄ alkylene)-in " C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; When there are multiple substituents, they may be the same or different; Each R ^4a and R ^4b are independently hydroxyl, halogen, amino, C _1-6 alkyl or C _1-6 substituted by one or more deuterium Alkyl; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo (=O); each R ⁷ is independently hydrogen, C _1-6 alkyl Or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclyl or 3-7 substituted by one or more R ^7a Heterocyclic group; when there are multiple substituents, they may be the same or different; each R ^7a and R ^7b is independently deuterium, halogen, hydroxyl or cyano; each R ⁹ is independently hydrogen or C _1-6 alkane base; Ring D is a 3-7 membered heterocyclyl group; R ¹⁰ is a C _1-6 alkyl group; R ¹¹ is a C _1-6 alkyl group; wherein, Not hydrogen; The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, a 3-7-membered heterocyclic group with 1, 2 or 3 heteroatoms."

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group; each R ¹ is independently is halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, by one or C _1-6 alkyl substituted by multiple R ^1a or C _1-6 alkyl-O- substituted by one or more R ^1b ; when the substituents are multiple, the same or different; each R ^1a and R ^1b is each independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, amine, cyano, C _1-6 alkyl or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl, 3 substituted by one or more R ^3e -7-membered heterocyclyl, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they are the same or different; each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _{1 -6} alkyl-O-, C _1-6 alkyl-O- substituted with one or more R ^3-b , C _3-7 cycloalkyl-O-, substituted with one or more R ^3-j C _3-7 cycloalkyl-O-, C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents, the same or different; each R ^3-a , R ^{3 -b} and R ^3-j are each independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O- (C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, -O-(C ₁ -C ₄ alkylene) - "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, substituted by one or more R ^4a 3-7 membered heterocyclyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; when the substituents are multiple, they are the same or different; each R ^4a and R ^4b is each independently hydroxyl, halogen, amine, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo (=O); Each R ⁷ is independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more R ^7b , or Two R ⁷ together with the attached nitrogen atom form a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^7a ; when there are multiple substituents, they may be the same or different; each Each R ^7a and R ^7b are independently deuterium, halogen, hydroxyl or cyano; each R ⁹ is independently hydrogen or C _1-6 alkyl; Ring D is a 3-7 membered heterocyclyl; R ¹⁰ is C _{1 -6} alkyl; R ¹¹ is C _1-6 alkyl; the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "Heteroatom types are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 3-7-membered heterocyclic groups."

In a certain embodiment, in the fused ring compound as shown in Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, Ring A is a C _6-12 aryl group; each R ¹ is independently a halogen, a cyano group, a C _1-6 alkyl group or a C _1-6 alkyl group substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different; each R ^1a is independently a halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently a hydroxyl, a halogen, -N(R ⁷ ) ₂ , a C _1-6 alkyl-O-, a C _1-6 alkyl-O- substituted by one or more R ^3-b , _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; when there are multiple substituents, they are the same or different; each R ^3-b is independently deuterium, hydroxyl or halogen; X is a linking bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, in "-O-(C ₁ -C ₄ alkylene)-", "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, cyano, hydroxyl, -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group ... ^R4a or R4b; when there are multiple substituents, they are the same or different; each ^R4a and ^R4b are independently amino, _C1-6 alkyl or _C1-6 alkyl substituted by one or more deuterium; ^R5 is hydrogen or _C1-6 alkyl; ^R6 is oxo (=O); each R7 is independently hydrogen, _C1-6 alkyl or _C1-6 alkyl substituted by one or more ^R7b , or two ^R7 together with the _nitrogen atom to which they are connected form a ^3-7 membered heterocyclic group; when there are multiple substituents, they are the same or different; each ^{R7b is} independently deuterium or hydroxyl; each ^R9 is independently _C1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R ¹⁰ is a C _1-6 alkyl group; R ¹¹ is a C _1-6 alkyl group; wherein, is not hydrogen; the 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by a substituent are each independently a "3-7 membered heterocyclic group having 1, 2 or 3 heteroatoms whose heteroatom types are independently selected from N, O and S".

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group; each R ¹ is independently is halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different; each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7-membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e Independently hydroxyl, halogen, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b or -C(=O)-R ⁹ ; when substituted When there are multiple groups, they may be the same or different; each R ^3-b is independently deuterium or halogen; X is a connecting bond, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ Alkylene)-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, "-O-(C ₁ -C ₄ alkylene) "-" in "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, cyano group, hydroxyl, -N(R ⁷ ) ₂ , surrounded by one or more R ^4a Substituted 3-7 membered heterocyclyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; when there are multiple substituents, they are the same or different; each R ^4a and R ^4b are independently Amino group, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is oxo (=O); each R ⁷ is independently hydrogen or C _1-6 alkyl; each R ⁹ is independently C _1-6 alkyl; Ring D is a 3-7 membered heterocyclyl; R ¹⁰ is C _1-6 alkyl; R ¹¹ It is C _1-6 alkyl.

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group, for example ; Each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; when the substituents are multiple, they are the same or different; each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7-membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; when there are multiple substituents, they may be the same or different; each R ^3-b is independently deuterium, hydroxyl or halogen; X is -(C ₁ -C ₄ alkylene)-, -O-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; Preferably, "C ₁ -C ₄ alkylene" in "-O-(C ₁ -C ₄ alkylene)-" is connected to R ⁴ ; R ⁴ is -N (R ⁷ ) ₂ , 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted by one or more R ^4a ; when there are multiple substituents, they are the same or different; each R ^4a is independently C _1-6 alkyl; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is oxo (=O); Each R ⁷ is independently hydrogen, C _1-6 alkyl or substituted by one or more A C _1-6 alkyl group substituted by R ^7b , or two R ^7s together with the attached nitrogen atom form a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R ^7b is independently is deuterium or hydroxyl; each R ⁹ is independently a C _1-6 alkyl group; Ring D is a 3-7 membered heterocyclic group; R ¹⁰ is a methyl group; R ¹¹ is a methyl group; the 3-7 membered heterocyclic group The 3-7-membered heterocyclic group in the base and the 3-7-membered heterocyclic group substituted by the substituent is each independently "the heteroatom type is independently selected from N, O and S, and the number of heteroatoms is 1 or 2 Or 3 3-7 membered heterocyclyl groups”.

In a certain aspect, in the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is a C _6-12 aryl group; each R ¹ is independently is halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different; each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7-membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e Independently hydroxyl, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b or -C(=O)-R ⁹ ; when the substituent is When multiple, they are the same or different; each R ^3-b is independently deuterium; X is -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, - (C ₂ -C ₄ alkylene)-or -(C ₂ -C ₆ alkynylene)-; preferably, "C ₁ -" in "-O-(C ₁ -C ₄ alkylene)-" C ₄ alkylene" is connected to R ⁴ ; R ⁴ is -N(R ⁷ ) ₂ or a 3-7-membered heterocyclyl substituted by one or more R ^4a ; when there are multiple substituents, they may be the same or different ; Each R ^4a is independently C _1-6 alkyl; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is oxo (=O); Each R ⁷ is independently hydrogen or C _1-6 Alkyl group; Each R ⁹ is independently a C _1-6 alkyl group; Ring D is a 3-7 membered heterocyclyl group; R ¹⁰ is a methyl group; R ¹¹ is a methyl group.

In one embodiment, ring A is .

In a certain scheme, each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a . When there are multiple substituents, the same Or different; for example: R ¹ is F, Cl, -CHF ₂ , -CF ₃ , cyano, -CH ₃ or -CF ₂ CH ₃ , preferably F, -CHF ₂ , -CH ₃ or cyano.

In one embodiment, ^R2 is hydrogen.

In a certain embodiment, R ⁵ is hydrogen or C _1-6 alkyl, for example: R ⁵ is hydrogen or methyl.

In one embodiment, X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)-, or -(C ₂ -C ₆ alkynylene)-, wherein the "C ₁ -C ₄ alkylene" in "-O-(C ₁ -C ₄ alkylene)-" is connected to R ⁴ ; for example: a connecting bond, , , , , , , , , , , , , , , or , for example: connection key, , , , , , , , , , , or , where the f end is connected to R ⁴ .

In a certain plan, can be , and can also be , , , , , , , or , can also be , , , , , , or ,For example , or , another example or .

In one embodiment, when ring D is a 3-7 membered heterocyclic group, ring D may be a 1,2-dihydropyridyl group, for example or , "c" indicates that the atom is located at the meta position relative to the N atom of the B ring.

In one plan, for or , "c" indicates that the atom is located at the meta position relative to the N atom of the B ring.

In a certain plan, can be , , or ; also can be or ;For example: or .

In one embodiment, when R ³ is C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^3d , the R ³ may be , , , , , , or .

In a certain scheme, when R ³ is a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^3e , the R ³ can be , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and can also be , , , , , , , , , , , , , , , , , or ,For example , , , , , , , , , , , , , , or , another example , , , , , , , , , , or , another example , , or , preferred , , , , , , , , or .

In one plan, Can , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and can also be , , , , , , , , , , , , , , , , , , , , , , , , , or ,For example , , , , , , , , , , , , , , or , for example , , , , , , , , , , or , for example , , or , preferred , , , , , , , , or .

In one embodiment, R ⁴ can be hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CD ₃ ) ₂ , , , , , , , , , , , , , or ; hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , , , , , , , , or .

In one plan, Can be methyl, methoxy, cyano, halogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and can also be hydrogen, methyl, methoxy, cyano, halogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , such as methyl, cyano, , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , preferred , , , , , , , , , , , , , , , , , , , , , , , , , or , also preferred , , , , , , , , , , , , , , or .

In one embodiment, the fused ring compound as shown in formula I is or .

In one embodiment, R ¹⁰ is methyl.

In one embodiment, R ¹¹ is methyl.

In a certain scheme, when R ⁴ is cyano, for .

In one embodiment, the compound represented by formula I is any of the following compounds: Serial number Compound No. Name Structure 1 Compound 1 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 2 Compound 2 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 3 Compound 3 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 4 Compound 4 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 5 Compound 5 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(methylamino)ethoxy)-1,6-naphthyridin-2(1H)-one 6 Compound 6 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile 7 Compound 7 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7,8-trimethyl-1,6-naphthyridin-2(1H)-one 8 Compound 8 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-ethynyl-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 9 Compound 9 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile 10 Compound 10 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-ethynyl-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 11 Compound 11 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 12 Compound 12 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 13 Compound 13 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one 14 Compound 14 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one 15 Compound 15 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 16 Compound 16 (R)-3-(1-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 17 Compound 17 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-((1-aminocyclopropyl)ethynyl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 18 Compound 18 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 19 Compound 19 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one 20 Compound 20 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one twenty one Compound 21 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one twenty two Compound 22 (R)-3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one twenty three Compound 23 (R)-3-(1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile twenty four Compound 24 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-8-((1-aminocyclopropyl)ethynyl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 25 Compound 25 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one 26 Compound 26 (R,Z)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-en-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 27 Compound 27 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one 28 Compound 28 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((Z)-2-((R)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one 29 Compound 29 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one 30 Compound 30 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)propyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 31 Compound 31 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)propyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 32 Compound 32 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one 33 Compound 33 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-((R)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one 34 Compound 34 (R)-3-(1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 35 Compound 35 (R)-3-(1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 36 Compound 36 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((E)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one 37 Compound 37 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((E)-2-((R)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one 38 Compound 38 (R,E)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-en-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 39 Compound 39 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)propyl)-7-methyl-1,6-naphthyridin-2(1H)-one 40 Compound 40 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(3-(methylamino)propyl)-1,6-naphthyridin-2(1H)-one 41 Compound 41 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 42 Compound 42 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,6-naphthyridin-2(1H)-one 43 Compound 43 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(1-methylpiperidin-4-yl)-1,6-naphthyridin-2(1H)-one 44 Compound 44 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 45 Compound 45 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 46 Compound 46 (R)-3-(1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 47 Compound 47 (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-7-methyl-1,6-naphthyridin-2(1H)-one 48 Compound 48 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 49 Compound 49 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 50 Compound 50 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-(((S)-1-(methyl-d ₃ )pyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 51 Compound 51 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-(((S)-1-(methyl-d ₃ )pyrrolidin-2-yl)ethynyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 52 Compound 52 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 53 Compound 53 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 54 Compound 54 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-((E)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 55 Compound 55 3-((R)-1-((3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-1,7-dimethyl-8-((E)-2-((R)-1-methylpyrrolidin-2-yl)vinyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 56 Compound 56 (R)-3-(1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(3-(dimethylamino)propyl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 57 Compound 57 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 58 Compound 58 3-((R)-1-((3-(1-acetyl-4-methoxypiperidin-4-yl)-1,7-dimethyl-8-(2-((R)-1-methylpyrrolidin-2-yl)ethyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 59 Compound 59 (3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 60 Compound 60 (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 61 Compound 61 (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile 62 Compound 62 (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 63 Compound 63 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 64 Compound 64 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 65 Compound 65 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 66 Compound 66 (R)-3-(1-acetyl-4-((2-hydroxyethyl)amino)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 67 Compound 67 (R)-3-(1-acetyl-4-(ethylamino)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 68 Compound 68 (R)-3-(1-acetyl-4-(2,2,2-trifluoroethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 69 Compound 69 (R)-3-(1-acetyl-4-(2,2-difluoroethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 70 Compound 70 (R)-3-(1-acetyl-4-(2-hydroxyethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 71 Compound 71 (R)-3-(1-acetyl-4-cyclopropoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 72 Compound 72 (R)-3-(1-acetyl-4-isopropoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 73 Compound 73 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(diethylamino)prop-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 74 Compound 74 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one 75 Compound 75 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d3)amino)prop-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 76 Compound 76 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d3)amino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 77 Compound 77 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d3)amino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile 78 Compound 78 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylpiperidin-4-yl)oxy)-1,6-naphthyridin-2(1H)-one 79 Compound 79 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylazolobutyl-3-yl)oxy)-1,6-naphthyridin-2(1H)-one 80 Compound 80 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-((1-methylazinocyclobutan-3-yl)oxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 81 Compound 81 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 82 Compound 82 3-((R)-1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 83 Compound 83 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one 84 Compound 84 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one 85 Compound 85 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(pyrrolidin-1-yl)ethoxy)-1,6-naphthyridin-2(1H)-one 86 Compound 86 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-2-oxo-8-(2-(pyrrolidin-1-yl)ethoxy)-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 87 Compound 87 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 88 Compound 88 3-((R)-1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)methoxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 89 Compound 89 (R)-3-(1-acetyl-4-(ethoxy-2,2,2-d3)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 90 Compound 90 (R)-3-(1-((3-(1-acetyl-4-(ethoxy-2,2,2-d3)piperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 91 Compound 91 (R)-3-(1-acetyl-4-(ethoxy-1,1-d2)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 92 Compound 92 (R)-3-(1-((3-(1-acetyl-4-(ethoxy-1,1-d2)piperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 93 Compound 93 (R)-3-(1-acetyl-4-(ethoxy-d5)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 94 Compound 94 (R)-3-(1-((3-(1-acetyl-4-(ethoxy-d5)piperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 95 Compound 95 (R)-3-(1-acetyl-4-(difluoromethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 96 Compound 96 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(3-(methylamino)prop-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one 97 Compound 97 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 98 Compound 98 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 99 Compound 99 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 100 Compound 100 (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(2-(bis(methyl-d3)amino)ethoxy)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 101 Compound 101 (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(2-(bis(methyl-d3)amino)ethoxy)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 102 Compound 102 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-(methyl-d3)pyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one 103 Compound 103 3-((R)-1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(((S)-1-(methyl-d3)pyrrolidin-2-yl)methoxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile 104 Compound 104 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((R)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1,6-naphthyridin-2(1H)-one 105 Compound 105 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1,6-naphthyridin-2(1H)-one 106 Compound 106 (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

The present invention also provides a method for preparing the fused ring compound shown in formula I as mentioned above, its stereoisomer or its pharmaceutically acceptable salt, wherein, when for , "c" means that when the atom is located at the meta position of the N atom of the B ring, the preparation method includes the following steps: intermediate I-A1 and raw material N-phenyl bis (trifluoromethanesulfonate) imine or trifluoromethanesulfonate The acid anhydride reaction obtains intermediate I-A2, which then undergoes a coupling reaction with raw material I-A3 to obtain intermediate I-A4, which then undergoes a substitution reaction or palladium-catalyzed Buchwald coupling reaction with raw material I-A5. , obtain the compound of general formula IA; If the substitution reaction between I-A4 and I-A5 occurs, it is carried out under the action of a base, and the base includes but is not limited to cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, etc.; If I -A4 and I-A5 undergo a Buchwald coupling reaction in the presence of a catalyst and a base. The catalyst includes but is not limited to RuPhos Pd G3, BrettPhos Pd G3, XPhos Pd G3, XantPhos Pd G3, RuPhos Pd G4, BrettPhos Pd G4, etc., the base includes but is not limited to cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc.; wherein, ring A, m, X, L, R ¹ , The definitions of R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ are as described in any of the above schemes; RG is hydrogen, -B(OH) ₂ , , , -ZnBr or -ZnI.

The present invention also provides a compound represented by formula I-A1: Among them, the definitions of L, R ² , R ³ , R ⁵ and R ¹⁰ are as described in any of the above solutions.

In a certain aspect, the compound represented by formula I-A1 is any of the following compounds: , , , .

The present invention also provides a compound as shown in formula I-A2: Wherein, L, R ² , R ³ , R ⁵ and R ¹⁰ are as defined in any of the above schemes.

In one embodiment, the compound as shown in formula I-A2 is any of the following compounds: , , , .

The present invention also provides any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , .

The present invention provides a pharmaceutical composition, which contains: (1) (a therapeutically effective amount) substance Q , which is a fused ring compound represented by formula I, its stereoisomer or its pharmaceutical acceptable salts, and (2) pharmaceutically acceptable excipients.

The present invention provides the use of substance Q or the pharmaceutical composition as described above in the preparation of SOS1 inhibitors. The substance Q is a fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable of salt.

In the above application, preferably, the SOS1 inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or a control sample for comparison, or prepared into a kit according to conventional methods in the field to provide a rapid test for the effect of the compound inhibiting SOS1.

The present invention provides an application of a substance Q or the above-mentioned drug composition in the preparation of a drug; the substance Q is a fused ring compound as shown in Formula I as mentioned above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the drug can be a drug for treating and/or preventing diseases related to SOS1 activity or expression.

In the application, preferably, the disease associated with SOS1 activity or expression is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granuloma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, neuroglioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer , urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic syndrome, and multiple myeloma, as well as diseases associated with genetic mutations in SOS1, including but not limited to neurofibroma type 1, Noonan syndrome, multiple lentiginous Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Costillo syndrome, Regis syndrome, and hereditary gingival fibroma type 1.

The present invention provides the use of substance Q or the pharmaceutical composition as described above in the preparation of medicines; the substance Q is the fused ring compound shown in formula I as mentioned above, its stereoisomer or its Pharmaceutically acceptable salt; the drug is a drug for treating and/or preventing the following types of diseases; the disease is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, Colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granulosa cell tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma , Cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, acute bone-associated leukemia, myelofibrosis, B-cell lymphoma, Monocytic leukemia, splenomegaly, eosinophilic syndrome, and multiple myeloma, as well as neurofibromatosis type 1, Noonan syndrome, multiple lentigo-like Noonan syndrome, capillary malformation-animal Venous malformation syndrome, cardio-facial-cutaneous syndrome, Costello syndrome, Regis syndrome and hereditary gingival fibroma type 1.

The present invention provides a method for inhibiting SOS1, which includes administering to a patient (such as a human) a therapeutically effective amount of substance Q or a pharmaceutical composition as described above; the substance Q is as shown in Formula I as described above fused ring compounds, their stereoisomers or their pharmaceutically acceptable salts.

The present invention provides a method for treating and/preventing diseases, which includes administering to a patient (such as a human) a therapeutically effective amount of substance Q or a pharmaceutical composition as described above; the substance Q is of the formula as described above The fused ring compound represented by I, its stereoisomer or its pharmaceutically acceptable salt; the disease is a disease related to the activity or expression level of SOS1.

In the method of treating and/preventing diseases, preferably, the disease related to SOS1 activity or expression is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, Colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granulosa cell tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma , Cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, acute bone-associated leukemia, myelofibrosis, B-cell lymphoma, Monocytic leukemia, splenomegaly, eosinophilic syndrome, and multiple myeloid carcinoma, as well as diseases associated with SOS1 genetic mutations, including but not limited to neurofibromatosis type 1, Noonan syndrome, and freckles multiplex Type 1 Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, cardio-facial-cutaneous syndrome, Costello syndrome, Regis syndrome and hereditary gingival fibroma type 1.

Unless otherwise specified, the terms used in the present invention have the following meanings: The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a saturated straight or branched chain alkyl group consisting only of carbon atoms and hydrogen atoms and having a specified number of carbon atoms (e.g., C _1-10 , preferably C _1-6 , more preferably C _1-4 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, or n-hexyl.

The term "alkylene" means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon group; that is, one of the hydrogens in the alkyl group is substituted, as defined above. . Examples of alkylene groups include methylene (-CH ₂ -), ethylene {including -CH ₂ CH ₂ - or -CH(CH ₃ )-}, n-propylene {including -CH ₂ CH ₂ CH ₂ -}, isopropylene {including -CH(CH ₃ )CH ₂ -, -CH(CH ₂ CH ₃ )- or -C(CH ₃ ) ₂ -}, etc.

The term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having a specified number of carbon atoms (e.g., _C2-10 , preferably _C2-6 , more preferably _C2-4 ) and connected to the rest of the molecule by a single bond, including cis-trans isomerism or ZE isomerism; for example, alkenyl includes but is not limited to vinyl (-CH= _CH2 ), propenyl (-CH=CH- _CH3 ), allyl ( _-CH2 -CH= _CH2 ), isopropenyl (-C( _CH3 )=CH2), -CH=CH- _CH2 - _CH3 , -CH2-CH=CH-CH3, -CH=CH- _{CH2 - CH2} - _CH3 , _-CH2 -CH=CH- _CH2 - _CH3 , -CH2-CH=CH- _CH2 - _CH3. , -CH=CH-CH(CH ₃ ) ₂ , -CH ₂ -CH=C(CH ₃ ) ₂ or -CH=CH-(CH ₂ ) ₃ -CH ₃ and the like.

The term "alkenylene" refers to an unsaturated divalent group derived from a straight or branched alkene molecule by removing two hydrogen atoms; that is, one hydrogen in the alkenyl group is substituted, and the alkenyl group is defined above. Examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CH- _CH2- , and the like.

The term "alkynyl" refers to a straight or branched hydrocarbon chain having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having a specified number of carbon atoms (e.g., _C2-10 , preferably _C2-6 , more preferably _C2-4 ) and connected to the rest of the molecule by a single bond; for example, alkynyl includes but is not limited to ethynyl (-C≡CH), propynyl (-C≡C- _CH3 ), -C≡C- _CH2 - _{CH3 , -CH2C≡C} -CH3, -C≡C- _{CH2 - CH2- CH3} , -CH2C≡C- _CH2- CH3, _-C≡C -CH2-CH2 _- CH3, -C≡C- _{CH2 -} CH2- _CH3 , -C≡C- _CH2 -CH( _CH3 ) ₂ , -C≡CC(CH ₃ ) ₃ , -C≡C-CH(CH ₃ ) ₂ or -CH ₂ C≡C-CH ₂ -CH ₂ -CH ₃ and the like.

The term "alkynylene" refers to an unsaturated divalent group derived from a straight or branched chain alkynyl molecule by removing two hydrogen atoms; that is, one of the hydrogen atoms in the alkynyl group is substituted, and the definition of alkynyl is as described above. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, pentynylene, and the like, for example, -C≡C-, -CH2 _- C≡CH, -C≡C- _CH2- , -C≡C-CH2 _{- CH2-} , -C≡C-CH( _CH3 )-CH2- _, -C≡CC( _CH3 ) _2- .

In the term "C _1-6 alkyl-O-", C _1-6 alkyl has the same meaning as defined above.

The term "cycloalkyl" means a saturated monocyclic or polycyclic (eg, bicyclic, tricyclic or multicyclic bridged, fused (fused) or spirocyclic ring system) carbocyclic substituent, and which may be Any suitable carbon atom is connected to the rest of the molecule by a single bond; for example, having 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, more preferably 3 to 7 ring carbon atoms; for example, C _{3- 7} Cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or wait.

The term "cycloalkenyl" means a non-aromatic cycloalkyl group which is monocyclic or polycyclic (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spirocyclic system) having at least one double bond (e.g., a carbon-carbon double bond), and which can be linked to the rest of the molecule via a single bond via any suitable carbon atom; for example, having 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, and more preferably 3 to 7 ring carbon atoms; for example, _C3-7 cycloalkenyl includes but is not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

The term "heterocyclic group" refers to a stable 3-20-membered (preferably 3-10-membered, further preferably 3-7-membered, further preferably 4-7-membered, most preferably 6-membered) saturated or partially unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged, fused or spirocyclic) heterocyclic alkyl group composed of ₂ to 14 (preferably 2 to 6) carbon atoms and 1 to 6 heteroatoms or heteroatom groups selected from N, O, S, S(=O) and S(=O)2; preferably containing 1 to 3 heteroatoms selected from N, O, S, S(=O) and S(=O)2. and S, and further preferably a 4-7 membered heterocyclic group having "1 or 2 heteroatoms, the heteroatoms being independently selected from N and O", wherein the 4-7 membered heterocyclic group may be a 4-7 membered monocyclic heterocyclic group, a 5-7 membered bridged heterocyclic group or a 5-7 membered spirocyclic heterocyclic group; examples of the 3-7 membered heterocyclic group include but are not limited to a cyclopropyl azo group, an oxirane group, Oxiranyl, thiocyclobutanyl, tetrahydrothienyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, tetrahydropyridinyl, azacyclobutyl, pyrrolidinyl, oxolinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2H-pyranyl, oxazepine, diazepine, thiazepine 1,2-dihydropyridinyl, homopiperazinyl, thiofuranyl, imidazolinyl, imidazolidinyl, thiocyclohexyl, triazinyl, dithiocyclohexyl, dithiocyclopentyl, dioxacyclohexyl, 2,6-diazaspiro[3.3]heptyl, 1,2-dihydropyridinyl, homopiperazinyl, thiofuranyl, thiopyranyl, tetrahydrofuranyl, 4H-pyranyl or dihydropyrrolyl, for example: , , , , , , , , , , , , , , , , , , or .

The term "aryl" refers to an aromatic group consisting of a conjugated hydrocarbon ring system composed of carbon atoms that satisfies the 4n+2 rule, and each ring is aromatic. In one embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 12) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.

The term "heteroaryl" means a 5-20-membered (preferably 5-12-membered, more preferably 5-10-membered, more preferably 5-8-membered, and most preferably 5-6-membered) concentric ring system radical having 2 to 15 carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, the heteroaryl may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused with a cycloalkyl, cycloalkenyl or heterocyclic group as defined above, provided that the heteroaryl is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. In one embodiment, the term "heteroaryl" refers to an aromatic group containing heteroatoms, each ring having aromaticity; preferably, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaryl or 5-6 membered heteroaryl. Examples of heteroaryl include but are not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, benzimidazolyl (e.g., ), benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzoisothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl or benzoisozolyl.

In the term "cycloalkyl-O-", cycloalkyl has the same meaning as described above.

In the term "cycloalkenyl-O-", cycloalkenyl is as defined above.

In the term "heterocyclyl-O-", heterocyclyl is as defined above.

The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.

It should be understood that as used herein, the singular forms, such as "a," and "an," include plural references unless otherwise specified.

The term "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

Unless otherwise stated, the present invention adopts traditional methods of mass spectrometry and elemental analysis, and each step and condition can refer to the conventional operating steps and conditions in the art.

Unless otherwise indicated, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis.

In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that each described individual is independent of each other and can be independent. Ground is the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols The specific options expressed between them do not affect each other.

It should be understood that in the "heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3" used in the present invention, "the heteroatom species are independently selected from N, O and S" It can be understood as "the heteroatom species is independently selected from one or more of N, O and S". When used in the present invention, "the number of heteroatoms is 1 or 2, and the heteroatom species are independently selected from N and O", "the heteroatom species are independently selected from N and O" can be understood as "the heteroatom species are independently selected from One or both of N and O".

Those skilled in the art can understand that, according to the conventions used in the art, the " ” means that the corresponding group R is connected to other fragments and groups in the compound through this site.

Unless otherwise defined, all technical and scientific terms used herein have their standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

As used herein, the fused ring compound represented by Formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. A compound contains enantiomers when it contains a chiral center. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the fused ring compound represented by formula I contains more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers as well as mixtures of diastereoisomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, Atropisomers, etc., the compounds of the present invention can also be in the form of any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, equal mixtures of atropisomers, etc. exist. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound described in the present invention contains an olefin double bond, unless otherwise stated, it includes cis isomers and trans isomers, and any combination thereof. The atropisomer of the present invention is an axial or planar chiral stereoisomer produced based on restricted intramolecular rotation.

As mentioned above, the present invention provides compounds represented by the above-mentioned types of structures, or their cis-trans isomers, meso, racemates, enantiomers, diastereomers, and atropisomers. isomers, tautomers or mixtures thereof, where "mixtures thereof" include any of the aforementioned stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, hindered Any form of mixture between transisomers), tautomers and/or mixtures (meso, racemate), such as mixtures of cis and trans isomers, enantiomers and diastereomers A mixture of enantiomers, a mixture of diastereomers, a mixture of atropisomers, or a mixture of cis-trans isomers and racemates, enantiomers and diastereomers Mixing of mixtures, mixtures of cis-trans isomers and tautomers, mixtures of atropisomers and diastereoisomers, etc.

The fused ring compound as shown in Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof is intended to encompass any fused ring compound as shown in Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof Isotopically labeled (or "radiolabeled") variants. Such a variant may be a fused ring compound as shown in Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in which one or more atoms have an atomic mass or mass number different from that normally found in nature. Obtained by atomic substitution of atomic mass or mass number. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, ³ H or ¹⁴ C are often useful. For radiography applications, ¹¹ C or ¹⁸ F are often useful.

Specific isotopic variants of the compounds of the invention, in particular those in which one or more radioactive isotopes have been incorporated, may be useful, for example, in investigating the mechanism of action or the distribution of the active ingredient in vivo; due to the relative ease of preparation and detectability properties, compounds labeled with ^3H or ^14C isotopes are particularly suitable for this purpose. In addition, the incorporation of isotopes such as deuterium can produce specific therapeutic benefits due to the greater metabolic stability of the compound, such as extending the half-life in the body or reducing the required effective dose; therefore, such modifications of the compounds of the invention can also be used in some This situation constitutes a preferred embodiment of the present invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods described below and in the operating examples, by using corresponding isotopically modified specific reagents and/or starting compounds. .

In the present invention, "pharmaceutical composition" refers to a preparation comprising the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote drug administration in an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

In the present invention, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

The term "pharmaceutical excipients", "pharmaceutically acceptable excipients" or "pharmaceutically acceptable carriers" refers to excipients and additives used in the production of drugs and the preparation of prescriptions, and is all substances contained in drug preparations except the active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional drug composition, and can also provide methods to dissolve the active ingredient at the desired rate after the subject receives the drug, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients may be inert fillers, or provide a certain function, such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavor correctors and sweeteners.

Pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

When used as a medicine, the fused ring compound represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt can be administered in any form of a pharmaceutical composition. These compositions may be prepared according to methods well known in the pharmaceutical art and may be administered by a variety of routes, depending on the desired local or systemic treatment and the area to be treated. Administration may be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal or intranasal) , oral (solid and liquid formulations) or parenteral forms of administration. Examples of solid oral dosage forms include, but are not limited to, powders, capsules, caplets, softgels, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, injectable solutions, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, salves, lotions, ointments, gels, drops, suppositories, sprays, liquids and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants. Oral administration may include dosage forms formulated for once daily or twice daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be by continuous infusion pump. Conventional pharmaceutical carriers, water, powdered or oily bases, thickening agents, and the like may be necessary or desirable. Pharmaceutical compositions including the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).

The term "treatment" refers to therapeutic therapy or palliative measures. When referring to a specific condition, treatment means: (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade that causes or causes the condition or (b) the condition one or more biological manifestations of, (3) ameliorating one or more symptoms, effects, or side effects associated with a condition, or one or more symptoms, effects, or side effects associated with a condition or its treatment, or (4) alleviating a condition or condition The development of one or more biological manifestations. "Treatment" may also refer to prolonging survival compared to expected survival without treatment.

The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that is effective to treat a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

The term "patient" refers to any animal, preferably a mammal, and most preferably a human, to which a compound or composition is or has been administered in accordance with embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively nontoxic, safe, and suitable for use by a patient) acid or base. When the compound contains relatively acidic functional groups, base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc. When the compound contains relatively basic functional groups, acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effects of the present invention are that the fused ring compound of the present invention as shown in Formula I has good inhibitory activity against SOS1 and is expected to treat and/or prevent diseases related to the activity or expression of SOS1.

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The nuclear magnetic resonance chemical shift ( δ ) is given in parts per million (ppm). The nuclear magnetic resonance is measured using a Bruker AVANCE-400 nuclear magnetic resonance instrument, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ) or deuterated chloroform (CDCl ₃ ), and the internal standard is tetramethylsilane (TMS). The mass spectrum is measured using an Agilent 1260-6125B single quadrupole liquid-mass spectrometer, which uses an electrospray ion source (ESI).

For silica column chromatography, a Biotage Selekt rapid preparation chromatograph and appropriate specifications of Biotage BK-SIL silica prepacked columns or Agela Claricep Flash silica prepacked columns were used.

The silicone plate used for thin layer chromatography uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plate, the specification used is 0.15 mm ~ 0.20 mm, and the specification used for preparing thin layer chromatography is 0.4 mm ~ 0.5 mm.

Preparative high performance liquid chromatography (preparative HPLC) was performed using an AutoPurification LC preparative system equipped with an ACQUITY QDa mass spectrometer produced by Waters. The preparative chromatographic column used was a SunFire C18 5 μm 19x250 mm OBD preparative column. The mobile phase used different gradients of water (containing 0.1% formic acid)-acetonitrile to elute the compounds.

The English abbreviations of the present invention are as follows: Boc: tert-butyloxycarbonyl; TIPS: triisopropylsilyl; Bn: benzyl; DMSO: dimethyl sulfoxide; Tf: trifluoromethanesulfonyl; Ms: methanesulfonyl.

Example 1 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) base)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-2(1H)- Ketone (Compound 1) and 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2- Fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine- 2(1H)-ketone (compound 2)

Step 1: 4-Bromo-6-chloro-2-methylpyridin-3-ol

Dissolve 6-chloro-2-methylpyridin-3-ol (10 g, 69.6 mmol) in acetonitrile (100 mL), add N-bromosuccinimide (13.6 g, 76.6 mmol). Stir the reaction at room temperature for 1.5 hours. The reactant is concentrated under reduced pressure, diluted with saturated aqueous sodium sulfite solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), and extracted with ethyl acetate (200 mL×2). The organic phase is then washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is slurried with ethanol (80 mL) to obtain the product 4-bromo-6-chloro-2-methylpyridin-3-ol, a yellow solid (14.0 g, yield 93%).

ESI-MS m/z：221.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.92 (s, 1H), 7.78 (s, 1H), 2.40 (s, 3H).

Step 2: tert-Butyl(S)-2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

4-Bromo-6-chloro-2-methylpyridin-3-ol (2.5 g, 11.2 mmol) and (S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (2.7 g , 13.5 mmol) was dissolved in tetrahydrofuran (50 mL), protected by nitrogen, and triphenylphosphine (3.5 g, 13.5 mmol) and diisopropyl azodicarboxylate (2.7 g, 13.5 mmol) were added at 0°C. The reaction was allowed to warm to room temperature and stirred for 2 hours. Add water (100 mL) to dilute, and extract with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 15:1, volume ratio) to obtain the product tert-butyl (S)-2-((4- Bromo-6-chloro-2-methylpyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate, colorless oil (4.7 g, yield 86%).

ESI-MS m/z: 405.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 4.12 (s, 1H), 4.05-3.75 (m, 2H), 3.42 (t, J = 6.7 Hz, 2H), 2.52 (s, 3H), 2.36-2.22 (m, 1H), 2.14-1.85 (m, 3H), 1.46 (s, 9H).

Step 3: tert-Butyl (S)-2-((6-chloro-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

tert-Butyl(S)-2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (5.0 g, 12.3 mmol) was dissolved in dimethylsulfoxide (20 mL), 23% methylamine aqueous solution (30 mL) was added, and the reaction was stirred at 105°C for 72 hours. The reaction was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product tert-butyl (S)-2-((6-chloro-2-methyl-4-(methylamino)pyridin-3-yl)oxy). )Methyl)pyrrolidine-1-carboxylate, colorless oil (4.4 g), the crude product was directly used in the next reaction.

ESI-MS m/z: 356.2 [M+H] ⁺ .

Step 4: tert-butyl (S)-2-((6-chloro-5-iodo-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve tert-butyl (S)-2-((6-chloro-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (4.4 g, 12.4 mmol) in acetic acid (20 mL), add N-iodosuccinimide (3.0 g, 13.3 mmol), and stir at room temperature for 1.5 hours. Add saturated aqueous sodium sulfite solution (100 mL) to dilute, add saturated aqueous sodium bicarbonate solution to neutralize, and extract with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 6:1, volume ratio) to give the product tert-butyl (S)-2-((6-chloro-5-iodo-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate as a yellow oil (4.6 g, yield 79%).

ESI-MS m/z: 482.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.44 (brs, 1H), 4.01 (s, 1H), 3.72 (s, 1H), 3.63 (t, J = 11.2 Hz, 1H), 3.27 (s, 3H), 3.08 (s, 3H), 2.24 (s, 3H), 2.03 (brs, 2H), 1.94 (s, 1H), 1.89-1.77 (m, 1H), 1.38 (s, 9H).

Step 5: tertiary butyl(S)-2-((6-chloro-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methyl-4- (Methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve tert-butyl (S)-2-((6-chloro-5-iodo-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (3.2 g, 6.65 mmol), sodium acetate (150 mg, 0.67 mmol), tri(o-methylphenyl)phosphine (405 mg, 1.33 mmol), triethylamine (1.3 g, 13.3 mmol) and ethyl acrylate (2.0 g, 20.0 mmol) in N,N-dimethylformamide (30 mL). Stir the mixture at 90°C for 4 hours under nitrogen protection. After the reaction mixture was cooled to room temperature, water (300 mL) was added to dilute it, and ethyl acetate (500 mL) was added to extract it. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 5:1, volume ratio) to give the product tert-butyl (S)-2-((6-chloro-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate as a yellow oil (2.4 g, yield 80%).

ESI-MS m/z: 454.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (d, J = 16.4 Hz, 1H), 6.13 (d, J = 16.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.09 (s , 1H), 3.95-3.80 (m, 2H), 3.54-3.35 (m, 2H), 2.90 (d, J = 4.4 Hz, 3H), 2.39 (s, 3H), 2.08 (s, 2H), 2.03- 1.95 (m, 1H), 1.94-1.83 (m, 1H), 1.47 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H).

Step 6: tert-butyl (S)-2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate

tert-Butyl(S)-2-((6-chloro-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methyl-4-(methane Amino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (2.4 g, 5.30 mmol) was dissolved in ethanol (20 mL), and sodium methylmercaptide (408 mg, 5.83 mmol) was added , stirred at room temperature for 0.5 hours. The reaction was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product tert-butyl (S)-2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate, yellow oil (2.0 g, yield 92%).

ESI-MS m/z: 408.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J = 9.8 Hz, 1H), 6.75 (d, J = 9.8 Hz, 1H), 4.18 (s, 1H), 3.94 (s, 3H), 3.73 (d, J = 61.2 Hz, 2H), 3.40 (s, 2H), 2.60 (s, 3H), 2.14 (brs, 2H), 2.02-1.86 (m, 2H), 1.45 (s, 9H).

Step 7: tert-butyl (S)-2-((3-bromo-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve tert-butyl (S)-2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate (2.0 g, 4.9 mmol) in acetic acid (30 mL), add N-bromosuccinimide (1.8 g, 9.83 mmol), and stir at 60°C for 5 hours. Add saturated sodium sulfite aqueous solution (100 mL) to dilute, and extract with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 4:1, volume ratio) to give the product tert-butyl (S)-2-((3-bromo-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate as a yellow solid (600 mg, yield 25%).

ESI-MS m/z：486.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 4.20 (s, 1H), 4.04 (s, 3H), 3.89-3.73 (m, 2H), 3.50 -3.37 (m, 2H), 2.59 (s, 3H), 2.16 (brs, 2H), 2.06-1.92 (m, 2H), 1.47 (s, 9H).

Step 8: tertiary butyl(S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxy Generation-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve tert-butyl (S)-2-((3-bromo-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate (600 mg, 1.23 mmol) and 1-acetylpiperidin-4-one (696 mg, 4.94 mmol) in tetrahydrofuran (35 mL). Add sodium iodide (49.4 mL, 4.94 mmol, 0.1 M tetrahydrofuran solution) dropwise at -30°C under nitrogen protection. Stir the reaction at -30°C for 0.5 hours. Add saturated aqueous ammonium chloride solution (100 mL) at -30°C to dilute, and extract with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 1:15, volume ratio) to give the product tert-butyl (S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate as a yellow oil (550 mg, yield 81%).

ESI-MS m/z: 549.2 [M+H] ⁺ .

Step 9: tertiary butyl(S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoro) Methyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy )Methyl)pyrrolidine-1-carboxylate

tert-butyl (S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate (550 mg, 1.0 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (91 mg, 0.1 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (570 mg, 3.0 mmol) and tert-sodium butoxide (288 mg, 3.0 mmol) were dissolved in toluene (150 mL). mL), nitrogen protection, stirring at 100°C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 25:1, volume ratio) to obtain the product tert-butyl (S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate, a yellow oil (350 mg, yield 50%).

ESI-MS m/z: 702.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67-7.57 (m, 1H), 7.55-7.40 (m, 2H), 7.15 (td, J = 7.6, 2.0 Hz, 1H), 6.92 (t, J = 55.2, 1H), 5.84 (brs, 1H), 5.59 (brs, 1H), 5.55-5.34 (m, 1H), 4.61 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 7.2 Hz, 3H), 3.76-3.56 (m, 4H), 3.52-3.40 (m, 1H), 3.36 (d, J = 7.8 Hz, 2H), 3.17 (td, δ ( d, J = 2.8 Hz, 3H), 2.09-2.05 (m, 1H), 1.94 (td, J = 12.8, 4.4 Hz, 3H) , 1.84-1.74 (m, 1H), 1.62 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H).

Step 10: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-pyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one

tert-Butyl(S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl) )-2-Fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl Pyrrolidine-1-carboxylate (350 mg, 0.50 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure to obtain 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) Ethyl)amino)-1,7-dimethyl-8-((S)-pyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one crude product, directly used for the next reaction.

ESI-MS m/z: 602.3 [M+H] ⁺ .

Step 11: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 1)

The crude product of 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-pyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one obtained in step 9 was dissolved in tetrahydrofuran (6 mL), and 30% aqueous formaldehyde solution (3 mL) and sodium triacetoxyborohydride (358 mg, 0.997 mmol) were added, and stirred at room temperature for 0.5 hours. Saturated aqueous sodium bicarbonate solution (100 mL) was added for dilution, and ethyl acetate (100 mL×3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 13:1, volume ratio) to obtain compound 1 as a yellow solid (170 mg, yield 55%).

ESI-MS m/z: 616.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 3.2 Hz, 1H), 7.51 (q, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 55.2 Hz, 1H), 5.77 (d, J = 5.6 Hz, 1H), 5.59 (p, J = 6.8 Hz, 1H), 5.31 (t, J = 7.6 Hz, 1H), 4.62 (d, J = 13.2 Hz, 1H), 3.92 (s, 3H), 3.71 (d, J = 8.5 Hz, 2H), 3.57 m/z 3H), 3.87 (d, J = 13.2, 2.4 Hz , 3H) , 1.71 (m, 4H), 1.63 (d, J = 7.0 Hz , 3H).

Step 12: (3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) yl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 59)

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 1, 150 mg, 0.244 mmol) was dissolved in dichloromethane (5 mL) and diethylaminosulfur trifluoride (78 mg, 0.487 mmol) was added at 0°C under nitrogen protection. The reaction mixture was heated to room temperature and stirred for 2 hours. Water (20 mL) was added to dilute the mixture and ethyl acetate (50 mL) was added to extract the mixture. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product (3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one, which was directly used in the next reaction.

ESI-MS m/z: 618.3 [M+H] ⁺ .

Step 13: (3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) )ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H) -Ketone (compound 2)

The (3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) obtained in step 12 )ethyl)amino)-1,7-dimethyl-8-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H) -The crude ketone was dissolved in methanol (15 mL), and 30% sodium methoxide in methanol (455 mg, 2.44 mmol) was added. The reaction solution was stirred at 40°C for 24 hours, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 2 as a white solid (26 mg, yield 17%).

ESI-MS m/z: 630.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.51 (q, J = 6.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz , 1H), 6.91 (t, J = 55.1 Hz, 1H), 5.59 (p, J = 7.2 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H ), 3.87 (s, 3H), 3.76-3.63 (m, 2H), 3.56-3.40 (m, 2H), 3.27 (s, 3H), 3.12 (t, J = 7.2 Hz, 1H), 2.93 (q, J =10.0 Hz, 1H), 2.72-2.49 (m, 4H), 2.47 (d, J = 2.0 Hz, 3H), 2.37 (d, J = 2.0 Hz, 3H), 2.30 (q, J = 9.2 Hz, 1H), 2.13 (s, 3H), 2.10-2.00 (m, 2H), 1.95-1.85 (m, 1H), 1.84-1.67 (m, 3H), 1.64 (d, J = 7.0 Hz, 3H). ¹³ C NMR (101 MHz, CDCl3) δ 168.91, 162.27, 152.21, 149.77, 149.75, 140.14, 133.22, 132.87, 132.75, 131.01, 129.76, 129.29, 125.20, 124 .21, 113.16, 110.87, 110.80, 101.91, 101.89, 64.83, 57.64 , 50.31, 46.58, 46.49, 42.32, 41.77, 37.31, 33.91, 32.87, 32.18, 31.70, 30.98, 29.14, 22.66, 21.89, 21.46, 20.10.

Embodiment 2

3-(1-ethyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 3)

Compound 2 was prepared by referring to the method of steps 2 to 13 in Example 1, wherein the raw material (S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol in step 2 was replaced with (R)- (-)-1-tert-Butoxycarbonyl-2-pyrrolidinemethanol.

ESI-MS m/z: 630.3 [M+H] ⁺ .

Example 3

(R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 4)

Step 1: tert-Butyl(2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)ethyl)(methyl)carbamate

Dissolve 4-bromo-6-chloro-2-methylpyridin-3-ol (21 g, 95 mmol) and tert-butyl (2-hydroxyethyl) (methyl) carbamate (18.2 g, 104.5 mmol) in tetrahydrofuran (400 mL), add triphenylphosphine (30 g, 114 mmol) and diisopropyl azodicarboxylate (23 g, 114 mmol) at 0°C under nitrogen protection. The reaction mixture was heated to room temperature and stirred for 1 hour. Water (400 mL) was added to dilute the mixture, and ethyl acetate (800 mL) was added to extract the mixture. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 15:1, volume ratio) to obtain the product, a colorless oil (32 g, yield 89%).

ESI-MS m/z: 379.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 4.01 (d, J = 16.7 Hz, 2H), 3.62 (s, 2H), 3.03 (s, 3H), 2.49 (s, 3H), 1.45 (s, 9H).

Step 2: tert-butyl (2-((6-chloro-2-methyl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate

tert-Butyl(2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)ethyl)(methyl)carbamate (32 g, 84.6 mmol) Dissolve in dimethyl sulfoxide (80 mL), add methylamine aqueous solution (80 mL, 23%), seal the tube at 120°C and stir for 16 hours. After cooling to room temperature, add water (300 mL) to dilute, and add ethyl acetate (600 mL) for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as a colorless oil (28.3 g, crude product).

ESI-MS m/z: 330.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.32 (s, 1H), 3.87 (s, 2H), 3.55 (t, J = 4.9 Hz, 2H), 2.98 (s, 3H), 2.82 (d, J = 5.1 Hz, 3H), 2.33 (s, 3H), 1.45 (s, 9H).

Step 3: tert-butyl (2-((6-chloro-5-iodo-yl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate

tert-Butyl(2-((6-chloro-2-methyl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate (28.3 g, 84.6 mmol) was dissolved in acetic acid (300 mL), add N-iodosuccinimide (28.5 g, 126.9 mmol), stir at room temperature for 20 hours. Add saturated sodium sulfite aqueous solution (200 mL) to dilute, add saturated sodium bicarbonate The aqueous solution (200 mL) was neutralized, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 6:1, volume ratio ) to obtain the product as a yellow oil (37.3 g, yield 96%).

ESI-MS m/z：456.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.62 (s, 1H), 3.88 – 3.75 (m, 2H), 3.57 (s, 2H), 3.16 (s, 3H), 2.99 (s, 3H), 2.35 (s, 3H), 1.45 (s, 9H).

Step 4: Ethyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate

tert-Butyl(2-((6-chloro-5-iodo-yl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate (28.1 g , 61.7 mmol), palladium acetate (1.38 mg, 6.17 mmol), tris(o-methylphenyl)phosphorus (3.74 mg, 12.3 mmol), triethylamine (18.7 g, 185.1 mmol) and ethyl acrylate (30.8 g, 308.8 mmol), dissolved in N,N-dimethylformamide (300 mL). Under nitrogen protection, the reaction was stirred at 100°C for 16 hours. After cooling to room temperature, water (900 mL) was added to dilute, and ethyl acetate ( 900 mL) for extraction. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was silica gel column chromatographed (petroleum ether/ethyl acetate = 5:1, volume ratio) to obtain the product as a yellow oil (24 g, collected rate 91%).

ESI-MS m/z: 428.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 16.2 Hz, 1H), 6.12 (d, J = 16.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.89 (s, 2H), 3.58 (t, J = 5.0 Hz, 2H), 3.00 (s, 3H), 2.89 (d, J = 5.3 Hz, 3H), 2.37 (s, 3H), 1.46 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H).

Step 5: tert-butyl (2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl (methyl)carbamate

3-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-chloro-6-methyl-4-(methylamino)pyridine-3- (ethyl) acrylate (24 g, 56.2 mmol) was dissolved in ethanol (250 mL), sodium methylmercaptide (4.73 g, 67.4 mmol) was added, and stirred at room temperature for 1 hour. Spin the solvent dry, add water (500 mL) to dilute, and add ethyl acetate (600 mL) for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as a yellow oil (14.3 g, yield 67%).

ESI-MS m/z: 382.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J = 9.8 Hz, 1H), 6.74 (d, J = 9.8 Hz, 1H), 3.93 (s, 3H), 3.85 (d, J = 18.7 Hz , 2H), 3.64 (d, J = 5.4 Hz, 2H), 3.03 (s, 3H), 2.56 (s, 3H), 1.47 (d, J = 3.7 Hz, 9H).

Step 6: tert-butyl(2-((3-bromo-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl )oxy)ethyl(methyl)carbamate

Dissolve tert-butyl (2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl (methyl)carbamate (6.3 g, 16.5 mmol) in acetic acid (120 mL), add dibromohydantoin (14.2 g, 49.6 mmol), and stir at 75°C for 5 hours. Add saturated sodium sulfite aqueous solution (200 mL) to dilute, and extract with ethyl acetate (400 mL). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is chromatographed on a silica gel column (petroleum ether/ethyl acetate = 4:1, volume ratio) to obtain the product, a yellow solid (6.5 mg, yield 85%).

ESI-MS m/z: 460.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 3.99 (s, 3H), 3.84 (d, J = 21.1 Hz, 2H), 3.64 (d, J = 5.5 Hz, 2H), 3.03 (s, 3H), 2.55 (s, 3H), 1.47 (s, 9H).

Step 7: tertiary butyl(2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl(methyl)carbamate

Dissolve tert-butyl (2-((3-bromo-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl (methyl)carbamate (600 mg, 1.3 mmol) and 1-acetylpiperidin-4-one (737 mg, 5.22 mmol) in tetrahydrofuran (15 mL). Under nitrogen protection, add sodium iodide (52 mL, 52 mmol, 0.1 M in THF) dropwise at -40°C. Stir the reaction at -40°C for 0.5 h. Add saturated aqueous ammonium chloride solution (100 mL) at -40°C to dilute the mixture. Add ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 1:15, volume ratio) to obtain the product, a yellow oil (500 mg, yield 73.7%).

ESI-MS m/z: 523.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 5.27 (s, 1H), 4.62 (d, J = 10.4 Hz, 1H), 3.97 (s, 3H), 3.92 – 3.82 (m, 2H), 3.76 (dd, J = 14.3, 7.8 Hz, 2H), 3.65 (t, J = 5.4 Hz, 2H), 3.19 (d, J = 18.2 Hz, 1H), 3.04 (s, 3H), 2.58 ( s, 3H), 2.14 (d, J = 9.9 Hz, 5H), 1.87 (td, J = 12.9, 5.1 Hz, 2H), 1.48 (s, 9H).

Step 8: tert-butyl (R)-(2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl(methyl)carbamate

tert-butyl (2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl (methyl)carbamate (500 mg, 0.957 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (96 mg, 0.096 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (271 mg, 1.436 mmol) and tert-sodium butoxide (275 mg, 2.87 mmol) were dissolved in toluene (10 mL), nitrogen protection, stirring reaction at 90°C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 25:1, volume ratio) to obtain the product, a yellow oil (400 mg, yield 62%).

ESI-MS m/z: 676.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.55 – 7.40 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 55.1 Hz, 1H) , 5.89 (s, 1H), 5.62 (dd, J = 17.5, 11.8 Hz, 2H), 4.61 (d, J = 11.1 Hz, 1H), 3.91 (s, 3H), 3.71 (d, J = 8.9 Hz, 4H), 3.56 (t, J = 5.2 Hz, 2H), 3.24 – 3.08 (m, 1H), 3.00 (s, 3H), 2.32 (d, J = 0.9 Hz, 3H), 2.23 (d, J = 13.3 Hz, 1H), 2.13 (d, J = 5.4 Hz, 3H), 2.05 (d, J = 12.9 Hz, 1H), 1.98 – 1.78 (m, 2H), 1.62 (d, J = 6.7 Hz, 3H), 1.46 (d, J = 8.7 Hz, 9H).

Step 9: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(methylamino)ethoxy)-1,6-naphthyridin-2(1H)-one

tert-Butyl(R)-(2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)- 2-Fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl ( Methyl)carbamate (180 mg, 0.267 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 0.5 hours. Concentrate under reduced pressure, and the residue was used directly in the next step One step reaction.

ESI-MS m/z: 576.3 [M+1] ⁺ .

Step 10: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Dissolve the residue obtained in step 9 in tetrahydrofuran (5 mL), add formaldehyde aqueous solution (1.5 mL, 30%) and sodium triacetyloxyborohydride (566 mg, 2.67 mmol), and stir at room temperature for 0.5 hours. Add saturated aqueous sodium bicarbonate solution (10 mL) to dilute, and add ethyl acetate (50 mL) to extract. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel column (dichloromethane/methanol = 13:1, volume ratio) to obtain the product as a yellow solid (130 mg).

ESI-MS m/z: 590.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, J = 3.7 Hz, 1H), 7.58 – 7.41 (m, 2H), 7.16 (dd, J = 7.6, 6.3 Hz, 1H), 6.93 (t, J = 55.1 Hz, 1H), 5.88 (s, 1H), 5.61 (d, J = 7.3 Hz, 2H), 4.61 (d, J = 12.3 Hz, 1H), 3.92 (s, 3H), 3.79 – 3.68 (m, 4H), 3.17 (td, J = 12.7, 2.5 Hz, 1H), 2.81 (s, 2H), 2.43 (s, 6H), 2.37 (d, J = 0.7 Hz, 3H), 2.26 – 2.19 (m, 1H), 2.13 (d, J = 5.1 Hz, 3H), 2.05 (d, J = 12.4 Hz, 1H), 1.99 – 1.89 (m, 1H), 1.87 – 1.75 (m, 1H), 1.62 (d, J = 6.0 Hz, 3H).

Step 11: (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (130 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and diethylaminosulfur trifluoride (70 mg, 0.447 mmol) was added at 0°C under nitrogen protection. The reaction mixture was heated to room temperature and stirred for 1 hour. Water (20 mL) was added to dilute the mixture and ethyl acetate (50 mL) was added to extract the mixture. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was directly used in the next reaction.

ESI-MS m/z: 592.3 [M+1] ⁺ .

Step 12: (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(2-(dimethylamino)ethoxy)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Dissolve the residue from step 11 in methanol (15 mL) and add sodium methoxide in methanol (455 mg, 2.44 mmol, 30% w.t. in MeOH). The reaction solution was stirred at 40°C for 24 hours, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 4 as a white solid (25 mg, yield 19%).

ESI-MS m/z: 604.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.55 – 7.42 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 55.1 Hz, 1H), 5.68 – 5.51 (m, 1H), 5.20 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 11.0 Hz, 1H), 4.15 (s, 2H), 3.85 (s, 3H), 3.73 (dd, J = 18.4, 12.4 Hz, 3H), 3.54 – 3.40 (m, 1H), 3.27 (s, 3H), 2.99 – 2.86 (m, δ 5.1 (d, J = 14.1 Hz, 1H), 2.82 (t, J = 6.0 Hz, 2H), 2.42 (s, 6H), 2.37 (d, J = 1.6 Hz, 3H), 2.13 (s, 3H), 2.04 (d, J = 14.1 Hz, 1H), 1.90 (dd, J = 18.5, 6.9 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H).

Example 4

(R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(methylamino)ethoxy)-1,6-naphthyridin-2(1H)-one (Compound 5)

Starting from the intermediate (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(methylamino)ethoxy)-1,6-naphthyridin-2(1H)-one (prepared in Step 9 of Example 3), Compound 5 was prepared with reference to Steps 11 and 12 of Example 3.

ESI-MS m/z: 590.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.69 (s, 1H), 7.46 (dd, J = 18.7, 11.7 Hz, 2H), 7.17 (s, 1H), 6.90 (t, J = 55.1 Hz, 1H), 5.66 – 5.54 (m, 1H), 5.25 (s, 1H), 4.57 (d, J = 11.5 Hz, 1H), 3.83 (s, 5H), 3.70 (d, J = 13.8 Hz, 1H), 3.48 (dd, J = 23.0, 10.3 Hz, 1H), 3.27 (s, 3H), 3.16 (d, J = 4.8 Hz, 2H), 2.99 – 2.86 (m, 1H), 2.64 (d , J = 13.0 Hz, 3H), 2.51 (ddd, J = 31.6, 13.8, 4.5 Hz, 2H), 2.37 (d, J = 1.3 Hz, 3H), 2.13 (s, 3H), 2.08 – 1.98 (m, 1H), 1.89 (t, J = 11.2 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H).

Embodiment 5

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (Compound 6)

Step 1: 3-(benzyloxy)-4-bromo-6-chloro-2-methylpyridine

Dissolve 4-bromo-6-chloro-2-methylpyridin-3-ol (14.0 g, 62.9 mmol) in N,N-dimethylformamide (50 mL), and add benzyl bromide (14.0 g, 81.8 mmol), and the reaction was stirred at room temperature for 16 hours. Add water (300 mL) to dilute, add methyl tert-butyl ether (250 mL×2) for extraction. The organic phase was washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was beaten with ethanol to obtain the product as a white solid (17.5 g, yield 89%).

ESI-MS m/z: 312.0 [M+H] ⁺ .

Step 2: 3-(benzyloxy)-6-chloro-N,2-dimethylpyridin-4-amine

Dissolve 3-(benzyloxy)-4-bromo-6-chloro-2-methylpyridine (17.5 g, 56.0 mmol) in dimethylstyrene (150 mL), and add 25% methylamine aqueous solution (80 mL ), stir and react at 105°C for 5 hours. After cooling to room temperature, add saturated aqueous ammonium chloride solution (250 mL) to dilute, and add ethyl acetate (300 mL×2) for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 6:1, volume ratio) to obtain the product, a white solid ( 8.0 g, yield 54%).

ESI-MS m/z: 263.1 [M+H] ⁺ .

Step 3: 3-(Benzyloxy)-6-chloro-5-iodo-N,2-dimethylpyridin-4-amine

Dissolve 3-(Benzyloxy)-6-chloro-N,2-dimethylpyridin-4-amine (8.0 g, 30.5 mmol) in acetic acid (40 mL), add N-iodosuccinimide (8.2 g, 36.6 mmol), and stir at room temperature for 6 hours. Add saturated sodium sulfite aqueous solution (200 mL) to dilute, add saturated sodium bicarbonate aqueous solution (400 mL) to neutralize, and extract with ethyl acetate (200 mL×2). The organic phase is washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is chromatographed on a silica gel column (petroleum ether/ethyl acetate = 10:1, volume ratio) to obtain the product, a white solid (8.3 g, yield 73%).

ESI-MS m/z: 389.0 [M+H] ⁺ .

Step 4: Ethyl 3-(5-(benzyloxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate

Dissolve 3-(Benzyloxy)-6-chloro-5-iodo-N,2-dimethylpyridin-4-amine (8.3 g, 21.4 mmol), sodium acetate (480 mg, 2.14 mmol), tri(o-methylphenyl)phosphine (1.3 g, 4.27 mmol), triethylamine (4.3 g, 42.7 mmol) and ethyl acrylate (6.4 g, 64.1 mmol) in N,N-dimethylformamide (120 mL). Stir the mixture at 95°C for 6 hours under nitrogen protection. After cooling to room temperature, add water (500 mL) to dilute, and extract with ethyl acetate (300 mL×2). The organic phase was washed with a saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 6:1, volume ratio) to obtain the product as a white solid (5.8 g, yield 75%).

ESI-MS m/z: 361.1 [M+H] ⁺ .

Step 5: 8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Ethyl 3-(5-(benzyloxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate (4 g, 11.1 mmol) was dissolved in anhydrous ethanol (40 mL), sodium methyl mercaptan (0.77 g, 11.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 5:1, volume ratio) to obtain the product (2.7 g, yield 77%).

ESI-MS m/z: 315 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 9.8 Hz, 1H), 7.46-7.35 (m, 5H), 6.75 (d, J = 9.8 Hz, 1H), 4.79 (s, 2H) , 3.89 (s, 3H), 2.59 (s, 3H).

Step 6: 8-(benzyloxy)-3-bromo-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Dissolve 8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (8.0 g, 25.4 mmol) in N,N-dimethyl formamide (120 mL), add dibromohydantoin (36.3 g, 127 mmol), react at 70°C, protect from light, and stir for 5 hours. Add saturated sodium sulfite aqueous solution (200 mL) to dilute, and add ethyl acetate (400 mL) to extract. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate = 5:1, volume ratio) to obtain the product as a light yellow solid (7 g, yield 70%).

ESI-MS m/z: 393.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.47-7.29 (m, 5H), 4.79 (s, 2H), 3.96 (s, 3H), 2.58 (s, 3H).

Step 7: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

To a 2L three-necked flask, add 8-(benzyloxy)-3-bromo-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (7.5 g, 19.03 mmol), tetrahydrofuran (200 mL) and 1-acetyl-4-piperidone (10.7 g, 76.10 mmol) to completely dissolve them. Under nitrogen protection, the reaction solution was cooled to -40°C, and 0.1 mol/L disodium iodide tetrahydrofuran solution (500 mL) was added dropwise. After the addition was completed, the reaction was continued at -40°C for 0.5 hour. Saturated ammonium chloride (300 mL) was added to quench the reaction, and then extracted with ethyl acetate (400 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate = 3:1, volume ratio) to obtain an off-white solid 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (6.6 g, yield 76%).

ESI-MS m/z: 456.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.45 – 7.36 (m, 5H), 5.35-5.2 (m, 1H), 4.80 (s, 2H), 4.68 – 4.52 (m, 1H) ), 3.92 (s, 3H), 3.80=-3.60(m, 1H), 3.33 – 3.10 (m, 1H), 2.61 (s, 3H), 2.18 (s, 1H), 2.16 (s, 3H), 1.92 -1.81 (m, 2H), 1.29 – 1.23 (m, 2H).

Step 8: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Add 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1 to a 250 mL round bottom flask, 6-Naphthyridin-2(1H)-one (9.6 g, 21.03 mmol), toluene (100 mL), sodium tert-butoxide (6.0 g, 63.10 mmol), methanesulfonic acid (2-dicyclohexylphosphine)- 3,6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (Brettphos Pd G3, 1.9 g, 2.10 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (6.0 g, 31.64 mmol ), nitrogen protection, stirring reaction at 80°C for 1 hour. The reaction solution was cooled to room temperature, and water and ethyl acetate were added to extract and separate the layers. The organic phase was washed once with 10% citric acid solution (300 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. , the residue was silica gel column chromatographed (petroleum ether/ethyl acetate = 3:1, volume ratio) to obtain a light yellow solid (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl) -8-(benzyloxy)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6- Naphthyridin-2(1H)-one (8.8 g, yield 70%).

ESI-MS m/z: 609.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.55 (m, 2H), 7.50-7.44 (m, 1H), 7.40-7.35 (m, 4H),7.23-7.16 (m, 1H), 7.16 – 7.08 (m, 1H), 7.07 – 6.95 (m, 1H), 6.86 (dd, J = 55.0, 3.4 Hz, 1H), 5.82-5.60 (m, J = 50.7 Hz, 2H), 4.73-4.53 (m, 3H), 3.88 (s, 3H), 3.73-3.64 (m, 2H), 3.16 (t, J = 12.7 Hz, 1H), 2.42 (s, 2H), 2.33 – 2.25 (m, 3H), 2.13 (d, J = 7.9 Hz, 3H), 2.06-1.98 (m, 1H), 1.75-1.60 (m, 4H).

Step 9: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) hydroxy)amino)-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Add (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-((1-(3-( Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (2.0 g, 3.23 mmol), methanol ( 50 mL), 10% palladium on carbon (1.5 g), stir and react at room temperature for 1 hour under hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate = 3:1, volume ratio) to obtain a light yellow solid (R)-3-(1-acetyl-4-hydroxy) Piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-hydroxy-1,7-dimethyl-1 ,6-naphthyridin-2(1H)-one (1.4 g, yield 80%).

ESI-MS m/z: 519.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.52 (q, J = 7.8 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.17-7.11 (m, 1H), 6.91 (t, J = 55.1 Hz, 1H), 5.93 (s, 1H), 5.63-5.51(m, 1H), 5.49-5.3 (m, 1H), 4.51 (d, J = 13.4 Hz, 1H), 3.95 (s, 3H), 3.71 – 3.59 (m, 2H), 3.10 (td, J = 12.8, 2.9 Hz, 1H), 2.35 (s, 2H), 2.23 – 2.12 (m, 1H), 2.08 (d, J = 2.2 Hz, 3H), 1.99 (d, J = 12.7 Hz, 2H), 1.90 – 1.75 (m, 3H), 1.61 (d, J = 6.9 Hz, 3H).

Step 10: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

To (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (300 mg, 0.58 mmol), N,N-diisopropylethylamine (150 mg , 1.16 mmol) and 4-dimethylaminopyridine (71 mg, 0.58 mmol) in dichloromethane (15 mL), N-phenylbis(trifluoromethanesulfonyl)imine (270 mg, 0.75 mmol) was added ), stir the reaction at room temperature for 1.5 hours, add dichloromethane and water to extract and separate the layers, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography (methanol/dichloromethane= 20:1, volume ratio) to obtain the product, a yellow solid product (340 mg, yield 90%).

ESI-MS m/z: 651 [M+H] ⁺ .

Step 11: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) (base)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl triflate (38 mg, 0.058 mmol) was dissolved in dry To N,N-dimethylformamide (5 mL), add tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) and zinc cyanide (68 mg, 0.58 mmol) under nitrogen protection, and the reaction solution was Stir for 1 hour at 110°C, cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate (20 mL), extract with ethyl acetate (100 mL), wash with water (20 mL), and saturated brine (20 mL). mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through silica gel column chromatography (dichloromethane/methanol = 20:1, volume ratio) to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 6, a white solid. (4 mg, yield 13%).

ESI-MS m/z: 528.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.6 Hz, 1H), 7.57 – 7.45 (m, 2H), 7.36 – 7.28 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 55.0 Hz, 1H), 6.00 – 5.73 (m, 2H), 4.63 – 4.50 (m, 1H), 4.07 (s, 3H), 3.78 – 3.64 (m, 2H), 3.23 – 3.10 (m, 1H), 2.62 (s, 3H), 2.24 – 2.16 (m, 1H), 2.10 (d, J = 33.5 Hz, 3H), 2.04 – 1.80 (m, 3H), 1.67 – 1.62 (m, 3H).

Example 6

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine methyl)-1,7,8-trimethyl-1,6-naphthyridin-2(1H)-one (compound 7)

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (66 mg, 0.1 mmol) was dissolved in 1,4-dioxane (5 mL), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) and potassium phosphate (106 mg, 0.5 mmol) were added. Under nitrogen protection, trimethylcyclotriboroxane (0.14 mL, 1 mmol) was added. The reaction solution was stirred at 100°C for 2 hours, cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate (20 mL), and then ethyl acetate (100 The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20:1) to obtain a crude product, which was further purified by preparative HPLC to obtain compound 7 as a white solid (2.5 mg, yield 4.8%).

ESI-MS m/z: 517.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 3.8 Hz, 1H), 7.58 – 7.50 (m, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.22 – 7.15 (m, 1H), 6.95 (t, J = 55.1 Hz, 1H), 5.91 (s, 1H), 5.69 – 5.60 (m, 1H), 5.34 (s, 1H), 4.68 – 4.60 (m, 1H), 3.76 – 3.72 (m, 2H), 3.69 (s, 3H), 3.25 – 3.15 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.29 – 2.22 (m, 1H), 2.16 (d, J = 3.4 Hz, 3H), 2.12 – 2.06 (m, 1H), 2.00 – 1.91 (m, 1H), 1.82 – 1.76 (m, 1H), 1.66 (d, J = 7.0 Hz, 3H).

Embodiment 7

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine methyl)-8-ethynyl-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 8)

Step 1: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((triisopropylsilyl)ethynyl)-1,6-naphthyridin-2(1H)-one

To a solution of (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (40 mg, 0.06 mmol) and triisopropylsilylacetylene (110 mg, 0.6 mmol) in tetrahydrofuran (5 mL) were added tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), cuprous iodide (5 mg, 0.03 mmol) and triethylamine (1 mL), replaced with argon for 3 times, stirred and reacted at 60°C for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column (methanol/dichloromethane = 20:1, volume ratio) to obtain a yellow solid product (30 mg).

ESI-MS m/z: 683.4 [M+H] ⁺ .

Step 2: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) (base)amino)-8-ethynyl-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

To a solution of (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((triisopropylsilyl)ethynyl)-1,6-naphthyridin-2(1H)-one (30 mg, 0.04 mmol) in tetrahydrofuran (15 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.15 mL, 1 M). After stirring at room temperature for 16 hours, ethyl acetate (60 mL) and water (50 mL) were added, the organic phase was separated, washed with water twice (30 mL×2), and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give compound 8 as a white solid (15 mg).

ESI-MS m/z: 527.2 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.49 – 8.41 (m, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.37 – 7.08 (m, 3H), 5.73 – 5.64 (m, 1H), 5.49 (s, 1H), 4.59 (s, 1H), 4.39 – 4.30 (m, 1H), 3.90 (s, 3H), 3.71 (d, J = 11.8 Hz, 1H), 3.50 – 3.44 (m, 1H), 2.96 (t, J = 12.8 Hz, 1H), 2.38 (s, 3H), 2.35-2.29 (m, 1H), 2.03 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H), 1.50 (d, J = 13.1 Hz, 1H), 1.26 – 1.20 (m, 1H).

Example 8

(R)-3-(1-ethyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (compound 9)

Step 1: (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Compound 6 (70 mg, 0.13 mmol) was dissolved in dry dichloromethane (8 mL), protected by nitrogen, cooled to 0°C, and diethylaminosulfur trifluoride (42 mg, 0.26 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and water (20 mL) was added to quench the reaction. Ethyl acetate (100 mL×2) was added for extraction, and the mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 20:1, volume ratio) to obtain the product as a yellow solid (47 mg, yield 68%).

ESI-MS m/z: 530.2 [M+H] ⁺ .

Step 2: (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (47 mg, 0.089 mmol) was dissolved in anhydrous methanol (5 mL ), under nitrogen protection, add methanol solution of sodium methoxide (5N 0.36 mL, 1.78 mmol), stir the reaction solution at room temperature for 12 hours, add water (20 mL) to quench the reaction, and add ethyl acetate (100 mL×2) Extract, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography (dichloromethane/methanol = 20:1) to obtain a crude product. The crude product is purified by preparative HPLC to obtain compound 9. , white solid (13 mg, yield 27%).

ESI-MS m/z: 542.2 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 6.89 (t, J = 55.0 Hz, 1H), 6.05 (d, J = 5.7 Hz, 1H), 5.77 – 5.68 (m, 1H), 4.58 (d, J = 12.1 Hz, 1H), 3.99 (s, 3H), 3.75 – 3.66 (m, 1H), 3.54 – 3.42 (m, 1H), 3.25 (s, 3H), 2.98 – 2.86 (m, 1H), 2.61 (s, 3H), 2.58 – 2.36 (m, 2H), 2.12 (s, 3H), 2.09 – 2.01 (m, 1H), 1.93 – 1.83 (m, 1H), 1.68 (d, J = 7.2 Hz, 3H).

Embodiment 9

(R)-3-(1-ethyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-8-ethynyl-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 10)

Starting from compound 8, compound 10 was prepared according to steps 1 and 2 of Example 8.

ESI-MS m/z: 541.2 [M+1] ⁺ .

Example 10

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-( (1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 11 )

Step 1: tert-butyl (R)-(4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (250 mg, 0.38 mmol) was dissolved in dry tetrahydrofuran (10 mL), and tetrakis(triphenylphosphine)palladium (87 mg, 0.076 mmol), tert-butyl (2-methylbut-3-yn-2-yl)carbamate (695 mg, 3.8 mmol), cuprous iodide (50 mg, 0.27 mmol), triethylamine (2 mL) were added. The reaction mixture was stirred at 60°C for 3 hours under nitrogen protection, cooled to room temperature, filtered through diatomaceous earth, and purified by ethyl acetate (20 The mixture was washed with 20 mL of ethyl acetate (100 mL×2), extracted with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 20:1, volume ratio) to obtain the product as a light yellow solid (59 mg, yield 22%).

ESI-MS m/z: 684.3 [M+H] ⁺ .

Step 2: (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

tert-butyl(R)-(4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2 -Fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbutan- 3-Alkyn-2-yl)carbamate (59 mg, 0.086 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. Dilute with dichloromethane (20 mL), wash with water (20 mL), wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is passed through silica gel column chromatography (dichloromethane/methanol = 20 :1, volume ratio) to obtain compound 11 as a pale white solid (20 mg, yield 40%).

ESI-MS m/z: 584.3 [M+H] ⁺ .

Example 11

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 12)

Starting from the intermediate (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (prepared in Step 10 of Example 5) and the raw material 2-methyl-3-butyn-2-ol, compound 12 was prepared according to Step 1 of Example 10.

ESI-MS m/z: 585.3 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 7.1 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.37 – 7.07 (m, 3H), 5.75 – 5.64 (m, 1H), 5.51 (s, 1H), 5.37 (s, 1H), 4.39 – 4.29 (m, 1H ), 3.89 (s, 3H), 3.74 – 3.67 (m, 1H), 3.50 – 3.42 (m, 1H), 2.93 (t, J = 12.7 Hz, 1H), 2.36 (s, 3H), 2.03 (s, 3H), 1.63 – 1.58 (m, 1H), 1.56 (d, J = 7.1 Hz, 3H), 1.53 – 1.48 (m, 1H), 1.44 (s, 6H), 1.06 (t, J = 7.2 Hz, 1H ).

Embodiment 12

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one (Compound 13)

Step 1: tertiary butyl(S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(di Fluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)acetylene pyrrolidine-1-carboxylate

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl triflate (150 mg, 0.23 mmol) and a third Butyl(S)-2-ethynylpyrrolidine-1-carboxylate (180 mg, 13.5 mmol), copper iodide (13 mg, 0.07 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol), and triethylamine (3.5 mL) were dissolved in tetrahydrofuran (15 mL). After nitrogen replacement, the mixture was heated to 60° C. and stirred for 10 hours. The solid was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100:3, volume ratio) to obtain the product. Yellow oil (100 mg, 63%).

ESI-MS m/z: 696.3 [M+1] ⁺ .

Step 2: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((S)-pyrrolidin-2-ylethynyl)-1,6-naphthyridin-2(1H)-one

tert-Butyl (S)-2-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)ethynyl)pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100:6, volume ratio) to obtain the product, a yellow oil (77 mg), which was directly used in the next reaction.

ESI-MS m/z: 596.2 [M+1] ⁺ .

Step 3: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one

The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% formaldehyde aqueous solution (3 mL) was added, sodium triacetoxyborohydride (360 mg, 1 mmol) was added, and stirred at room temperature for 0.5 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added to dilute, and ethyl acetate (100 mL×3) was added to extract. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 13, a yellow solid product (5 mg).

ESI-MS m/z: 610.3 [M+H] ⁺ .

Embodiment 13

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine yl)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one (compound 14 )

Starting from the intermediate (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (prepared in Step 10 of Example 5) and the raw material tert-butyl (R)-2-ethynylpyrrolidine-1-carboxylate, Compound 14 was prepared according to Example 12.

ESI-MS m/z: 610.3 [M+1] ⁺ .

Example 14

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine base)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 15)

Starting from the intermediate (R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (prepared in Step 10 of Example 5) and the raw material N,N-dimethylpropargylamine, compound 15 was prepared according to Step 1 of Example 10.

ESI-MS m/z: 584.3 [M+1] ⁺ .

Example 15

(R)-3-(1-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbutan-1-yne-1) -yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile ( Compound 16)

Step 1: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-Acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(benzyloxy)-1,6-naphthyridin-2( 1H)-ketone (2.4 g, 5.27 mmol) was dissolved in dichloromethane (24 mL), protected by nitrogen, and boron trichloride (53 mL, 52.7 mmol) was added at 0°C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was added dropwise to cold methanol (200 mL), concentrated under reduced pressure, the residue was dissolved in methanol (50 mL), a saturated methanol solution of amine (3 mL) was added, concentrated under reduced pressure, and the residue was passed through a silica gel column Chromatography (dichloromethane/methanol = 20:1, volume ratio) gave the product as a white foamy solid (1 g, yield 52%).

ESI-MS m/z: 366.1 [M+H] ⁺ .

Step 2: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6 -Naphthyridin-8-yl triflate

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (1 g, 2.7 mmol) was dissolved in dichloromethane (20 mL). Under nitrogen protection, triethylamine (1.1 g, 10.8 mmol), 4-dimethylaminopyridine (330 mg, 2.7 mmol) and phenylbis(trifluoromethanesulfonyl)imide (1.17 g, 3.28 mmol) were added at 0°C. The reaction was stirred at 0°C for 0.5 hours. The mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 99:1, volume ratio) to obtain the product (1 g, yield 72%).

ESI-MS m/z: 498.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 4.62 (m, 1H), 3.81 (s, 3H), 3.79 – 3.50 (m, 2H), 3.40-3.00 (m, 1H), 2.69 (s, 3H), 2.16 (s, 3H), 1.90 (td, J = 13.0, 5.0 Hz, 2H).

Step 3: tertiary butyl (4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1, 2-Dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (395 mg, 6.65 mmol), tert-butyl (2-methylbut-3-yn-2-yl)carbamate (160 mg, 0.87 mmol), cuprous iodide (45 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (91 mg, 0.08 mmol) and triethylamine (1 mL) were dissolved in tetrahydrofuran (10 mL). The mixture was stirred at 40°C for 10 minutes under nitrogen protection. After the reaction was cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20:1, volume ratio) to obtain the product (420 mg, yield 99%).

ESI-MS m/z: 531.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 4.58 (t, J = 20.8 Hz, 1H), 4.14 (s, 3H), 3.75 – 3.67 (m, 2H), 3.16 (td, J = 12.8, 2.3 Hz, 1H), 2.74 (s, 3H), 2.15 (s, 3H), 1.95 – 1.75 (m, 4H), 1.68 (s, 6H), 1.46 (s, 9H).

Step 4: tert-butyl (4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate

tert-butyl(4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate (360 mg, 0.68 mmol), (R)-3-(1 -Aminoethyl)-2-methylbenzonitrile (326 mg, 2 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (Brettphos Pd G3, 61 mg, 0.067 mmol) and Sodium tert-butoxide (136 mg, 1.4 mmol) was dissolved in toluene (10 mL). Under nitrogen protection, the reaction was stirred at 80°C for 50 minutes. After the reaction was cooled to room temperature, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (300 mg, yield 67%).

ESI-MS m/z: 654.4 [M+H] ⁺ .

Step 5: (R)-3-(1-((3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(3-amino-3-methylbutan-1- Alkyn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzene Carbonitrile

tert-butyl (R)-(4-(3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate (25 mg, 0.038 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 16 as a white solid (11 mg, yield 52%).

ESI-MS m/z: 555.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (d, J = 27.6 Hz, 1H), 7.69 (t, J = 7.1 Hz, 1H), 7.49 (t, J = 14.6 Hz, 1H), 7.31 – 7.21 (m, 1H), 4.00 (s, 3H), 3.85 (d, J = 11.8 Hz, 1H), 3.70-3.60 (m, 1H),3.2- 3.08 (m, 2H), 2.74 (s, 3H) , 2.47 (s, 3H), 2.42-2.32 (m, 3H), 2.20 (s, 3H), 1.92 – 1.88 (m, 1H), 1.86 (s, 3H), 1.85-1.75 (m, 1H), 1.72 (s, 6H), 1.57 (d, J = 7.0 Hz, 3H).

Example 16

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-((1-aminocyclopropyl)ethynyl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 17)

Compound 17 was prepared with reference to steps 3 to 5 of Example 15, wherein the raw material (2-methylbut-3-yn-2-yl)carbamic acid tert-butyl ester in step 3 was replaced with (1-ethynyl) Cyclopropyl)carbamic acid tert-butyl ester, the raw material (R)-3-(1-aminoethyl)-2-methylbenzonitrile in step 4 is replaced with (R)-1-(3- (Difluoromethyl)-2-fluorophenyl)ethane-1-amine.

ESI-MS m/z: 582.3 [M+1] ⁺ .

Embodiment 17

(R)-3-(1-ethyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 18)

Step 1: 3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-Acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2( 1H)-ketone (5 g, 10.96 mmol) was dissolved in N,N-dimethylformamide (50 mL). Add sodium hydrogen (2.19 g, 54.8 mmol) at 0°C and stir for 5 minutes. Add methyl iodide ( 6.2 g, 43.84 mmol), stir and react at 0°C for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a yellow solid (4.0 g, collected rate 78%).

ESI-MS m/z: 470.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.40 (s, 5H), 4.79 (s, 2H), 4.58 (d, J = 12.9 Hz, 1H), 3.88 (s, 3H), 3.70 (dd, J = 11.1, 4.7 Hz, 1H), 3.49 (ddd, J = 13.0, 9.1, 3.7 Hz, 1H), 3.28 (s, 3H), 2.94 (dd, J = 14.6, 9.5 Hz, 1H), 2.59 (s, 3H), 2.55 – 2.38 (m, 2H), 2.13 (s, 3H), 2.09 – 1.93 (m, 2H).

Step 2: 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (4.0 g, 8.51 mmol) was dissolved in methanol (40 mL), and platinum dioxide (800 mg) was added. The mixture was hydrogenated at room temperature for 30 minutes under a hydrogen balloon atmosphere. The reactant was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 95:5, volume ratio) to obtain the product as a white solid (2.6 g, yield 81%).

ESI-MS m/z: 380.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 7.93 (s, 1H), 4.30 (d, J = 12.7 Hz, 1H), 3.86 (s, 3H), 3.68 (d, J = 1.8 Hz, 1H), 3.33 – 3.26 (m, 1H), 3.18 (s, 3H), 2.76 (dd, J = 13.3, 11.3 Hz, 1H), 2.44 (s, 3H), 2.30 (dq, J = 8.3, 4.7 Hz, 2H), 2.02 (s, 4H), 1.89 – 1.76 (m, 2H).

Step 3: 3-(1-ethyl-4-methoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-8-yl trifluoromethanesulfonate

3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (2.0 g, 5.26 mmol), 4-dimethylaminopyridine (641 mg, 5.26 mmol), and triethylamine (2.12 mg, 21 mmol) were dissolved in dichloromethane (40 mL), and phenylbis(trifluoromethanesulfonyl)imide (2.25 g, 6.31 mmol) was added at 0°C, and the reaction was continued at 0°C for 30 minutes. The reactants were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a white solid (2.2 g, yield 90%).

ESI-MS m/z: 512.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 4.59 (d, J = 10.9 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 1H), 3.51 (d, J = 11.0 Hz, 1H), 3.30 (s, 3H), 2.93 (dd, J = 21.1, 9.3 Hz, 1H), 2.68 (s, 3H), 2.48 (d, J = 12.7 Hz, 2H), 2.15 (s, 3H), 2.02 – 1.90 (m, 2H).

Step 4: 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-ethyl-4-methoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6 -Naphthyridin-8-yl triflate (510 mg, 1.0 mmol), N,N-dimethylpropargylamine (250 mg, 3.0 mmol), copper iodide (57 mg, 0.3 mmol), Tetrakis(triphenylphosphine)palladium (115 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine (1 mL), under nitrogen protection, and reacted at 55°C for 30 minutes. The reactant was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a white solid (370 mg, yield 83%).

ESI-MS m/z: 445.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 4.60 – 4.50 (m, 1H), 4.08 (s, 3H), 3.72 (s, 2H), 3.68 (d, J = 2.1 Hz, 1H), 3.48 (td, J = 13.1, 2.5 Hz, 1H), 3.26 (s, 3H), 2.99 – 2.88 (m, 1H), 2.75 (s, 3H), 2.46 – 2.36 (m, 9H), 2.12 (s, 3H), 2.05 – 1.92 (m, 2H).

Step 5: (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl))-2-fluorophenyl )ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridine-2(1H)- ketone

3-(1-ethyl-4-methoxypiperidin-4-yl)-5-chloro-8-(3-(dimethylamino)prop-1-yn-1-yl)-1 ,7-dimethyl-1,6-naphthyridin-2(1H)-one (175 mg, 0.394 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35 mg, 0.039 mmol ), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (223 mg, 1.18 mmol) and sodium tert-butoxide (75 mg, 0.78 mmol) Dissolve in 1,4-dioxane (5 mL), protect with nitrogen, stir and react at 80°C for 1 hour. After cooling to room temperature, it was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 18 as a white solid (100 mg, yield 42%).

ESI-MS m/z: 598.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J = 1.4 Hz, 1H), 8.01 (d, J = 7.0 Hz, 1H), 7.64 (s, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.24 (dt, J = 64.5, 41.7 Hz, 2H), 5.68 (p, J = 7.0 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 3.87 (s, 3H) , 3.70 (d, J = 13.7 Hz, 1H), 3.48 (s, 2H), 3.42 – 3.29 (m, 3H), 3.10 (d, J = 2.9 Hz, 3H), 2.82 (t, J = 12.4 Hz, 1H), 2.38 (s, 3H), 2.28 – 2.11 (m, 8H), 2.11 – 1.95 (m, 4H), 1.57 (d, J = 7.1 Hz, 3H).

Example 18

3-(1-ethyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one( Compound 19)

Starting from compound 13, compound 19 was prepared by referring to step 1 and step 2 of Example 8.

ESI-MS m/z: 624.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (s, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 54.9 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H), 4.01 (s, 3H), 3.81 (d, J = 13.4 Hz, 1H), 3.53 (dd, J = 17.4, 10.2 Hz, 2H), 3.16 (s, 3H), 3.09 – 2.91 (m, 5H), 2.55 – 2.46 (m, 4H), 2.45 (s, 3H), 2.43 – 2.15 (m, 6H), 2.14 (s, 3H), 2.06 – 1.81 (m, 3H), 1.63 (d, J = 7.1 Hz, 3H).

Example 19

3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)ethynyl)-1,6-naphthyridin-2(1H)-one (Compound 20)

Starting from compound 14, compound 20 was prepared according to steps 1 and 2 of Example 8.

ESI-MS m/z: 624.3 [M+1] ⁺ .

Example 20

(R)-3-(1-ethyl-4-methoxypiperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5 -((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one( Compound 21)

Starting from compound 11, compound 20 was prepared according to steps 1 and 2 of Example 8.

ESI-MS m/z: 598.3 [M+1] ⁺ .

Example twenty one

(R)-3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-amino-3-methylbutan-1-yne-1 -yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridine-2( 1H)-ketone (compound 22)

Step 1: 3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Dissolve 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (1.1 g, 2.41 mmol) in N,N-dimethylformamide (50 mL). Add sodium hydride (290 mg, 7.25 mmol, 60%) at 0°C under nitrogen protection. Stir at 0°C for 10 minutes. Add deuterated iodomethane (1.05 g, 7.25 mmol), slowly warm to room temperature, and stir for 12 hours. Add water (100 mL) to dilute, extract with ethyl acetate (100 mL), and wash the organic phase with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 99:1, volume ratio) to give the product 3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-8-(benzyloxy)-1,6-naphthyridin-2(1H)-one as a yellow solid (800 mg, yield 70%).

ESI-MS m/z: 473.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.46 – 7.34 (m, 5H), 4.80 (s, 2H), 4.70-4.50 (m, 1H), 3.88 (s, 3H), 3.80-3.60 (m, 1H), 3.60-3.40 (m, 1H), 3.05-2.90 (m, 1H), 2.59 (s, 3H), 2.55-2.40 (m, 2H), 2.15 (s, 3H), 2.10-1.90 (m, 2H).

Step 2: 3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6- Naphthyridin-2(1H)-one

3-(1-ethyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-8-(benzyloxy)-1, 6-Naphthyridin-2(1H)-one (800 mg, 1.69 mmol) was dissolved in methanol (20 mL), platinum dioxide (160 mg) was added, and hydrogenation was carried out with a hydrogen balloon at room temperature for 30 minutes. The reactant was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the product as a white solid (600 mg, yield 93%). used directly for the next reaction.

ESI-MS m/z: 383.1 [M+1] ⁺ .

Step 3: 3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

3-(1-Acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (660 mg, 1.72 mmol), 4-dimethylaminopyridine (210 mg, 1.72 mmol) and triethylamine (516 mg, 5.16 mmol) were dissolved in dichloromethane (10 mL). Phenylbis(trifluoromethanesulfonyl)imide (740 mg, 2 mmol) was added at 0°C under nitrogen protection and the reaction was carried out at 0°C for 30 minutes. The residue was concentrated at low temperature and chromatographed on a silica gel column (dichloromethane/methanol = 99:1, volume ratio) to give 3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate as a white solid (740 mg, yield 83%).

ESI-MS m/z: 515.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 4.80-4.40 (m, 1H), 3.90-3.50 (m, 4H), 3.60 – 3.32 (m, 1H), 3.10-2.80 (m, 1H), 2.67 (s, 3H), 2.55-2.45 (m, 2H), 2.15 (s, 3H), 2.05-1.85 (m, 2H).

Step 4: tertiary butyl(4-(3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl- 2-Oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate

3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (350 mg, 0.68 mmol), tert-butyl(2-methylbut-3-yn-2-yl)carbamate (125 mg, 0.68 mmol), cuprous iodide (39 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (78 mg, 0.068 mmol) and triethylamine (1 mL) were dissolved in tetrahydrofuran (10 mL). The mixture was stirred at 50°C for 2 hours under nitrogen protection. After the reaction was cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product (300 mg, yield 81%).

ESI-MS m/z：548.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 4.70-4.50 (m, 1H), 4.08 (s, 3H), 3.79 – 3.61 (m, 1H), 3.60-3.4 (m, 1H), 3.00-2.80 (m, 1H), 2.73 (s, 3H), 2.50-2.30 (m, 2H), 2.13 (s, 3H), 2.10-1.90 (m, 2H), 1.67 (s, 6H), 1.44 (s, 9H).

Step 5: tertiary butyl(R)-(4-(3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-((1-(3) -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8- (yl)-2-methylbut-3-yn-2-yl)carbamate

tert-butyl(4-(3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)-2-methylbut-3-yn-2-yl)carbamate (300 mg, 0.55 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)-ethyl)1-amine (342 mg, 1.8 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (Brettphos Pd G3, 54 mg, 0.059 mmol) and tert-butyl sodium (120 mg, 0.55 mmol) were added. mg, 1.25 mmol) was dissolved in toluene (10 mL). Under nitrogen protection, the reaction was stirred at 80°C for 50 minutes. After the reactants were cooled to room temperature, water (50 mL) was added to dilute them, and ethyl acetate (50 mL) was added to extract. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (400 mg). It was used directly in the next reaction.

ESI-MS m/z: 701.4 [M+H] ⁺ .

Step 6: (R)-3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-amino-3-methylbut-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

tert-Butyl(R)-(4-(3-(1-acetyl-4-(methoxy-d ₃ )piperidin-4-yl)-5-((1-(3-( (Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl) -2-Methylbut-3-yn-2-yl)carbamate (400 mg, 0.57 mmol) was dissolved in dichloromethane (3 mL), added trifluoroacetic acid (1 mL), and stirred at room temperature for 1 hours. It was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 22 as a white solid (30 mg, yield 9%).

ESI-MS m/z: 601.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 6.9 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 54.9 Hz, 1H), 5.72 (q, J = 6.9 Hz, 1H), 4.44 (d, J = 13.3 Hz, 1H), 3.98 (s, 3H), 3.81 ( d, J = 12.1 Hz, 1H), 3.54 (td, J = 13.1, 2.5 Hz, 1H), 3.03 (dd, J = 12.8, 10.3 Hz, 1H), 2.46 (s, 3H), 2.42 – 2.16 (m , 4H), 2.14 (s, 3H), 1.72 (s, 6H), 1.64 (d, J = 7.1 Hz, 3H).

Embodiment twenty two

(R)-3-(1-((3-(1-ethyl-4-methoxypiperidin-4-yl)-8-(3-amino-3-methylbutan-1-yn) -1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzyl Nitrile (compound 23)

Starting from compound 16, compound 23 was prepared by referring to step 1 and step 2 of Example 8.

ESI-MS m/z: 569.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 5.62 (q, J = 7.0 Hz, 1H), 4.44 (d, J = 12.8 Hz, 1H), 3.99 (s, 3H), 3.81 (d, J = 13.6 Hz, 1H), 3.62 – 3.45 (m, 1H), 3.15 (s, 3H), 3.10-3.00 (m, 1H), 2.73 (s, 3H), 2.47 (s, 3H), 2.44 – 2.16 (m, 4H), 2.14 (s, 3H), 1.72 (s, 6H), 1.57 (d, J = 7.0 Hz, 3H).

Embodiment twenty three

(R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-8-((1-aminocyclopropyl)ethynyl)-5-((1-(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 24)

Starting from compound 17, compound 24 was prepared according to steps 1 and 2 of Example 8.

ESI-MS m/z: 596.3 [M+1] ⁺ .

Embodiment twenty four

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine base)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)ethenyl)-1,6-naphthyridine-2(1H )-ketone (compound 25)

Compound 13 (20 mg, 0.03 mmol) was dissolved in tetrahydrofuran (5 mL), 10% palladium on carbon (5 mg) was added, and the mixture was hydrogenated with a hydrogen balloon at room temperature for 4 hours. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 25 as a white solid (1.74 mg, yield 9%).

ESI-MS m/z: 612.2 [M+H] ⁺ .

Embodiment 25

(R,Z)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-en-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 26)

Starting from compound 18, compound 26 was obtained by referring to the method of Example 24.

ESI-MS m/z: 600.3 [M+1] ⁺ .

Embodiment 26

3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((Z)-2-((S)-1-methylpyrrolidin-2-yl)vinyl)-1,6-naphthyridin-2(1H)-one (Compound 27)

Starting from compound 19, compound 27 was obtained by referring to the method of Example 24.

ESI-MS m/z: 626.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (s, 1H), 7.57 (d, J = 5.5 Hz, 1H), 7.40 (t, J = 6.8 Hz, 1H), 7.15 (dd, J = 14.5 , 6.8 Hz, 1H), 7.13 – 6.81 (m, 2H), 5.78-5.55 (m, 2H), 4.44 (d, J = 11.3 Hz, 1H), 3.81 (d, J = 12.9 Hz, 1H), 3.67 – 3.43 (m, 2H), 3.39 (s, 2H), 3.16 (s, 3H), 3.11 – 2.92 (m, 2H), 2.63 – 1.90 (m, 14H), 1.88 – 1.45 (m, 9H).

Example 27

3-(1-ethyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-((Z)-2-((R)-1-methylpyrrolidin-2-yl)ethenyl)-1,6-naphthyridine-2 (1H)-ketone (compound 28)

Starting from compound 20, compound 28 was obtained according to the method of Example 24.

ESI-MS m/z: 626.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.41 (t, J = 7.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.15-6.80 (m, 2H), 5.66 (dt, J = 20.0, 8.9 Hz, 2H), 4.44 (d, J = 12.8 Hz, 1H), 3.88 – 3.73 (m, 1H), 3.65 – 3.46 (m, 2H), 3.38 (m, 2H), 3.16 (s, 3H), 3.11 – 2.86 (m, 2H), 2.69 – 1.90 (m, 14H), 1.90 – 1.45 (m, 9H).

Embodiment 28

3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine yl)-1,7-dimethyl-8-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one( Compound 29)

Compound 25 (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran (5 mL), 10% palladium on carbon (10 mg) was added, and the mixture was hydrogenated with a hydrogen balloon at 60°C for 5 hours. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 29.

ESI-MS m/z: 614.2 [M+H] ⁺ .

Example 29

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amine methyl)-8-(3-(dimethylamino)propyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 30)

Starting from compound 15, compound 30 was obtained by referring to the method of Example 28.

ESI-MS m/z: 588.3 [M+1] ⁺ .

Example 30

(R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)propyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 31)

Starting from compound 30, compound 31 was prepared by referring to step 1 and step 2 of Example 8.

ESI-MS m/z: 602.3 [M+1] ⁺ .

Embodiment 31

3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one (Compound 32)

Starting from compound 28, compound 32 was obtained according to the method of Example 28.

ESI-MS m/z: 628.3 [M+1] ⁺ .

Example 32

3-(1-acetyl-4-methoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-((R)-1-methylpyrrolidin-2-yl)ethyl)-1,6-naphthyridin-2(1H)-one (Compound 33)

Starting from compound 27, compound 33 was obtained according to the method of Example 28.

ESI-MS m/z: 628.3 [M+1] ⁺ .

Embodiment 33

(R)-3-(1-((3-(1-ethyl-4-methoxypiperidin-4-yl)-8-(3-(dimethylamino)propan-1-yne- 1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile (Compound 34)

Compound 34 was prepared according to step 5 of Example 17, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced by (R)-3-(1-aminoethyl)-2-methylbenzonitrile.

ESI-MS m/z: 569.3 [M+1] ⁺ .

Example 34

(R)-3-(1-((3-(1-ethyl-4-(methoxy-d ₃ )piperidin-4-yl)-8-(3-amino-3-methyl) But-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2 -Methyl benzonitrile (compound 35)

Compound 35 was prepared with reference to steps 5 and 6 of Example 21, wherein the raw material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine in step 5 was replaced by (R)-3-(1-Aminoethyl)-2-methylbenzonitrile.

ESI-MS m/z: 572.3 [M+1] ⁺ .

Example 35

(R)-3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (compound 63)

Step 1: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthalene Dino-2(1H)-one

3-(1-Acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (8.8 g, 19.3 mmol) was dissolved in N,N-dimethylformamide (100 mL). Sodium hydrogen (3.86 g, 96.5 mmol) was added at 0°C. After stirring for 5 minutes, iodoethane (9.0 g, 57.9 mmol) was added and the reaction was continued at 0°C for 1 hour. The reaction was quenched by adding water, and then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a yellow solid (8.0 g, yield 86%).

ESI-MS m/z: 484.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.14 (s, 1H), 7.39 (s, 5H), 4.77 (s, 2H), 4.57 (ddt, J = 13.2, 4.8, 2.2 Hz, 1H), 3.86 (s, 3H), 3.69 (ddq, J = 8.9, 4.7, 2.1 Hz, 1H), 3.50 (td, J = 13.0, 2.7 Hz, 1H), 3.45 – 3.36 (m, 2H), 2.93 (td, J = 13.0, 2.7 Hz, 1H), 2.62 – 2.48 (m, 5H), 2.12 (s, 3H), 1.94 – 1.83 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H).

Step 2: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2( 1H)-ketone

3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin- 2(1H)-one (8.0 g, 16.5 mmol) was dissolved in methanol (160 mL), platinum dioxide (1.6 g) was added, and stirred at room temperature for 30 minutes under a hydrogen balloon atmosphere. The reactant was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product as a white solid (6.0 g, yield 92%).

ESI-MS m/z: 394.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.44 (s, 1H), 7.95 (s, 1H), 4.36 – 4.26 (m, 1H), 3.86 (s, 3H), 3.74 – 3.66 (m, 1H ), 3.39 – 3.28 (m, 4H), 2.82 – 2.71 (m, 1H), 2.43 (s, 3H), 2.37 (td, J = 13.6, 4.8 Hz, 1H), 2.03 (s, 3H), 1.79 – 1.68 (m, 2H), 1.27 (t, J = 6.9 Hz, 3H).

Step 3: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-8-yl trifluoromethanesulfonate

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H) -Ketone (3.2 g, 8.14 mmol), 4-dimethylaminopyridine (993 mg, 8.14 mmol) and triethylamine (3.29 g, 32.56 mmol) were dissolved in dichloromethane (60 mL). The reactant was cooled to 0°C, phenylbis(trifluoromethanesulfonyl)imine (3.49 g, 9.77 mmol) was added, and the reaction was continued at 0°C for 30 minutes. The reactant was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a white solid (3.7 g, yield 87%).

ESI-MS m/z: 526.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.18 (s, 1H), 4.60 (ddt, J = 13.2, 4.6, 2.1 Hz, 1H), 3.76 (s, 3H), 3.71 (dt, J = 4.5, 2.1 Hz, 1H), 3.56 – 3.38 (m, 3H), 2.96 (td, J = 13.0, 2.8 Hz, 1H), 2.63 – 2.48 (m, 2H), 2.15 (s, 3H), 1.89 (ddq, J = 30.9, 14.2, 2.7 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H).

Step 4: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (1.1 g, 2.09 mmol), N,N-dimethylpropargylamine (863 mg, 10.4 mmol), cuprous iodide (114 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), and triethylamine (3 mL) were dissolved in tetrahydrofuran (15 mL). The mixture was reacted at 55°C for 1 hour under nitrogen protection. The reactants were concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a white solid (800 mg, yield 83.6%).

ESI-MS m/z: 459.1 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 4.62 – 4.50 (m, 1H), 4.07 (s, 3H), 3.68 (ddt, J = 13.2, 4.5, 2.2 Hz, 1H), 3.61 (s, 2H), 3.48 (td, J = 13.1, 2.7 Hz, 1H), 3.43 – 3.33 (m, 2H), 2.98 – 2.85 (m, 1H), 2.74 (s, 3H), 2.51 (dtd, J = 18.7, 13.4, 4.8 Hz, 2H), 2.40 (s, 6H), 2.11 (s, 3H), 1.95 – 1.79 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H).

Step 5: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl))-2-fluorophenyl )ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridine-2(1H)- ketone

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-(dimethylamino)prop-1-yn-1-yl)-1 ,7-dimethyl-1,6-naphthyridin-2(1H)-one (600 mg, 1.31 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (119 mg, 0.131 mmol ), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (743 mg, 3.93 mmol) and sodium tert-butoxide (377 mg, 3.93 mmol) Dissolve in toluene (12 mL). Under nitrogen protection, the reaction was stirred at 80°C for 1 hour. After the reactant was cooled to room temperature, it was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product. , white solid (500 mg, yield 62.5%).

ESI-MS m/z: 612.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 – 8.11 (m, 1H), 7.97 (dd, J = 7.1, 2.3 Hz, 1H), 7.65 (q, J = 6.7, 6.1 Hz, 1H), 7.45 (t, J = 7.1 Hz, 1H), 7.36 – 7.04 (m, 2H), 5.65 (t, J = 7.1 Hz, 1H), 4.37 – 4.26 (m, 1H), 3.86 (s, 3H), 3.69 (d, J = 13.2 Hz, 1H), 3.47 (s, 2H), 3.41 – 3.28 (m, 3H ), 3.2 13.5, 8.9, 4.4 Hz, 2H), 2.84 (tt, J = 12.9, 3.1 Hz, 1H), 2.38 (s, 3H), 2.20 (s, 6H), 2.16 – 2.11 (m, 1H), 2.02 (s, 4H), 1.55 (d, J = 7.1 Hz, 3H), 1.18 (td, J = 7.0, 1.7 Hz, 3H).

Embodiment 36

(R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile (Compound 64)

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-(dimethylamino)prop-1-yn-1-yl)-1 ,7-Dimethyl-1,6-naphthyridin-2(1H)-one (400 mg, 0.873 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (79 mg, 0.087 mmol ), (R)-3-(1-aminoethyl)-2-fluorobenzonitrile (427 mg, 2.62 mmol) and sodium tert-butoxide (251 mg, 2.62 mmol) were dissolved in 1,4-diox Six Rings (8 mL). Under nitrogen protection, the reaction was stirred at 80°C for 1 hour. After the reactant was cooled to room temperature, it was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product. , off-white solid (310 mg, yield 60.6%).

ESI-MS m/z: 587.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (s, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.78 (dt, J = 18.6, 6.0 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 5.57 (t, J = 7.0 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.86 (s, 3H), 3.70 (d, J = 13.4 Hz, 1H) , 3.48 (s, 2H), 3.42 – 3.33 (m, 3H), 3.22 (dq, J = 15.4, 7.8 Hz, 2H), 2.84 (d, J = 11.0 Hz, 1H), 2.38 (s, 3H), 2.21 (s, 6H), 2.12 (d, J = 15.9 Hz, 1H), 2.03 (s, 4H), 1.56 (d, J = 7.1 Hz, 3H), 1.22 – 1.17 (m, 3H).

Embodiment 37

(R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile (Compound 65)

Compound 65 was prepared according to Example 36, wherein the starting material (R)-3-(1-aminoethyl)-2-fluorobenzonitrile was replaced by (R)-3-(1-aminoethyl)-2-methylbenzonitrile.

ESI-MS m/z: 583.3 [M+1] ⁺ .

Embodiment 38

(R)-3-(1-acetyl-4-((2-hydroxyethyl)amino)piperidin-4-yl)-5-((1-(3-(difluoromethyl)- 2-Fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridine- 2(1H)-ketone (compound 66)

Step 1: (R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 106)

(R)-3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 15, 100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). Under nitrogen protection, diethylaminosulfur trifluoride (110 mg, 0.69 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 12 hours. A saturated aqueous sodium bicarbonate solution was added to quench the reaction, and then extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was directly used in the next reaction.

ESI-MS m/z: 586.3 [M+1] ⁺ .

Step 2: (R)-3-(1-acetyl-4-((2-hydroxyethyl)amino)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

(R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (110 mg, 0.17 mmol), ethanolamine (207 mg, 3.4 mmol) and triethylamine (0.5 mL) were dissolved in acetonitrile (5 mL) and stirred at 90°C for 16 hours. The reactant was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the product as a white solid (60 mg).

ESI-MS m/z: 627.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 – 8.05 (m, 2H), 7.74 (q, J = 7.7 Hz, 1H), 7.45 (t, J = 7.1 Hz, 1H), 7.38 – 7.05 ( m, 2H), 5.67 (h, J = 7.3 Hz, 1H), 4.67 (s, 1H), 4.19 (d, J = 10.2 Hz, 1H), 3.87 (d, J = 2.7 Hz, 3H), 3.46 – 3.27 (m, 7H), 3.08 (s, 3H), 2.47 – 2.34 (m, 4H), 2.20 (s, 7H), 2.00 (s, 3H), 1.89 – 1.72 (m, 2H), 1.59 (t, J = 6.7 Hz, 3H).

Example 39

(R)-3-(1-acetyl-4-(ethylamino)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 67)

(R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (110 mg , 0.17 mmol), 30% ethanol solution of ethylamine (2.5 mL) and triethylamine (0.5 mL) were dissolved in ethanol (5 mL), stirred at 90°C for 16 hours, the reactants were concentrated under reduced pressure, and the residue was analyzed by preparative HPLC Purification gave the product as a white solid (40 mg).

ESI-MS m/z: 611.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (s, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.92 (t, J = 6.3 Hz, 1H), 7.63 (q, J = 6.8 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.36 – 7.07 (m, 2H), 5.66 (p, J = 7.3 Hz, 1H), 4.14 (t, J = 12.0 Hz, 2H), 3.90 (s, 3H), 3.59 (d, J = 10.6 Hz, 2H), 3.50 (s, 2H), 3.15 (p, J = 9.4, 7.8 Hz, 1H), 2.37 (d, J = 1.6 Hz, 3H), 2.22 (s, 9H), 2.03 – 1.97 (m, 3H), 1.86 – 1.72 (m, 2H), 1.57 (d, J = 7.1 Hz, 3H), 0.95 (t, J = 7.0 Hz, 3H).

Embodiment 40

(R)-3-(1-acetyl-4-(2,2,2-trifluoroethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 68)

(R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (110 mg , 0.17 mmol) was added to the reaction system of sodium hydrogen (136 mg, 3.4 mmol) and 2,2,2-trifluoroethanol (5 mL), stirred at 50°C for 16 hours, the reactant was diluted with water, and extracted with dichloromethane. , the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a white solid (15 mg, yield 13.2%).

ESI-MS m/z: 666.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (d, J = 1.7 Hz, 1H), 7.90 (t, J = 6.5 Hz, 1H), 7.64 (q, J = 7.1 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.37 – 7.07 (m, 2H), 5.72 – 5.59 (m, 1H), 4.33 (d, J = 10.5 Hz, 1H), 3.87 (s, 3H), 3.83 – 3.70 (m, 3H), 3.48 (s, 2H), 3.41 – 3.31 (m, 2H), 2.86 (t, J = 12.6 Hz, 1H), 2.38 (d, J = 1.2 Hz, 4H), 2.21 (s, 6H), 2.03 (s, 5H), 1.60 – 1.53 (m, 3H).

Example 41

(R)-3-(1-acetyl-4-(2,2-difluoroethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one)(Compound 69)

Compound 69 was prepared according to the method of Example 40, in which the raw material 2,2,2-trifluoroethanol was replaced with 2,2-difluoroethanol.

ESI-MS m/z: 648.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (s, 1H), 7.90 (t, J = 5.9 Hz, 1H), 7.63 (q, J = 6.7 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.37 – 7.06 (m, 2H), 6.33 – 6.01 (m, 1H), 5.65 (p, J = 7.0 Hz, 1H), 4.31 (d, J = 11.8 Hz, 1H), 3.87 ( s, 3H), 3.71 (d, J = 13.3 Hz, 1H), 3.47 (s, 2H), 3.37 (t, J = 12.4 Hz, 3H), 2.87 (t, J = 12.4 Hz, 1H), 2.37 ( s, 4H), 2.20 (s, 7H), 2.13 – 2.05 (m, 2H), 2.03 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

Example 42

(R)-3-(1-acetyl-4-(2-hydroxyethoxy)piperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 70)

Compound 70 was prepared according to the method of Example 40, wherein the starting material 2,2,2-trifluoroethanol was replaced by ethylene glycol.

ESI-MS m/z: 628.3 [M+1] ⁺ . ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.71 – 8.63 (m, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.0 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 54.9 Hz, 1H), 5.70 (q, J = 7.1 Hz, 1H), 4.55 – 4.43 (m, 1H), 4.02 (s, 3H), 3.96 – 3.88 (m, 2H), 3.84 (d, J = 13.7 Hz, 1H), 3.67 (s, 2H), 3.63 – 3.50 (m, 3H), 3.11 – 2.97 (m, 1H), 2.67 – 2.53 (m, 2H), 2.46 (d, J = 4.4 Hz, 9H), 2.17 (s, 3H), 2.05 – 1.88 (m, 2H), 1.62 (d, J = 7.1 Hz, 3H).

Embodiment 43

(R)-3-(1-acetyl-4-cyclopropoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one)(Compound 71)

(R)-3-(1-acetyl-4-fluoropiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (260 mg), cyclopropanol (2 mL) and cesium carbonate (690 mg, 2.12 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 50°C for 16 hours. The reaction was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a white solid (12 mg).

ESI-MS m/z: 624.3 [M+1] ⁺ .

Embodiment 44

(R)-3-(1-acetyl-4-isopropoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) base)amino)-8-(3-(dimethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one( Compound 72)

Compound 72 was prepared according to the method of Example 40, wherein the starting material 2,2,2-trifluoroethanol was replaced by isopropanol.

ESI-MS m/z: 626.3 [M+1] ⁺ .

Embodiment 45

(R)-3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(3-(diethylamino)prop-1-yn-1-yl)-5- ((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (Compound 73)

Step 1: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-(diethylamino)prop-1-yn-1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Dissolve 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (250 mg, 0.48 mmol) in tetrahydrofuran (10 mL), add N,N-diethylpropargylamine (63 mg, 0.57 mmol), iodide (10 mg, 0.048 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol) and triethylamine (1 mL), and stir at 40°C for 30 minutes under nitrogen protection. Add water (20 mL) to dilute, and extract with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient elution of dichloromethane/methanol = 100~100:6) to obtain the product (225 mg, yield 70%).

ESI-MS m/z: 487.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.17 (s, 1H), 4.59 – 4.52 (m, 1H), 4.05 (s, 3H), 3.97 (s, 1H), 3.74 – 3.65 (m, 1H) , 3.55 – 3.33 (m, 4H), 2.98 – 2.82 (m, 4H), 2.73 (s, 3H), 2.57 – 2.46 (m, 2H), 2.12 (s, 3H), 1.88 (ddd, J = 27.3, 13.9, 2.7 Hz, 2H), 1.37 (t, J = 7.0 Hz, 9H).

Step 2: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(diethylamino)prop-1-yn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Add 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-(diethylamino)propan-1-yne to a 50 mL round-bottom flask -1-yl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (150 mg, 0.31 mmol), toluene (6 mL), sodium tert-butoxide (89 mg, 0.93 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2' -Amino-1,1'-biphenyl-2-yl)palladium(II) (28 mg, 0.031 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl) Ethane-1-amine (176 mg, 0.93 mmol), under nitrogen protection, reacted at 90°C for 1 hour. Ethyl acetate (100 mL) was added to the reaction solution, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the product (30 mg).

ESI-MS m/z: 640.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.64 (t, J = 6.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.36 – 7.08 (m, 2H), 5.65 (t, J = 7.1 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H), 3.87 (s, 3H), 3.71 (d, J = 13.4 Hz, 1H), 3.65 (s, 2H), 3.25 – 3.18 (m, 4H), 2.85 (t, J = 12.9 Hz, 1H), 2.49 – 2.46 (m , 4H), 2.37 (s, 3H), 2.23 – 2.11 (m, 3H), 2.03 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.19 (td, J = 7.0, 2.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 6H).

Embodiment 46

(R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one (Compound 74)

Step 1: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(3-(pyrrolidin-1-yl) Propan-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6 -Naphthyridin-8-yl triflate (392 mg, 0.75 mmol) was dissolved in tetrahydrofuran (15 mL), and 1-(prop-2-yn-1-yl)pyrrolidine (97 mg, 0.89 mmol) was added ), ketone iodide (14 mg, 0.074 mmol), tetrakis(triphenylphosphine)palladium (172 mg, 0.15 mmol) and triethylamine (1.2 mL), under nitrogen protection, stir at 40°C for 30 minutes. The reaction was diluted with water (20 mL), and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100~100:6) to obtain the product (210 mg, yield 58%).

ESI-MS m/z: 485.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.16 (s, 1H), 4.58 – 4.54 (m, 1H), 4.07 (s, 3H), 3.77 (s , 2H), 3.71 – 3.66 (m, 2H), 3.59 (d, J = 4.2 Hz, 1H), 3.49 (td, J = 13.2, 2.7 Hz, 2H), 3.43 – 3.32 (m, 2H), 2.93 (td, J = 13.1, 2.8 Hz, 2H), 2.74 (d, J = 4.1 Hz, 3H), 2.59 – 2.46 (m, 3H), 2.12 – 2.8 1.81 (m,4H), 1.40 – 1.32 (m, 4H).

Step 2: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one

To a 50 mL round-bottom flask were added 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-1,6-naphthyridin-2(1H)-one (170 mg, 0.35 mmol), toluene (6 mL), sodium tert-butoxide (100 mg, 1.05 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32 mg, 0.035 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (200 mg, 1.05 mmol), nitrogen protection, react at 90°C for 1 hour. Ethyl acetate (150 mL) was added to the reaction solution, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product, a light yellow solid (68 mg).

ESI-MS m/z: 638.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (d, J = 1.5 Hz, 1H), 7.98 (dd, J = 7.0, 2.2 Hz, 1H), 7.65 (q, J = 6.6 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.38 – 7.06 (m, 2H), 5.65 (p, J = 7.0 Hz, 1H), 4.32 (d, J = 12.6 Hz, 1H), 3.86 (s, 3H), 3.69 (dd, J = 13.6, 9.5 Hz, 1H), 3.63 (s, 2H), 3.42 – 3.31 (m, 2H), 3.21 (qd, J = 8.9, 4.0 Hz, 2H), 2.85 (ddd, J = 13.3, 10.0, 3.3 Hz, 1H), 2.54 (d, J = 6.1 Hz, 4H), 2.37 (s, 3H), 2.19 (dtd, J = 30.4, 13.2, 12.8, 4.2 Hz, 3H), 2.03 (s, 3H), 1.69 (q, J = 3.4, 3.0 Hz, 4H), 1.56 (d, J = 7.0 Hz, 3H), 1.19 (td, J = 7.0, 2.0 Hz, 3H).

Embodiment 47

(R)-3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino)propan-1-yne-1 -yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridine-2( 1H)-Ketone (Compound 75)

Step 1: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-hydroxyprop-1-yn-1-yl)-1,7- Dimethyl-1,6-naphthyridin-2(1H)-one

3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (1.05 g, 2.0 mmol), propynyloxytrimethylsilane (1.28 g, 10. mmol), cuprous iodide (114 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and triethylamine (3 mL) were dissolved in tetrahydrofuran (15 mL), and the mixture was reacted at 55°C for 60 minutes under nitrogen protection. The reactants were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 99:1, volume ratio) to obtain the product as a brown solid (460 mg, yield 53%).

ESI-MS m/z: 432.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.15 (s, 1H), 4.59 (s, 2H), 4.54 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 4.7 Hz, 3H), 3.68 (d, J = 13.6 Hz, 1H), 3.55 – 3.43 (m, 1H), 3.38 (p, J = 7.9 Hz, 2H), 2.97 – 2.87 (m, 1H), 2.73 (s, 3H), 2.51 (ddt, J = 17.9, 13.4, 6.5 Hz, 2H), 2.12 (s, 3H), 1.86 (dd, J = 26.9, 13.9 Hz, 2H), 1.35 (s, 3H).

Step 2: 3-(3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-di Hydrogen-1,6-naphthyridin-8-yl)prop-2-yn-1-yl methanesulfonate

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-(3-hydroxyprop-1-yn-1-yl)-1,7-dimethyl 1,6-naphthyridin-2(1H)-one (460 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (321 mg, 3.18 mmol) and methylsulfonate were added at 0°C. Add chloride (241 mg, 2.12 mmol) and continue the stirring reaction at 0°C for 30 minutes. The reactant was diluted with water, extracted with dichloromethane, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was passed through silica gel column chromatography (dichloromethane/methanol=98:2, volume ratio) to obtain the product as a white solid (300 mg, yield 55.6%).

ESI-MS m/z: 510.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.17 (s, 1H), 5.15 (s, 2H), 4.57 (d, J = 14.0 Hz, 1H), 4.04 (s, 3H), 3.70 (d, J = 16.1 Hz, 1H), 3.57 – 3.45 (m, 1H), 3.39 (t, J = 7.2 Hz, 2H), 3.12 (s, 3H), 3.01 – 2.91 (m, 1H), 2.75 (s, 3H) , 2.52 (d, J = 13.5 Hz, 2H), 2.15 (s, 3H), 1.97 – 1.80 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H).

Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino)prop-1-yn-1-yl)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

3-(3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro- 1,6-Naphthyridin-8-yl)prop-2-yn-1-yl methanesulfonate (300 mg, 0.589 mmol) and potassium carbonate (243 mg, 1.76 mmol) were dissolved in N,N-dimethyl Acetamide (60 mL), add dimethyl-d ₆ -amine hydrochloride (102 mg, 1.17 mmol), and react at 50°C for 1 hour. Dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography (dichloromethane/methanol=95:5, volume ratio) to obtain the product, a light yellow solid ( 160 mg, yield 58.6%).

ESI-MS m/z: 465.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.17 (s, 1H), 4.63 – 4.53 (m, 1H), 4.08 (s, 3H), 3.73 – 3.64 (m, 1H), 3.60 (s, 2H), 3.49 (td, J = 13.1, 2.6 Hz, 1H), 3.39 (qd, J = 8.7, 4.4 Hz, 2H), 2.98 – 2.89 (m, 1H), 2.75 (s, 3H), 2.53 (dtd, J = 18.3, 13.4, 4.8 Hz, 2H), 2.12 (s, 3H), 1.94 – 1.86 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H).

Step 4: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino)propan-1- Alkyn-1-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-1,6-naphthyridine -2(1H)-ketone

3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino)prop-1-yn-1-yl) -5-Chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (160 mg, 0.344 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31 mg, 0.034 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (195 mg, 1.03 mmol), and sodium tert-butoxide ( 99 mg, 1.03 mmol) was dissolved in toluene (5 mL), protected by nitrogen, and stirred at 80°C for 1 hour. After the reactant was cooled to room temperature, it was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product, which was white. Solid (170 mg, yield 80.5%).

ESI-MS m/z: 618.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (s, 1H), 7.97 (dd, J = 7.2, 2.3 Hz, 1H), 7.65 (q, J = 6.4, 6.0 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.36 – 7.06 (m, 2H), 5.65 (p, J = 7.0 Hz, 1H), 4.36 – 4.27 (m, 1H), 3.86 (s, 3H), 3.70 (d, J = 13.3 Hz, 1H), 3.47 (s, 2H), 3.21 (dtt, J = 13.3, 8.7, 4.3 Hz, 2H), 2.84 (tt, J = 12.8, 3.1 Hz, 1H), 2.38 (s, 3H), 2.26 – 2.09 (m, 3H), 2.02 (s, 5H), 1.55 (d, J = 7.1 Hz, 3H), 1.17 (dd, J = 6.9, 1.9 Hz, 3H).

Embodiment 48

(R)-3-(1-((3-(1-ethyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino) Propan-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2 -Fluorobenzonitrile (compound 76)

Compound 76 was prepared according to step 4 of Example 47, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile.

ESI-MS m/z: 593.3 [M+1] ⁺ .

Embodiment 49

(R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d ₃ )amino)prop-1-yn-1-yl)-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-methylbenzonitrile (Compound 77)

Compound 77 was prepared according to step 4 of Example 47, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced with (R)-3-(1-aminoethyl)-2-methylbenzonitrile.

ESI-MS m/z: 589.4 [M+1] ⁺ .

Embodiment 50

(R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylpiperidin-4-yl)oxy)-1,6-naphthyridin-2(1H)-one (Compound 78)

Step 1: tert-butyl 4-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)piperidine-1-carboxylate

3-(1-Acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (393 mg, 1.0 mmol), N-tert-butoxycarbonyl-4-hydroxypiperidine (519 mg, 3.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, diisopropyl azodicarboxylate (909 mg, 4.5 mmol) was added at 0°C and the mixture was stirred for 1 hour. The reactant was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 99:2, volume ratio) to obtain the product as a yellow solid (540 mg, yield 93%).

ESI-MS m/z: 577.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.12 (s, 1H), 4.56 (d, J = 13.0 Hz, 1H), 4.19 – 4.07 (m, 2H), 3.80 (s, 4H), 3.75 – 3.62 (m, 1H), 3.56 – 3.31 (m, 3H), 2.99 – 2.86 (m, 1H), 2.73 – 2.57 (m, 3H), 2.55 (m, 4H), 2.11 (s, 3H), 1.87 (dd , J = 23.9, 13.8 Hz, 4H), 1.68 – 1.57 (m, 2H), 1.44 (s, 9H), 1.35 (t, J = 6.9 Hz, 3H).

Step 2: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(piperidin-4-yloxy)- 1,6-Naphthyridin-2(1H)-one

Dissolve tert-butyl 4-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)piperidine-1-carboxylate (520 mg, 0.903 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 15 minutes. The reactant is concentrated under reduced pressure, and the residue is directly used in the next reaction.

ESI-MS m/z: 477.1 [M+1] ⁺ .

Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylpiperidin-4-yl)oxy)-1,6-naphthyridin-2(1H)-one

Dissolve the crude product obtained in step 2 in tetrahydrofuran (10 mL), add 30% formaldehyde aqueous solution (1 mL) and sodium triacetoxyborohydride (1.82 g, 9.03 mmol), and stir at room temperature for 1 hour. Dilute with water and extract with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is passed through silica gel column chromatography (dichloromethane/methanol=95:5, volume ratio) to obtain the product as a light yellow solid (420 mg).

ESI-MS m/z：491.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.11 (s, 1H), 4.55 (ddt, J = 13.1, 4.6, 2.1 Hz, 1H), 3.81 (s, 3H), 3.75 – 3.63 (m, 2H), 3.53 – 3.33 (m, 3H), 2.99 – 2.80 (m, 3H), 2.63 – 2.47 (m, 5H), 2.26 (s, 3H), 2.11 (s, 3H), 1.97 – 1.81 (m, 8H), 1.34 (t, J = 6.9 Hz, 3H).

Step 4: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl))-2-fluorophenyl )ethyl)amino)-1,7-dimethyl-8-((1-methylpiperidin-4-yl)oxy)-1,6-naphthyridin-2(1H)-one

3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylpiperidin-4-yl)oxy)-1,6-naphthyridin-2(1H)-one (400 mg, 0.816 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (74 mg, 0.081 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (461 mg, 2.44 mmol) and sodium tert-butoxide (234 mg, 2.44 mmol) were dissolved in toluene (10 mL), and the mixture was stirred at 80°C for 1 hour under nitrogen protection. The reactant was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 95:5, volume ratio) to obtain the product as a white solid (370 mg, yield 70%).

ESI-MS m/z: 644.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (s, 1H), 7.67 (q, J = 6.1, 5.2 Hz, 1H), 7.51 – 7.39 (m, 2H), 7.36 – 7.07 (m, 2H ), 5.56 (t, J = 7.1 Hz, 1H), 4.41 – 4.26 (m, 1H), 3.69 (d, J = 12.8 Hz, 1H), 3.63 (s, 3H), 3.47 (dt, J = 10.0, 4.5 Hz, 2H), 3.43 – 3.32 (m, 3H), 3.28 – 3.16 (m, 2H), 2.84 (dddd, J = 13.3, 10.7, 6.8, 3.7 Hz, 1H), 2.72 – 2.61 (m, 2H) , 2.20 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.85 – 1.75 (m, 2H), 1.72 – 1.54 (m, 4H), 1.52 (d, J = 7.1 Hz, 3H ), 1.20 (dd, J = 7.0, 1.6 Hz, 3H).

Example 51

(R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylazolocyclobutane-3-yl)oxy)-1,6-naphthyridin-2(1H)-one (Compound 79)

Step 1: tert-butyl 3-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)azinecyclobutane-1-carboxylate

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H) -Ketone (393 mg, 1.0 mmol), N-tert-butoxycarbonyl-3-hydroxyazetidine (519 mg, 3.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL), under nitrogen protection, add diisopropyl azodicarboxylate (909 mg, 4.5 mmol) at 0°C, and stir for 1 hour. The reactant was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through silica gel column chromatography (dichloromethane/methanol = 99:2, volume ratio) to obtain the product as a yellow solid (280 mg, collected rate 51%).

ESI-MS m/z: 549.1 [M+1] ⁺ .

Step 2: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(azacyclobutan-3-yloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

tertiary butyl 3-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1, 2-Dihydro-1,6-naphthyridin-8-yl)oxy)azetidine-1-carboxylate (260 mg, 0.474 mmol) was dissolved in dichloromethane (4 mL), and trifluoride was added Acetic acid (2 mL), stir at room temperature for 15 minutes. The reactants were concentrated under reduced pressure, and the residue was directly used in the next reaction.

ESI-MS m/z: 449.1 [M+1] ⁺ .

Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylazolocyclobutane-3-yl)oxy)-1,6-naphthyridin-2(1H)-one

The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% aqueous formaldehyde solution (0.5 mL) and sodium triacetoxyborohydride (1.0 g, 4.74 mmol) were added, and stirred at room temperature for 1 hour. The reactant was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 95:5, volume ratio) to obtain the product as a light yellow solid (180 mg, yield 82%).

ESI-MS m/z: 463.1 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.12 (s, 1H), 4.62 – 4.52 (m, 1H), 4.31 (p, J = 6.1 Hz, 1H), 3.80 (s, 3H), 3.75 – 3.65 (m, 3H), 3.53 – 3.34 (m, 3H), 3.27 (td, J = 6.2, 2.0 Hz, 2H), 2.92 (td, J = 13.1, 2.8 Hz, 1H), 2.60 – 2.46 (m, 5H), 2.41 (s, 3H), 2.12 (s, 3H), 1.95 – 1.80 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H).

Step 4: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylazinocyclobutane-3-yl)oxy)-1,6-naphthyridin-2(1H)-one

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(1-methylazetidine-3 -yl)oxy)-1,6-naphthyridin-2(1H)-one (165 mg, 0.357 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32 mg, 0.036 mmol ), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (202 mg, 1.07 mmol) and sodium tert-butoxide (98 mg, 1.07 mmol) Dissolve in toluene (5 mL), protect with nitrogen, stir and react at 80°C for 1 hour. After the reactant was cooled to room temperature, it was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product, which was white. Solid (150 mg, yield 68%).

ESI-MS m/z: 616.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (s, 1H), 7.67 (q, J = 6.5, 5.7 Hz, 1H), 7.54 (dd, J = 7.3, 2.3 Hz, 1H), 7.44 ( t, J = 7.1 Hz, 1H), 7.35 – 7.07 (m, 2H), 5.56 (p, J = 7.1 Hz, 1H), 4.31 (d, J = 12.6 Hz, 1H), 4.17 (p, J = 5.9 Hz, 1H), 3.69 (d, J = 14.3 Hz, 1H), 3.62 (s, 3H), 3.59 – 3.53 (m, 2H), 3.36 (tt, J = 13.0, 3.3 Hz, 2H), 3.27 – 3.17 (m, 2H), 3.09 (d, J = 7.0 Hz, 2H), 2.85 (ddt, J = 13.9, 10.0, 4.1 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.03 ( s, 5H), 1.52 (d, J = 7.1 Hz, 3H), 1.21 – 1.17 (m, 3H).

Example 52

(R)-3-(1-((3-(1-ethyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-((1-methylnitrogen Heterocyclobutan-3-yl)oxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile ( Compound 80)

Compound 80 was prepared with reference to step 4 of Example 51, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced with (R)-3- (1-Aminoethyl)-2-fluorobenzonitrile.

ESI-MS m/z: 591.3 [M+1] ⁺ .

Example 53

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 81)

Step 1: tertiary butyl(S)-2-(((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl- 2-Oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate

Add 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6 to a 50 mL round-bottomed flask. -Naphthyridin-2(1H)-one (600 mg, 1.53 mmol), (S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (920 mg, 4.58 mmol), anhydrous tetrahydrofuran (10 mL), and Triphenylphosphine (800 mg, 3.05 mmol) was protected by nitrogen, the reaction solution was cooled to 0°C, diisopropyl azodicarboxylate (616 mg, 3.05 mmol) was added, and the reaction was continued at 0°C for 2 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution, and extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100~100:5) to obtain the product as a yellow solid (526 mg, 60%).

ESI-MS m/z:577.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.12 (d, J = 3.5 Hz, 1H), 5.01 – 4.93 (m, 1H), 4.87 – 4.81 (m, 1H), 4.54 (s, 2H), 4.36 – 4.11 (m, 1H), 3.90 (s, 3H), 3.82 (s, 2H), 3.40 – 3.29 (m, 5H), 2.57 (s, 2H), 2.47 – 2.28 (m, 2H), 2.15 (d, J = 4.4 Hz, 3H), 2.00 – 1.84 (m, 4H), 1.44 – 1.42 (m, 4H), 1.39 – 1.22 (m, 10H).

Step 2: (S)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(pyrrolidin-2-yl) Methoxy)-1,6-naphthyridin-2(1H)-one

Add tert-butyl(S)-2-(((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1) to a 50 mL round bottom flask, 7-Dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)methyl)pyrrolidine-1-carboxylate (500 mg, 0.86 mmol) , dichloromethane (6 mL) and trifluoroacetic acid (3 mL), react at room temperature for 1 hour. The reactants were evaporated to dryness and the solvent was evaporated under reduced pressure to obtain a crude product, which was directly used in the next reaction.

ESI-MS m/z: 477.2 [M+1] ⁺ .

Step 3: (S)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one

The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% formaldehyde aqueous solution (0.5 mL) and sodium triacetoxyborohydride (936 mg, 4.47 mmol) were added, and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reactant, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product (383 mg, yield 90%).

ESI-MS m/z: 491.2 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.14 (s, 1H), 4.62 – 4.53 (m, 1H), 3.91 (s, 3H), 3.81 (s, 1H), 3.75 – 3.59 (m, 2H) , 3.50 (td, J = 13.1, 2.6 Hz, 1H), 3.45 – 3.36 (m, 2H), 2.97 – 2.90 (m, 1H), 2.77 (s, 1H), 2.61 (s, 3H), 2.59 – 2.45 (m, 5H), 2.36 – 2.27 (m, 1H), 2.13 (s, 3H), 1.99 – 1.81 (m, 6H), 1.36 (t, J = 6.9 Hz, 3H).

Step 4: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl) )ethyl)amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-2(1H )-ketone

To a 50 mL round-bottom flask were added (S)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (370 mg, 0.75 mmol), toluene (8 mL), sodium tert-butoxide (217 mg, 2.26 mmol), (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (68 mg, 0.075 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (429 mg, 2.26 mmol), nitrogen protection, and reaction at 90°C for 1 hour. The reaction solution was cooled to room temperature, ethyl acetate (150 mL) was added, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol = 95:5, volume ratio) to obtain the product (371 mg, yield 76%).

ESI-MS m/z: 644.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (s, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.53 – 7.41 (m, 2H), 7.37 – 7.07 (m, 2H), 5.58 (p, J = 7.1 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.75 (s, 3H), 3.71 (d, J = 13.6 Hz, 1H), 3.57 (dd, J = 9.2, 5.3 Hz, 1H), 3.46 – 3.40 (m, 2H), 3.29 – 3.81 (m, 2H), 2.80 – 2.81 (m, 2H), 2.98 (dd, J = 9.2, 4.9 Hz, 1H), 2.85 (t, J = 12.6 Hz, 1H), 2.34 (s, 3H), 2.31 – 2.26 (m, 1H), 2.23 (s, 3H), 2.23 – 2.11 (m, 3H), 2.04 (s, 3H), 1.99 – 1.93(m, 1H), 1.71 – 1.56 (m, 3H), 1.53 (d, J = 7.1 Hz, 3H), 1.27 – 1.17 (m, 5H).

Example 54

3-((R)-1-((3-(1-ethyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzyl Nitrile (compound 82)

Compound 82 was prepared according to step 4 of Example 53, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile.

ESI-MS m/z: 619.3 [M+1] ⁺ .

Embodiment 55

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one( Compound 83)

Step 1: tertiary butyl(R)-3-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2 -Oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate

To a 50 mL round-bottom flask, 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (250 mg, 0.64 mmol), (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, 1.91 mmol), anhydrous tetrahydrofuran (8 mL) and triphenylphosphine (833 mg, 3.18 mmol) were added. Under nitrogen protection, the reaction solution was cooled to 0°C, and diisopropyl azodicarboxylate (513 mg, 2.54 mmol) was added dropwise. After the addition was complete, the reaction was continued at 0°C for 2 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100~100:5) to obtain the product.

ESI-MS m/z: 563.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.15 (s, 1H), 4.59 (s, 1H), 4.51 – 4.40 (m, 2H), 3.81 (s, 3H), 3.63 (dd, J = 34.3, 8.9 Hz, 3H), 3.55 – 3.20 (m, 6H), 2.54 (s, 3H), 2.16 (s, 3H), 2.03 – 1.84 (m, 6H), 1.47 (s, 9H), 1.38 (t, J = 6.9 Hz, 3H).

Step 2: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(pyrrolidin-3-yl) Oxy)-1,6-naphthyridin-2(1H)-one

To a 50 mL round-bottom flask, add tert-butyl (R)-3-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate (430 mg, 0.76 mmol), dichloromethane (6 mL) and trifluoroacetic acid (3 mL) and react at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain a crude product, which was directly used in the next reaction.

ESI-MS m/z: 463.2 [M+1] ⁺ .

Step 3: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one

The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% formaldehyde aqueous solution (0.5 mL) and sodium triacetoxyborohydride (812 mg, 3.83 mmol) were added, and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reactant, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio) to obtain the product (280 mg, yield 77%).

ESI-MS m/z: 477.2 [M+1] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.13 (d, J = 0.9 Hz, 1H), 4.58 (d, J = 13.2 Hz, 1H), 4.46 (s, 1H), 3.85 (s, 3H), 3.69 (d, J = 13.8 Hz, 1H), 3.57 – 3.34 (m, 3H), 3.03 – 2.79 (m, 3H), 2.64 – 2.60 (m, 16H), 2.59 (s, 3H), 2.56 – 2.38 (m, 6H), 2.13 (s, 3H), 2.07 (d, J = 6.6 Hz, 1H), 1.96 – 1.80 (m, 3H), 1.36 (t, J = 6.9 Hz, 3H).

Step 4: 3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl) )ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H) -ketone

Add (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(( 1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one (114 mg, 0.24 mmol), toluene (8 mL), sodium tert-butoxide (69 mg , 2.26 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.023 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl )Ethane-1-amine (136 mg, 0.72 mmol), under nitrogen protection, react at 90°C for 1 hour. The reaction solution was cooled to room temperature, ethyl acetate (150 mL) was added, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95 :5, volume ratio) to obtain the product (120 mg, yield 79%).

ESI-MS m/z: 630.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 1.5 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.54 – 7.41 (m, 2H), 7.39 – 7.06 (m, 2H), 5.57 (p, J = 7.0 Hz, 1H), 4.32 (d, J = 12.7 Hz, 1H), 4.26 (td, J = 5.4, 2.5 Hz, 1H), 3.72 (s, 1H), 3.68 (s, 3H), 3.37 (qd, J = 12.4, 11.5, 4.9 Hz, 2H), 3.29 – 3.17 (m, 3H), 2.88 – : 2.79 (m, 2H), 2.66 (d, J = 10.8 Hz, 1H), 2.23 (d, J = 6.1 Hz, 6H), 2.21 – 2.09 (m, 4H), 2.04 (s, 3H), 1.91 (s, 1H), 1.83 – 1.74 (m, 1H), 1.53 (d, J = 7.0 Hz, 3H), 1.20 (ddd, J = 9.0, 5.8, 2.3 Hz, 3H).

Example 56

3-(1-ethyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )Amino)-1,7-dimethyl-8-(((S)-1-methylpyrrolidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one( Compound 84)

Compound 84 was prepared according to the method of Example 55, in which the raw material (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in step 1 was replaced with (R)-3-hydroxypyrrolidine-1-carboxylic acid. tert-butyl acid.

ESI-MS m/z: 630.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (s, 1H), 7.68 (q, J = 6.8, 6.4 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.39 – 7.07 (m, 2H), 5.58 (p, J = 7.0 Hz, 1H), 4.33 (d, J = 12.7 Hz, 1H), 4.26 (d, J = 6.7 Hz, 1H), 3.72 (d, J = 6.7 Hz, 1H), 3.68 (s, 3H), 3.40 – 3.34 (m, 4H), 3.29 – 3.17 (m, 2H), 2.90 – 2.80 (m, 2H), 2.65 – 2.59 (m, 1H), 2.23 (d, J = 5.2 Hz, 6H), 2.19 – 2.07 (m, 3H), 2.04 (s, 3H), 1.87 – 1.78 (m, 1H), 1.53 (d, J = 7.1 Hz, 3H), 1.24 – 1.16 (m, 4H).

Embodiment 57

(R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(2-(pyrrolidin-1-yl)ethoxy)-1,6-naphthyridin-2(1H)-one (Compound 85)

Step 1: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(2-(pyrrolidin-1-yl)ethoxy)-1,6-naphthyridin-2(1H)-one

Add 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6 to a 50 mL round-bottomed flask. -Naphthyridin-2(1H)-one (100 mg, 0.25 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (43 mg, 0.25 mmol), N,N-dimethylformamide (8 mL) and potassium carbonate (833 mg, 3.18 mmol), under nitrogen protection, the reaction solution was reacted at 60°C for 2 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reactant, the organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purification (dichloromethane/methanol = 100~100:5) gave the product as a yellow solid (81 mg, 65%).

ESI-MS m/z: 491.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform- d ) δ 8.14 (s, 1H), 4.58 (d, J = 13.0 Hz, 1H), 4.09 (s, 2H), 3.88 (s, 3H), 3.70 (d, J = 13.1 Hz, 1H), 3.57 – 3.34 (m, 4H), 3.26 (s, 2H), 2.99 – 2.88 (m, 1H), 2.64 (s, 3H), 2.61 – 2.46 (m, 3H), 2.13 (s, 3H), 2.02 (s, 5H), 1.95 – 1.82 (m, 4H), 1.36 (t, J = 6.9 Hz, 3H).

Step 2: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl))-2-fluorophenyl )ethyl)amino)-1,7-dimethyl-8-(2-(pyrrolidin-1-yl)ethoxy)-1,6-naphthyridin-2(1H)-one

Add 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(2-(pyrrolidine) into a 50 mL round-bottomed flask. -1-yl)ethoxy)-1,6-naphthyridin-2(1H)-one (80 mg, 0.16 mmol), toluene (5 mL), sodium tert-butoxide (47 mg, 0.49 mmol), Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino- 1,1'-Biphenyl-2-yl)palladium(II) (15 mg, 0.016 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1 -Amine (93 mg, 0.49 mmol), nitrogen protection, reaction at 90°C for 1 hour. Ethyl acetate (150 mL) was added to the reaction solution, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol = 95:5, volume ratio ) to obtain the product (66 mg, yield 70%).

ESI-MS m/z: 644.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (s, 1H), 7.68 (s, 1H), 7.54 – 7.41 (m, 2H), 7.38 – 7.07 (m, 2H), 5.57 (p, J = 7.1 Hz, 1H), 4.31 (dd, J = 11.6, 8.4 Hz, 1H), 3.73 (s, 3H), 3.67 (q, J = 6.9, 6.0 Hz, 3H), 3.30 – 3.18 (m, 2H) , 2.85 (ddd, J = 13.2, 10.0, 3.8 Hz, 1H), 2.71 (t, J = 5.9 Hz, 2H), 2.43 (q, J = 3.8 Hz, 4H), 2.32 – 2.24 (m, 1H), 2.23 (s, 3H), 2.21 – 2.08 (m, 1H), 2.04 (s, 3H), 1.65 – 1.61 (m, 4H), 1.53 (d, J = 7.1 Hz, 3H), 1.34 (d, J = 6.1 Hz, 1H), 1.24 – 1.17 (m, 5H).

Example 58

(R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-2-oxo-8-(2-(pyrrolidin-1-yl)ethoxy)-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile (Compound 86)

Compound 86 was prepared with reference to step 2 of Example 57, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was replaced with (R)-3- (1-Aminoethyl)-2-fluorobenzonitrile.

ESI-MS m/z: 619.3 [M+1] ⁺ .

Embodiment 59

3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-(((R)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-2(1H)-one (Compound 87)

Compound 87 was prepared according to the method of Example 53, in which the raw material (S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol in step 1 was replaced with (R)-1-tert-butoxycarbonyl-2- Pyrrolidinemethanol.

ESI-MS m/z: 644.3 [M+1] ⁺ .

Example 60

3-((R)-1-((3-(1-ethyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-(((R)-1 -methylpyrrolidin-2-yl)methoxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzyl Nitrile (compound 88)

Compound 88 was prepared according to the method of Example 53, wherein the raw material (S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol in step 1 was replaced by (R)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, and the raw material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine in step 4 was replaced by (R)-3-(1-aminoethyl)-2-fluorobenzonitrile.

ESI-MS m/z: 619.3 [M+1] ⁺ .

Biological test examples

Example A: The compound inhibits the cell growth of NCI-H358 and MIA PaCa-2 tumor cell lines under 3D culture conditions.

Cell source: NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., Ltd.; MIA PaCa-2 was purchased from Shanghai Dio Biotechnology Co., Ltd.

Cells in the logarithmic growth phase were seeded into ultra-low adsorption 96-well plates (4000 and 2000 cells/well for NCI-H358 and MIA PaCa-2 cells respectively, 180 μl/well), and cultured at 37°C and 5% _CO2 , the cells were aggregated to form microspheres, and a gradient dilution of the test compound was added after 1 day. The details are as follows: Take the compound stock solution (10 mM) previously dissolved in DMSO, dilute it twice (4 times) to 10 gradient concentrations, and use culture medium to dilute it to 10 times the target concentration in another 96-well plate, and then Add 20 μl/well of the compound solution to the 96-well plate in which cells are seeded to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Set up 3 duplicate wells for each concentration and set up a blank control. After culturing for 6 days at 37°C and 5% _CO2 , add 50 μl CellTiter-Glo ^® 3D reagent (luciferase ATP bioluminescence detection reagent for detecting 3D cell microspheres, purchased from Promega, to each well). (Cat. No. G9683), shake for 10 minutes, incubate at room temperature for 20 minutes, and then detect the fluorescence intensity (light collection time is 100 ms). Calculate the activity inhibition rate of each concentration of compounds on 3D cell microspheres, cell activity inhibition rate (%) = [(luminescence intensity _{6 days containing cell culture medium control group} - luminescence intensity _{6 days compound group} )/(luminescence intensity _{6 days containing cell culture medium} ) _{Control group} – luminescence intensity _{for 6 days (cell-free medium control group} )] × 100%. Data were analyzed using GraphPad Prism 8.3 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC ₅₀ value was calculated. The results are shown in Table 1.

Table 1 compound NCI-H358 IC ₅₀ (nM) MIA PaCa-2 IC ₅₀ (nM) BI-3406 38.5 48.5 Compound 1 76.0 50.5 Compound 2 11.9 13.7 Compound 3 17.8 16.7 Compound 4 20.7 89.8 Compound 5 12.2 53.2 Compound 9 121.2 257.7 Compound 11 56.2 88.4 Compound 13 87.3 241.4 Compound 14 86.8 113.1 Compound 15 50.1 160.3 Compound 16 42.9 105.5 Compound 18 19.8 44.6 Compound 19 21.2 38.6 Compound 20 40.1 45.6 Compound 21 33.8 61.5 Compound 22 18.1 37.7 Compound 23 8.5 10.4 Compound 24 275.4 568.0 Compound 25 26.8 45.5 Compound 26 14.3 55.2 Compound 27 17.3 22.7 Compound 28 25.1 75.7 Compound 29 86.2 411.8 Compound 30 23.4 86.4 Compound 34 11.0 20.4 Compound 35 16.3 39.3 Compound 63 13.8 53.4 Compound 64 22.9 34.2 Compound 66 135.2 145.0 Compound 67 79.7 142.7 Compound 68 51.9 197.2 Compound 69 81.1 180.3 Compound 70 14.7 25.6 Compound 71 26.9 50.6 Compound 73 46.5 121.4 Compound 74 26.0 47.7 Compound 75 21.5 -- Compound 78 13.4 104.8 Compound 79 20.8 63.0 Compound 81 8.3 34.8 Compound 83 34.8 103.1 Compound 84 9.3 103.4 Compound 85 9.7 45.9

"--" in the table means not detected.

Among them, BI-3406 is an SOS1 inhibitor reported in the literature (Cancer Discovery 2021 (11) 142-157), and its structure is: .

The results show that the compounds of the present invention exhibit good cell growth inhibitory effects on NCI-H358 and MIA PaCa-2 tumor cell lines.

Example B: Pharmacokinetics test in rats

SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in rats after oral and intravenous administration.

Oral administration group: 3 female SD rats, fasted for 12 hours and then administered the test compound by gavage (dose: 5 mg/kg, administration volume: 10 mL/kg, solvent: 10% DMSO/10% Solutol/80 % saline). The sampling time points were 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 24 h after administration. [Solutol refers to polyethylene glycol (15)-hydroxystearate. ]

Intravenous administration group: 3 female SD rats were fasted for 12 hours and then intravenously injected with the test compound (dose of 1 mg/kg, administration volume of 5 mL/kg, solvent of 10% DMSO/10% Solutol/80% saline). The sampling time points were 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration.

At the above set time points, 0.2 mL of venous blood was taken from the retroocular venous plexus of the rat, placed in a K ₂ -EDTA (dipotassium ethylenediaminetetraacetate) test tube, centrifuged at 6800 g for 6 min at 4°C, and the plasma was separated. Store at -80℃.

20 μL of plasma sample was taken, 200 μL of methanol (containing 10 ng/mL internal standard verapamil) was added, vortexed for 1 min and centrifuged at 18000 g for 7 min. 200 μL of supernatant was transferred to a 96-well plate, and the concentration of the compound in plasma was determined by liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters of the compound were calculated using WinNonlin 7.0 software. The results are shown in Table 2.

Table 2 Intravenous injection (1 mg/kg) Oral (5 mg/kg) compound C _max (ng/mL) AUC (h*ng/mL) V (L/kg) CL (mL/min/kg) C _max (ng/mL) AUC (h*ng/mL) F (%) Compound 2 403.0 301.0 3.44 54.5 40.0 199.0 13.2 Compound 4 1182.9 1165.8 2.34 28.8 177.8 892.0 15.3 Compound 18 930.2 703.9 1.95 23.8 158.9 804.7 22.9 Compound 19 691.2 508.5 2.27 32.4 92.7 496.1 19.5 Compound 22 373.1 379.2 7.67 41.8 26.4 236.2 12.5 Compound 63 655.9 914.1 2.18 18.2 328.1 1950.4 42.7 Compound 75 731.1 940.0 2.75 17.2 518.8 2804.3 59.7 Compound 81 517.07 618.0 3.13 26.6 229.4 1423.8 46.1

AUC: plasma exposure; C _max : maximum plasma concentration; V: apparent volume of distribution; CL: clearance; F: oral bioavailability.

The results show that the pharmacokinetic properties of the compounds of the present invention, such as plasma exposure AUC and maximum plasma concentration C _max , are better.

Claims (19)

A fused ring compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt, Wherein, Ring A is C _6-12 aryl, 5-10 membered heteroaryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; each R ¹ is independently It is deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , cyano, oxo, nitro, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkene group, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a , C _1-6 alkyl-O- substituted by one or more R ^1b , substituted by one or more R C _2-6 alkenyl substituted by ^1c , C _2-6 alkynyl substituted by one or more R ^1d , C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^1e , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^1f , C _6-12 aryl, C _6-12 aryl substituted by one or more R ^1g , 5 -10-membered heteroaryl, 5-10-membered heteroaryl substituted by one or more R ^1h , C _3-7 cycloalkenyl, C _3-7 cycloalkenyl substituted by one or more R ¹ⁱ , - C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O ) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ , or two R ¹ together with the attached ring atoms form a C _3-7 cycloalkyl group, substituted by one or more R ^1e C _3-7 cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^1f , C _3-7 cycloalkenyl or substituted by one or more R ¹ⁱ C _3-7 cycloalkenyl; when there are multiple substituents, they may be the same or different; each R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h and R ¹ⁱ respectively Independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , nitro, cyano, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1-a , C _1-6 alkyl-O- substituted by one or more R ^1-b , substituted by one or C _2-6 alkenyl substituted by multiple R ^1-c , C _2-6 alkynyl substituted by one or more R ^1-d , C _3-7 cycloalkyl, C _3-7 cycloalkyl-O -, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl -O-, C _3-7 cycloalkyl substituted by one or more R ^1-e , substituted by one or more R ^1-e C _3-7 cycloalkyl-O-, 3-7-membered heterocyclyl substituted by one or more R ^1-f , 3-7-membered heterocyclyl substituted by one or more R ^1-f - O-, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^1-g , 5-10 membered heteroaryl, 5-10 substituted by one or more R ^1-h Yuanheteroaryl, C _3-7 cycloalkenyl, C _3-7 cycloalkenyl-O-, C _3-7 cycloalkenyl substituted by one or more R ^1-i , substituted by one or more R ^{1 -i} substituted C _3-7 cycloalkenyl -O-, -C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , - S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ ; when there are multiple substituents, they are the same or different; each R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h and R ^1-i are each independently deuterium , hydroxyl, halogen, -N(R ⁷ ) ₂ , -SR ⁹ , nitro, cyano, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; Ring D is C _6-12 aryl, 5-6 membered heteroaryl, C _3-7 Cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl; R ² is absent, hydrogen, deuterium, hydroxyl, halogen, amine, cyano, oxo, nitro, C _1-6 Alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclyl ; L is the connecting key, -C(=O)-, -C(=O)O-, -C(=O)NR ⁸ -, -NR ⁸ -, -S-, -O-, -S(O )-, -S(O) ₂ - or -(CH ₂ ) _p -; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is hydrogen, deuterium, C _1-6 alkyl, and C _1-6 alkyl substituted by one or more R ^3a , C _2-6 alkenyl, C _2-6 alkenyl substituted by one or more R 3b, C _2-6 alkynyl, substituted by one or more R ^3b C _2-6 alkynyl substituted by R ^3c , C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl, substituted by one or more R ^3e -substituted 3-7-membered heterocyclyl, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3f , 5-10-membered heteroaryl, substituted by one or more R ^3g 5-10 membered heteroaryl, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when the substituents are multiple, they are the same or different; each R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h are each independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano group, nitro group, C _1-6 alkane group, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 alkenyl substituted by one or more R ^3-c , C _2-6 alkynyl substituted by one or more R ^3-d , C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3-e , 3-7 membered heterocyclyl, 3-7 substituted by one or more R ^3-f Membered heterocyclyl, C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3-g , 5-10 membered heteroaryl, 5 substituted by one or more R ^3-h -10-membered heteroaryl, C _3-7 cycloalkenyl, C _3-7 cycloalkenyl substituted by one or more R ^3-i , C _3-7 cycloalkyl-O-, substituted by one or more R ^3-j substituted C _3-7 cycloalkyl -O-, -SR ⁹ , -C(=O)-OR ⁹ , -OC(=O)-R ⁹ , -C(=O)-N( R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -S(O)-N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ⁹ , -NR ⁸ -S(O )-N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ , or two R ^3d , two Each R ^3e , two R ^3f , two R ^3g or two R ^3h together with the attached ring atom form a C _3-7 cycloalkyl group, a C _3-7 ring substituted by one or more R ^3-e Alkyl, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^3-f , C _3-7 cycloalkenyl or C substituted by one or more R ^3-i _3-7 cycloalkenyl; when there are multiple substituents, they may be the same or different; each R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i and R ^3-j are each independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , nitro, cyano, C _1-6 alkyl , C _1-6 alkyl-O-, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 3-7 membered heterocyclyl, -SR ⁹ , -C(=O)-OR ⁹ , - OC(=O)-R ⁹ , -C(=O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ - S(O) ₂ -N(R ⁷ ) ₂ , -S(O) ₂ -N(R ⁷ ) ₂ , -C(=O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or - NR ⁸ C(=O)-OR ⁹ ; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -( C ₂ -C ₄ alkenylene)-or -(C ₂ -C ₆ alkynylene)-; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano group, halogen , hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or substituted by one or more R ^4b substituted C _3-7 cycloalkyl; when there are multiple substituents, they may be the same or different; each R ^4a and R ^4b are independently hydrogen, deuterium, hydroxyl, halogen, amine, cyano, nitro , amino protecting group, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is absent, oxo, hydrogen, deuterium, hydroxyl, halogen, amine group, cyanide base, nitro, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^5a , C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkyne base, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^5b , 3-7 membered heterocyclyl, 3-7 membered heterocycle substituted by one or more R ^5c group, C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^5d ; when there are multiple substituents, they are the same or different; each R ^5a , R ^5b and R ^5c respectively is independently deuterium, C _1-6 alkyl, hydroxyl, halogen, amine or cyano; R ⁶ is hydrogen, deuterium, hydroxy, halogen, amine, cyano, oxo, C _1-6 alkyl, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl or absent; each R ⁷ is independently hydrogen, C _1-6 alkyl, substituted by one or more R ^7b C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or amino protecting group, or two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclic group Or a 3-7-membered heterocyclic group substituted by one or more R ^7a ; when there are multiple substituents, they may be the same or different; each R ^7a and R ^7b are independently deuterium, C _1-6 alkyl, Halogen, hydroxyl, amine, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl or C _2-6 alkynyl; each R ⁸ and R ⁹ are independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl or 3-7 membered heterocyclic group; R ¹⁰ is hydrogen, deuterium, hydroxyl , halogen, amino, cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl or C _1-6 alkyl; R ¹¹ is cyano, C _1-6 Alkyl or C _1-6 alkyl substituted by one or more R ^11a ; when the substituents are multiple, they are the same or different; each R ^11a is independently deuterium, halogen or hydroxyl; m is 0, 1, 2, 3, 4 or 5; p is 1, 2, 3, 4, 5 or 6; 3-7 members in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent The heterocyclic groups are each independently "a 3-7-membered heterocyclic group with heteroatom species independently selected from N, O and S, with 1, 2 or 3 heteroatoms"; the 5-10-membered heterocyclic group The 5-10-membered heteroaryl group in the aryl group and the 5-10-membered heteroaryl group substituted by the substituent is each independently "the heteroatom type is independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10-membered heteroaryl groups"; the 5-6-membered heteroaryl groups are "the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 "5-6 membered heteroaryl"; The amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, phthalyl, benzyl, p- Methoxybenzyl, trityl or p-toluenesulfonyl group; When the carbon atom of * has chirality, the fused ring compound shown in formula I is , or mixtures thereof. The fused ring compound as shown in formula I as described in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, when X is a connecting bond, R ⁴ is C _1-6 alkyl, C _1-6 alkyl-O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R ^4a , a C _3-7 cycloalkyl group or a C _3-7 cycloalkyl group substituted by one or more R ^4b ; when there are multiple substituents, they are the same or different. The fused ring compound as shown in formula I as described in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; when X is a connecting bond, R ⁴ is cyano, or . The fused ring compound as shown in formula I as described in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ⁶ is oxo; L is a connecting bond, -C(=O)-, -C(=O)O-, -C(=O)NR ⁸ -, -NR ⁸ -, -O-, -S-, -S(O)-, -S(O) ₂ - or -(CH ₂ ) _p -; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently deuterium, hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, nitro, C _1-6 alkyl, C 1-6 alkyl substituted by one or more R ^3-a C _1-6 alkyl, C _1-6 alkyl-O-, C 1-6 alkyl-O- substituted by one or more R ^3-b , C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 alkenyl substituted by one or more R ^3-c , C _2-6 alkynyl substituted by one or more R ^3-d , C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3-e , _3-7 membered heterocyclic group, 3-7 membered heterocyclic group substituted by one or more R ^3-f , C _6-12 aryl, C _6-12 aryl substituted by one or more R ^3-g , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R ^3-h , C 3-7 cycloalkenyl, C _3-7 cycloalkenyl substituted by one or more R C _3-7 cycloalkenyl substituted with R ^3-i , C _{3-7 cycloalkyl-O-, C 3-7 cycloalkyl} -O- substituted with one or more R ^3-j , -SR ⁹ , -C(═O)-OR ⁹ , -OC(═O)-R ⁹ , -C(═O)-N(R ⁷ ) ₂ , -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -R ⁹ , -NR ⁸ -S(O) ₂ -N(R ⁷ ) ₂ , -S(O ⁾ ₂ -N(R ⁷ ) ₂ , -S(O)-R ⁹ , -NR ⁸ -S(O)-R ₉ ^, -NR ⁸ -S(O)-N(R ⁷ ) ₂ , -C(═O)-R ⁹ , -NR ⁸ C(=O)-R ⁹ or -NR ⁸ C(=O)-OR ⁹ ; when there are multiple substituents, they are the same or different; further, R ⁶ is oxo; L is a connecting bond; when L is a connecting bond, it means that R ³ is directly connected to the D ring; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C 1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl-O- substituted by one or more R ^3-j _3-7 cycloalkyl-O-, C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents, they may be the same or different. The fused ring compound represented by formula I as described in any one of claims 1 to 4, its stereoisomer or its pharmaceutically acceptable salt, wherein it satisfies one or more of the following conditions: ( 1)R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^{1h , R 1i ,} R ^1-a , R ^1-b , R ^1-c , R ^{1- d} , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^{3- i} , R ^3-j , R ⁴ , R ^4a , R ^4b , R ⁵ , R ^5a , R ^{5b , R 5c ,} R ⁶ , R ⁷ , R ^7a , R ^7b , R ⁸ , R ⁹ , R ¹⁰ and R In ¹¹ , the C _1-6 alkyl group and _{the C 1-6 alkyl} group substituted by a substituent are each independently methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, isobutyl, second butyl or third butyl, for example methyl or ethyl; (2) R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^{1 -i} , R ² , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^{3g , R 3h ,} R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i , R ^3-j , R ⁴ , R ^4a , R ^4b , R ⁵ , R ^5a , R ^5b , R ^5c , R ⁶ , R ^7a , R ^7b , R ¹⁰ and R ^11a , the halogen is each independently F, Cl, Br or I, such as F; (3) In a certain scheme, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^{3- a} , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i , R ^3-j , R ⁴ , Among R ⁵ , R ⁶ , R ^7a , R ^7b and R ¹⁰ , the C _1-6 alkyl group in the C _1-6 alkyl-O- and the C _1-6 alkyl-O- substituted by a substituent -O- is each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third butoxy, for example, it is methyl Oxygen group; (4) R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^{1h , R 1i ,} R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R Among ^3e , R ^3f , R ^3g , R ^3h , R ⁵ , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ and R ¹⁰ , the C _2-6 alkenyl group, C _2- substituted by a substituent The C _2-6 alkenyl groups in _{the 6-} alkenyl group are each independently -CH=CH ₂ , -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH =CH-CH ₂ -CH ₃ , -CH ₂ -CH=CH-CH ₃ , -CH=CH-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -CH=CH-CH ₂ -CH ₃ , -CH =CH-CH(CH ₃ ) ₂ , -CH ₂ -CH=C(CH ₃ ) ₂ or -CH=CH-(CH ₂ ) ₃ -CH ₃ ; (5) R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^{3f , R 3g ,} R ^3h , R ⁵ , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ and R ¹⁰ , the C _2-6 alkynyl group and the C _2-6 alkynyl group in the C _2-6 alkynyl group substituted by a substituent are each independently - C≡CH, -C≡C-CH ₃ , -C≡C-CH ₂ -CH ₃ , -CH ₂ C≡C-CH ₃ , -C≡C-CH ₂ -CH ₂ -CH ₃ , -CH ₂ C≡C-CH ₂ -CH ₃ , -C≡C-CH ₂ -CH ₂ -CH ₂ -CH ₃ , -C≡C-CH ₂ -CH(CH ₃ ) ₂ , -C≡CC(CH ₃ ) _3. -C≡C-CH(CH ₃ ) ₂ or -CH ₂ C≡C-CH ₂ -CH ₂ -CH ₃ ; (6) C _3-7 cycloalkyl group in ring A, C in R ¹ _3-7 cycloalkyl, C _3-7 cycloalkyl in C _3-7 cycloalkyl substituted by a substituent, the two R ¹ and the connected ring atom together form a C _3-7 cycloalkyl, two Each R ¹ together with the attached ring atom forms a C _3-7 cycloalkyl group in a C _3-7 cycloalkyl group substituted by a substituent, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , C _3-7 cycloalkyl in R ^1g , R ^1h and R ¹ⁱ , C _3-7 cycloalkyl in C _3-7 cycloalkyl substituted by a substituent, C _3-7 cycloalkyl-O C _3-7 cycloalkyl in -, C _3-7 cycloalkyl substituted by a substituent - C _3-7 cycloalkyl in O-, ring D, R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i and C _3-7 cycloalkyl group in ^{R 3} C _3-7 cycloalkyl, C _3-7 cycloalkyl in C _3-7 cycloalkyl substituted by a substituent, R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and C _3-7 cycloalkyl in R ^3h , C _3-7 cycloalkyl in C _3-7 cycloalkyl substituted by a substituent, C _3- in C _3-7 cycloalkyl-O- ₇ cycloalkyl, C _3-7 cycloalkyl in C _3-7 cycloalkyl-O- substituted by a substituent, two R ^3d , two R ^3e , two R ^3f , two R ^3g or Two R ^3h and the connected ring atoms together form a C _3-7 cycloalkyl group, two R ^3d , two R ^3e , two R ^3f , two R ^3g or two R ^3h and the connected ring atoms Together, they form a C _3-7 cycloalkyl group in a C _3-7 cycloalkyl group substituted by a substituent, R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , C _3-7 cycloalkyl in R ^3-i and R ^3-j , C _3-7 cycloalkyl in R ⁴ , substituted by a substituent C _3-7 cycloalkyl in C _3-7 cycloalkyl, C _3-7 cycloalkyl in R ⁵ , C _3-7 cycloalkyl in C _3-7 cycloalkyl substituted by a substituent , C _3-7 cycloalkyl in R ⁷ , C _3-7 cycloalkyl in R ⁸ and R ⁹ are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or , for example, cyclopropyl; (7) C _3-7 cycloalkenyl in ring A, C _3-7 cycloalkenyl in R ¹ , C ₃ in C _3-7 cycloalkenyl substituted by a substituent _-7 cycloalkenyl, two R ¹ and the connected ring atom together form a C _3-7 cycloalkenyl, two R ¹ and the connected ring atom together form a C _3-7 cycloalkenyl substituted by a substituent The C _3-7 cycloalkenyl group in R ^1a , R ^1b , R ^1c _, R ^1d , R ^1e , R ^1f , R ^1g , R ^1h and R ¹ⁱ is substituted by a substituent C _3-7 cycloalkenyl in C _3-7 cycloalkenyl, C _3-7 cycloalkenyl in C _3-7 cycloalkenyl-O-, C _3-7 cycloalkenyl substituted by a substituent C _3-7 cycloalkenyl in -O-, ring D, R ^1-a , R ^1-b , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , C _3-7 cycloalkenyl in R ^1-h , R ^1-i and R ² , C _3-7 cycloalkenyl in R ³ , C in C _3-7 cycloalkenyl substituted by a substituent _3-7 cycloalkenyl, C _3-7 cycloalkenyl in R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , C _3-7 ring substituted by a substituent For the C _3-7 cycloalkenyl group in the alkenyl group, two R ^3d , two R ^3e , two R ^3f , two R ^3g or two R ^3h together with the connected ring atoms form a C _3-7 cycloalkene. group, two R ^3d , two R ^3e , two R ^3f , two R ^3g or two R ^3h together with the connected ring atoms form C ₃ in the C _3-7 cycloalkenyl substituted by the substituent _-7 cycloalkenyl, R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^3-g , R ^3-h , R ^3-i and C _3-7 cycloalkenyl in R ^3-j , C _3-7 cycloalkenyl in R ⁵ , C _3-7 cycloalkenyl in the C _3-7 cycloalkenyl substituted by a substituent, R ^7. C _3-7 cycloalkenyl in R ⁸ and R ^9. The C _3-7 cycloalkenyl groups are each independently cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloalkenyl. Heptenyl; (8) Ring A, Ring D, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R 1f , R ^1g , R ^1h , R ¹ⁱ , R ^{1 -a} , R ^{1 -b} , R ^1-c , R ^1-d , R ^1-e , R ^1-f , R ^1-g , R ^1-h , R ^1-i , R ² , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ^3-a , R ^3-b , R ^3-c , R ^3-d , R ^3-e , R ^3-f , R ^{3 -g} , R ^3-h , R ^3-i , R ^3-j , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ , the 3-7 membered heterocyclic group, 3 substituted by a substituent -3-7-membered heterocyclyl in 7-membered heterocyclyl, 3-7-membered heterocyclyl in 3-7-membered heterocyclyl-O-, 3-7-membered heterocyclyl-O substituted by a substituent The 3-7-membered heterocyclic groups in - are each independently a saturated or partially unsaturated non-aromatic monocyclic or polycyclic heterocyclic group. Specifically, the monocyclic heterocyclic group can be pyrrolidinyl, tetrahydropyranyl Pyryl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, piperazinyl, azetidinyl, 1,2-dihydropyridyl, tetrahydropyridyl, etc. Polycyclic rings can It is a bridged ring, a fused ring or a spiro ring; (9) In R ³ , the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by one or more R ^3e The ring groups are each independently "a 3-7-membered heterocyclic group with 1 or 2 heteroatoms independently selected from one or two types of N and O"; further, the 3- The 3-7-membered heterocyclic group in the 7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^3e is each independently "the number of heteroatoms is 1 or 2, and the type of heteroatom A 4-7-membered heterocyclyl group independently selected from N and O"; the 4-7-membered heterocyclyl group can be a 4-7-membered monocyclic heterocyclyl group, a 5-7-membered bridged ring heterocyclyl group or a 5- 7-membered spirocyclic heterocyclyl; specifically, when R ³ is a 4-7-membered monocyclic heterocyclyl, the 4-7-membered monocyclic heterocyclyl can be piperidinyl, tetrahydropyranyl, piperidyl Azinyl, azetidinyl, morpholinyl or pyrrolidinyl; when R ³ is a 5-7-membered bridged heterocyclyl, the 5-7-membered bridged heterocyclyl can be , , or ; When R ³ is a 5-7-membered spirocyclic heterocyclyl group, the 5-7-membered spirocyclic heterocyclyl group can be ; for example , , , , , , , , , , or ; (10) In R ⁴ , the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^4a are each independently a "heteroatom" The species is independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 3-7-membered heterocyclic groups"; further, the 3-7-membered heterocyclic groups are substituted by one or more The 3-7-membered heterocyclyl groups in the 3-7-membered heterocyclyl groups substituted by R ^4a are each independently "the heteroatom species is independently selected from one or two types of N and O, and the number of heteroatoms is 1 or 2 4-7 membered heterocyclic groups"; such as azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, tetrahydropyridyl or morpholinyl; another example , , , , , , , , or ;Another example , , , or ; (11) In R ⁷ , the two R ⁷ together with the connected nitrogen atom form a 3-7-membered heterocyclic group, 3- of the 3-7-membered heterocyclic group substituted by one or more R ^7a The number of heteroatoms of the 7-membered heterocyclyl group is independently 1 or 2; the two R ⁷ together with the connected nitrogen atoms form a 3-7 membered heterocyclyl group, 3 substituted by one or more R ^7a -The heteroatom species of the 3-7-membered heterocyclyl in the 7-membered heterocyclyl group are independently selected from one or two types of N and O; the two R ⁷ together with the connected nitrogen atom form a 3-7 membered The 3-7-membered heterocyclyl groups in the heterocyclyl group and the 3-7-membered heterocyclyl group substituted by one or more R ^7a are each independently "the heteroatom species is independently selected from one or two types of N and O, "4-7-membered heterocyclic group with 1 or 2 heteroatoms"; for example: pyrrolidinyl, another example ; (12) In Ring D, the 3-7-membered heterocyclic group is "a 6-membered heterocyclic group with N heteroatom type and 1 or 2 heteroatoms", for example, 1,2-bis Hydropyridyl, another example is or , "c" means that the atom is located in the meta position of the N atom of ring B; (13) Ring A, ring D, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , R Among ^1h , R ¹ⁱ , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , the C _6-12 aryl group, C _6- substituted by a substituent The C _6-12 aryl groups in the ₁₂ aryl groups are each independently phenyl or naphthyl; for example: phenyl; (14) Ring A, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , Among R ^1f , R ^1g , R ^1h , R ¹ⁱ , R ³ , R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f , R ^3g and R ^3h , the 5-10 membered heteroaryl group, The 5-10-membered heteroaryl groups in the 5-10-membered heteroaryl groups substituted by substituents are each independently "the number of heteroatoms is 1, 2 or 3, and the heteroatom types are independently selected from N, O and "5-8 membered heteroaryl group of S"; (15) In X, the -( in -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)- C ₁ -C ₄ alkylene) - each independently methylene, ethylene, n-propylene or isopropylene, for example: -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ -, -CH(CH ₂ CH ₃ )- or -C(CH ₃ ) ₂ -, preferably -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )- or -CH ₂ CH ₂ CH ₂ -; further, “C ₁ -C ₄ alkylene” in “-O-(C ₁ -C ₄ alkylene)-” "group" is connected _to R ⁴ ; ( ₁₆ ) In =CH-, -CH=CH-CH ₂ -; further, the -(C ₂ -C ₄ alkenylene)- can be , , or _, wherein the _f end is connected to R ⁴ ; and in (17) Or pentynylene, such as -C≡C-, -CH ₂ -C≡CH, -C≡C-CH ₂ -, -C≡C-CH ₂ -CH ₂ -, -C≡C-CH(CH ₃ ) -CH ₂ -, -C≡CC(CH ₃ ) ₂ -, preferably -C≡C-, -C≡C-CH ₂ - or -C≡CC(CH ₃ ) ₂ -; further, The -(C ₂ -C ₆ alkynylene)- can be -C≡C-*, -C≡C-CH ₂ -* or -C≡CC(CH ₃ ) ₂ -*, where the * end is with R ⁴ connected. The fused ring compound of formula I as described in any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein it satisfies one or more of the following conditions: (1) in R ³ , the number of heteroatoms of the 3-7-membered heterocyclic group or the 3-7-membered heterocyclic group substituted by one or more R ^3e is independently 1 or 2; (2) in R ³ , the type of heteroatoms of the 3-7-membered heterocyclic group or the 3-7-membered heterocyclic group substituted by one or more R ^3e is independently selected from one or both of N and O; (3) in R 3, the number of heteroatoms of the 3-7-membered heterocyclic group or the 3-7-membered heterocyclic group substituted by one or more R ^3e is independently selected from one or both of N and O; (4) in R ⁴ , the number of heteroatoms in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^4a is independently ¹ , 2 or 3; further, the number of heteroatoms in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R ^4a is independently 1 or 2; (5) in R ⁴ , the number of heteroatoms in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by one or more R 4a is independently 1 or 2; ^wherein the hetero atom species of the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R 4a is independently selected from one or more of N, O and S; further, the hetero atom species of the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R ^4a are independently selected from one or more of N and O; (6) in R ⁴ , the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R ^4a are each independently a 4-7-membered heterocyclic group; (7) in R ⁷ , the two R ⁷ together with the nitrogen atom to which they are connected form a 3-7-membered heterocyclic group substituted by one or more R (8) In R ⁷ , the two R ^7s together with the nitrogen atom to which they are attached form a 3-7-membered heterocyclic group, and the heteroatom types of the 3-7-membered heterocyclic group in ^the 3-7-membered heterocyclic group substituted by one or more R ^7a are independently selected from one or both of N and O; (9) In R ⁷ , the two R ^7s together with the nitrogen atom to which they are attached form a 3-7-membered heterocyclic group, and the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group substituted by one or more R ^7a are each independently a 4-7-membered heterocyclic group; (10) In ring D, the type of the heteroatom of the 3- to 7-membered heterocyclic group is N; (11) In ring D, the number of heteroatoms of the 3- to 7-membered heterocyclic group is 1 or 2; and (12) In ring D, the 3- to 7-membered heterocyclic group is a 6-membered heterocyclic group. The fused ring compound represented by formula I as described in any one of claims 1 to 4, its stereoisomer or its pharmaceutically acceptable salt, wherein it satisfies one or more of the following conditions: ( 1) Ring A is C _6-12 aryl; preferably, ring A is phenyl; (2) Each R ¹ is independently halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, Cyano, C _1-6 alkyl-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a or one or more R ^1b Substituted C _1-6 alkyl-O-; preferably, each R ¹ is independently halogen, C _1-6 alkyl, cyano or C _1-6 alkyl substituted by one or more R ^1a ; When there are multiple substituents, they may be the same or different; (3) Each R ^1a and R ^1b is independently halogen; preferably, each R ^1a and R ^1b is independently F or Cl; (4)m is 0, 1, 2 or 3; preferably, m is 2; (5) R ² is hydrogen, hydroxyl, halogen, amino, cyano, C _1-6 alkyl or C _1-6 alkyl-O- ; Preferably, R ² is hydrogen; (6) L is a connecting bond; (7) R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3- 7-membered heterocyclyl, 3-7-membered heterocyclyl substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; preferably , R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocyclyl substituted by one or more R ^3e , C _3-7 Cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; more preferably, R ³ is a 3-7 membered heterocyclyl substituted by one or more R ^3e ; when the substituent is poly each time, the same or different; (8) Each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano group, C _1-6 alkyl, substituted by one or more C _1-6 alkyl substituted by R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 ring Alkyl-O-, C _3-7 cycloalkyl-O- substituted by one or more R ^3-j , C _2-6 alkynyl or -C(=O)-R ⁹ ; further, each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a base, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _2-6 alkynyl or -C(=O)-R ⁹ ; Preferably, each R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, substituted by one or more R ^3-b C _1-6 alkyl-O-, C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; preferably, each R ^3d , R ^3e and R ^3h is independently a hydroxyl group , -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O- Or -C(=O)-R ⁹ ; further preferably, each R ^3d , R ^3e and R ^3h are each independently hydroxyl, halogen, C _1-6 alkyl-O-, substituted by one or more R ^{3 -b} substituted C _1-6 alkyl-O-, C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl-O- or -C ( substituted by one or more R ^3-j =O)-R ⁹ ; more preferably, each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, C _1-6 alkyl-O-, substituted by one or more R ^3-b C _1-6 alkyl-O- or -C(=O)-R ⁹ ; when there are multiple substituents, the same or different; (9) Each R ^3-a , R ^3-b and R ^{3- j} is each independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; further, each R ^3-a and R ^3-b is independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl ;Further, each R ^3-b is independently deuterium, hydroxyl or halogen; (10)X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, -O-(C ₁ -C ₄ alkylene) Alkyl)- in "C ₁ -C ₄ alkylene" is connected to R ⁴ ; further, X is a connecting bond, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ Alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, -O-(C ₁ -C ₄ alkylene)- "C ₁ -C ₄ alkylene" is connected to R ⁴ ; preferably, X is -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene) )-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, "C in -O-(C ₁ -C ₄ alkylene)- ₁ -C ₄ alkylene" is connected to R ⁴ ; (11) R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkyl-O-, cyano group, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3-7 ring substituted by one or more R ^4b Alkyl; preferably, R ⁴ is hydrogen, C _1-6 alkyl, cyano, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3- substituted by one or more R ^4a 7-membered heterocyclyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; more preferably, R ⁴ is hydrogen, C _1-6 alkyl, cyano, hydroxyl, -N(R ⁷ ) _2. A 3-7-membered heterocyclyl group substituted by one or more R ^4a or a C _3-7 cycloalkyl group substituted by one or more R ^4b ; further preferably, R ⁴ is -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; Most preferably, R ⁴ is -N(R ⁷ ) ₂ , a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^4a ; when there are multiple substituents, they are the same or different; (12) Each R ^4a and R ^4b are independently hydroxyl, halogen, amino, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; preferably, each Each of R ^4a and R ^4b is independently an amino group, a C _1-6 alkyl group or a C _1-6 alkyl group substituted by one or more deuterium; more preferably, each R ^4a and R ^4b is independently C _1-6 alkyl or amino group; further preferably, each R ^4a is independently C _1-6 alkyl; (13) R ⁵ is hydrogen, hydroxyl, halogen, amine group, cyano group or C _1-6 Alkyl; preferably, R ⁵ is hydrogen or C _1-6 alkyl; more preferably, R ⁵ is C _1-6 alkyl; (14) R ⁶ is oxo; (15) Each R ⁷ is independently is hydrogen, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclyl or substituted by one or Multiple R ^7a substituted 3-7 membered heterocyclyl; further, each R ⁷ is independently hydrogen, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^7b , or Two R ⁷ together with the connected nitrogen atom form a 3-7 membered heterocyclic group; further, each R ⁷ is independently hydrogen or C _1-6 alkyl; when there are multiple substituents, the same or Different; (16) Each R ^7b is independently deuterium, halogen, hydroxyl or cyano; preferably, each R ^7b is independently deuterium or hydroxyl; more preferably, each R ^7b is independently deuterium; (17 ) Each R ⁹ is independently hydrogen or C _1-6 alkyl; preferably, each R ⁹ is independently C _1-6 alkyl; (18) Ring D is a 3-7 membered heterocyclyl; (19 ) R ¹⁰ is C _1-6 alkyl; preferably, R ¹⁰ is methyl; (20) R ¹¹ is C _1-6 alkyl; preferably, R ¹¹ is methyl; and (21) Not hydrogen. The fused ring compound as shown in formula I as described in any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C _6-12 aryl group; each R ¹ is independently a halogen, a hydroxyl, -N(R ⁷ ) ₂ , a C _1-6 alkyl, a cyano, a C _1-6 alkyl-O-, a C 2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 alkyl substituted by one or more R ^1a , or _{a C 1-6 alkyl} -O- substituted by one or more R ^1b ; when there are multiple substituents, they are the same or different; each R ^1a and R ^1b is independently a halogen; m is 0, 1, 2 or 3; R ² is hydrogen, a hydroxyl, a halogen, an amino, a cyano, a C _1-6 alkyl or a C _1-6 alkyl-O-; L is a connecting bond; R ³ is a C _3-7 cycloalkyl, a C _3-7 cycloalkyl substituted by one or more R ^3d , a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R ^3e , a C _3-7 cycloalkenyl, or a C _3-7 cycloalkenyl substituted by one or more R ^3h ; when there are multiple substituents, they may be the same or different; each of R ^3d , R ^3e and R ^3h is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C wherein the substituents are substituted with one or more R ^3-j , the substituents are the same or different; each of R ^3-a , R ₃ ^-b and R ₃ ^-j is independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; ^X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O- ₍ C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₄ alkynylene)-; preferably, in -O-(C ₁ -C ₄ alkylene)-, "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl ... R _{5 is} hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo; each R ⁷ is independently hydrogen _, C _1-6 alkyl ^or C _1-6 alkyl substituted by one or ^more R ^7b , or two R ^7a _and R ^{4b are} substituted by one _or more R ^7b _; ^{R 7} together with the nitrogen atom to which it is attached forms a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R ^7a ; when there are multiple substituents, they are the same or different; each R ^7a and R ^7b are independently deuterium, halogen, hydroxyl or cyano; each R ⁹ is independently hydrogen or C _1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R ¹⁰ is C _1-6 alkyl; R ¹¹ is C _1-6 alkyl; the 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by the substituent are each independently "a 3-7 membered heterocyclic group having 1, 2 or 3 heteroatoms in which the heteroatoms are independently selected from N, O and S"; further, Ring A is C _6-12 aryl; each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different; each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; when there are multiple substituents, they are the same or different; each R ^3-b is independently deuterium, hydroxyl or halogen; X is a linking bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, in "-O-(C ₁ -C ₄ alkylene)-", "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, cyano, hydroxyl, -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R ^4a , or a C _3-7 cycloalkyl substituted by one or more R ^4b ; when there are multiple substituents, they may be the same or different; each R ^4a and R ^R4b is independently an amino group, a _C1-6 alkyl group or a _C1-6 alkyl group substituted by one or more deuterium groups; ^R5 is hydrogen or a _C1-6 alkyl group; ^R6 is oxo; each ^R7 is independently hydrogen, a _C1-6 alkyl group or a _C1-6 alkyl group substituted by one or more ^R7b , or two ^R7s together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each ^R7b is independently deuterium or a hydroxyl group; each ^R9 is independently a _C1-6 alkyl group; Ring D is a 3-7 membered heterocyclic group; ^R10 is a _C1-6 alkyl group; ^R11 is a _C1-6 alkyl group; The 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by a substituent are each independently a "3-7 membered heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S"; further, Ring A is a C _6-12 aryl group (e.g., ); each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; when there are multiple substituents, they are the same or different; each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is a 3-7 membered heterocyclic group substituted by one or more R ^3e ; when there are multiple substituents, they are the same or different; each R ^3e is independently hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ ; when there are multiple substituents, they are the same or different; each R ^3-b is independently deuterium, hydroxyl or halogen; X is -(C ₁ -C ₄ alkylene)-, -O-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, in "-O-(C ₁ -C ₄ alkylene)-", "C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is -N(R ⁷ ) ₂ , a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R ^4a ; when there are multiple substituents, they are the same or different; each R ^4a is independently C _1-6 alkyl; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is oxo; each R ⁷ is independently hydrogen, C wherein the 3-7-membered heterocyclic group is a C _1-6- membered alkyl group or a C _1-6- membered alkyl group substituted by one or more R ^7b , or two R ⁷ together with the nitrogen atom to which they are connected form a 3-7-membered heterocyclic group; when there are multiple substituents, they are the same or different; each R ^7b is independently deuterium or hydroxyl; each R ⁹ is independently a C _1-6- alkyl group; Ring D is a 3-7-membered heterocyclic group; R ¹⁰ is methyl; R ¹¹ is methyl; the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by the substituent are each independently a "3-7-membered heterocyclic group whose heteroatom types are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3". The fused ring compound represented by Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein the fused ring compound represented by Formula I The compound is the following scheme 1, scheme 2, scheme 3 or scheme 4: Scheme 1: In the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, ring A is C _6-12 aryl; each R ¹ is independently halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl-O-, C _2-6 alkene group, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a or C _1-6 alkyl-O- substituted by one or more R ^1b ; when the substituent is multiple when, the same or different; each R ^1a and R ^1b are independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, amine, cyano, C _1-6 alkyl Or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted by one or more R ^3d , 3-7 membered heterocycle group, a 3-7-membered heterocyclyl group substituted by one or more R ^3e , a C _3-7 cycloalkenyl group, or a C _3-7 cycloalkenyl group substituted by one or more R ^3h ; when the substituent is multiple , the same or different; each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkyl, surrounded by one or more R ^{3- a} -substituted C _1-6 alkyl, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O -, C _3-7 cycloalkyl-O-, C _2-6 alkynyl or -C(=O)-R ⁹ substituted by one or more R ^3-j ; when there are multiple substituents, they are the same or different; each R ^3-a , R ^3-b and R ^3-j is independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene)-; Preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 Alkyl -O-, cyano, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 Cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; when there are multiple substituents, they are the same or different; each R ^4a and R ^4b are independently hydroxyl, halogen, and amino groups , C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo (=O); Each R ⁷ is independently hydrogen, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ are formed together with the attached nitrogen atom 3-7-membered heterocyclyl or 3-7-membered heterocyclyl substituted by one or more R ^7a ; when there are multiple substituents, they may be the same or different; each R ^7a and R ^7b are independently deuterium or halogen , hydroxyl or cyano group; each R ⁹ is independently hydrogen or C _1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R ¹⁰ is C _1-6 alkyl; R ¹¹ is C _1-6 alkyl; where, Not hydrogen; The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, a 3-7-membered heterocyclic group with 1, 2 or 3 heteroatoms"; Scheme 2: The fused ring compound shown in formula I, its stereoisomer or its pharmaceutical In acceptable salts, Ring A is C _6-12 aryl; each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a ; When there are multiple substituents, they may be the same or different; Each R ^1a is independently halogen; m is 2; R ² is hydrogen; L is a connecting bond; R ³ is 3- substituted by one or more R ^3e 7-membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R ^3e is independently hydroxyl, halogen, -N(R ⁷ ) ₂ , C _1-6 alkyl-O-, by one or C _1-6 alkyl-O-, C _3-7 cycloalkyl-O- or -C(=O)-R ⁹ substituted by multiple R ^3-b ; when there are multiple substituents, they are the same or different ; Each R ^3-b is independently deuterium, hydroxyl or halogen; X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene) )-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene)-; preferably, in "-O-(C ₁ -C ₄ alkylene)-""C ₁ -C ₄ alkylene" is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, cyano group, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclic group, surrounded by a Or a 3-7-membered heterocyclyl group substituted by multiple R ^4a or a C _3-7 cycloalkyl group substituted by one or more R ^4b ; when the substituents are multiple, they are the same or different; each R ^4a and R ^4b is each independently an amino group, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is oxo (=O ); Each R ⁷ is independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom form 3-7 When there are multiple substituents, they may be the same or different; Each R ^7b is independently deuterium or hydroxyl; Each R ⁹ is independently a C _1-6 alkyl group; Ring D is a 3-7 membered heterocyclic group Ring group; R ¹⁰ is C _1-6 alkyl; R ¹¹ is C _1-6 alkyl; wherein, Not hydrogen; The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, a 3-7-membered heterocyclic group with 1, 2 or 3 heteroatoms"; Scheme 3: The fused ring compound shown in formula I, its stereoisomer or its pharmaceutical In acceptable salts, Ring A is C _6-12 aryl; each R ¹ is independently halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl Base-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a or C _1-6 alkyl substituted by one or more R ^1b -O-; when there are multiple substituents, they may be the same or different; each R ^1a and R ^1b are independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, or amino group , cyano, C _1-6 alkyl or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 substituted by one or more R ^3d Cycloalkyl, 3-7 membered heterocyclyl substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 cycloalkenyl substituted by one or more R ^3h ; when the substituent is When there are multiple, they may be the same or different; each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano group, C _1-6 alkyl, surrounded by one or more R ^3-a substituted C _1-6 alkyl, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl -O-, C _3-7 cycloalkyl-O- substituted by one or more R ^3-j , C _2-6 alkynyl or -C(=O)-R ⁹ ; when there are multiple substituents , the same or different; each R ^3-a , R ^3-b and R ^3-j are independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connecting bond, -O-, -( C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkylene)- or -(C ₂ -C ₆ alkynylene) -; Preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ ; R ⁴ is hydrogen, C _1-6 alkyl, C _{1 -6} alkyl-O-, cyano group, halogen, hydroxyl, -N(R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _{3 -7} cycloalkyl or C _3-7 cycloalkyl substituted by one or more R ^4b ; when the substituents are multiple, they are the same or different; each R ^4a and R ^4b are independently hydroxyl, halogen, Amino, C _1-6 alkyl or C _1-6 alkyl substituted by one or more deuterium; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is Oxo (=O); Each R ⁷ is independently hydrogen, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ and the nitrogen atom to which they are attached Together they form a 3-7 membered heterocyclyl group or a 3-7 membered heterocyclyl group substituted by one or more R ^7a ; when there are multiple substituents, they are the same or different; each R ^7a and R ^7b is independently deuterium , halogen, hydroxyl or cyano; each R ⁹ is independently hydrogen or C _1-6 alkyl; Ring D is a 3-7 membered heterocyclyl; R ¹⁰ is C _1-6 alkyl; R ¹¹ is C _{1 -6} alkyl; where, Not hydrogen; The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group and the 3-7-membered heterocyclic group substituted by a substituent is each independently "the heteroatom species is independently selected from N, O and S, a 3-7-membered heterocyclic group with 1, 2 or 3 heteroatoms"; Scheme 4: The fused ring compound shown in formula I, its stereoisomer or its pharmaceutical In acceptable salts, Ring A is C _6-12 aryl; each R ¹ is independently halogen, hydroxyl, -N(R ⁷ ) ₂ , C _1-6 alkyl, cyano, C _1-6 alkyl Base-O-, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by one or more R ^1a or C _1-6 alkyl substituted by one or more R ^1b -O-; when there are multiple substituents, they may be the same or different; each R ^1a and R ^1b are independently halogen; m is 0, 1, 2 or 3; R ² is hydrogen, hydroxyl, halogen, or amino group , cyano, C _1-6 alkyl or C _1-6 alkyl-O-; L is a connecting bond; R ³ is C _3-7 cycloalkyl, C _3-7 substituted by one or more R ^3d Cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^3e , C _3-7 cycloalkenyl or C _3-7 substituted by one or more R ^3h Cycloalkenyl; when there are multiple substituents, they may be the same or different; each R ^3d , R ^3e and R ^3h are independently hydroxyl, halogen, -N(R ⁷ ) ₂ , cyano, C _1-6 alkane group, C _1-6 alkyl substituted by one or more R ^3-a , C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted by one or more R ^3-b , C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl-O- substituted by one or more R ^3-j , C _2-6 alkynyl or -C(=O)-R ⁹ ; When there are multiple substituents, they may be the same or different; Each R ^3-a , R ^3-b and R ^3-j are independently deuterium, hydroxyl, halogen or C _3-7 cycloalkyl; X is a connection bond, -O-, -(C ₁ -C ₄ alkylene)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-; Preferably, "C ₁ -C ₄ alkylene" in -O-(C ₁ -C ₄ alkylene)- is connected to R ⁴ ; R ⁴ is -N( R ⁷ ) ₂ , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R ^4a , C _3-7 cycloalkyl or C _3- substituted by one or more R ^4b ₇ cycloalkyl; when there are multiple substituents, they may be the same or different; each R ^4a and R ^4b are independently hydroxyl, halogen, amino, C _1-6 alkyl or substituted by one or more deuterium C _1-6 alkyl; R ⁵ is hydrogen, hydroxyl, halogen, amine, cyano or C _1-6 alkyl; R ⁶ is oxo (=O); each R ⁷ is independently hydrogen, C _{1 -6} alkyl or C _1-6 alkyl substituted by one or more R ^7b , or two R ⁷ together with the attached nitrogen atom form a 3-7 membered heterocyclyl or substituted by one or more R ^7a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R ^7a and R ^7b are independently deuterium, halogen, hydroxyl or cyano; each R ⁹ is independently hydrogen or C _1-6 alkyl; Ring D is a 3-7-membered heterocyclyl; R ¹⁰ is a C _1-6 alkyl; R ¹¹ is a C _1-6 alkyl; the 3-7-membered heterocyclyl and the substituted group Each of the 3-7-membered heterocyclyl groups in the substituted 3-7-membered heterocyclyl group is independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3. -7-membered heterocyclyl”. The fused ring compound represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt as described in any one of claims 1 to 7, wherein it satisfies one or more of the following conditions: ( 1) Ring A is ; (2) Each R ¹ is independently halogen, cyano, C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1a . When there are multiple substituents, they may be the same or different. ; For example: R ¹ is F, Cl, -CHF ₂ , -CF ₃ , cyano, -CH ₃ or -CF ₂ CH ₃ , preferably F, -CHF ₂ , -CH ₃ or cyano; (3) R ² is hydrogen; (4) R ⁵ is hydrogen or C _1-6 alkyl, for example: R ⁵ is hydrogen or methyl; (5) X is a connecting bond, -O-, -(C ₁ -C ₄ alkylene base)-, -O-(C ₁ -C ₄ alkylene)-, -(C ₂ -C ₄ alkenylene)- or -(C ₂ -C ₆ alkynylene)-, "-O-( "C ₁ -C ₄ alkylene)-" in "C ₁ -C ₄ alkylene" is connected to R ⁴ ; for example: connecting bond, , , , , , , , , , , , , , , or , another example: connection key, , , , , , , , , , , or , where the f end is connected to R ⁴ ; (6) When ring D is a 3-7-membered heterocyclyl group, ring D is a 1,2-dihydropyridyl group, for example or , "c" means that the atom is located in the meta position of the N atom of the B ring; (7) When R ³ is a C _3-7 cycloalkyl group or a C _3-7 cycloalkyl group substituted by one or more R ^3d , then The R ³ mentioned above is , , , , , , or ; (8) When R ³ is a 3-7-membered heterocyclyl group or a 3-7-membered heterocyclyl group substituted by one or more R ^3e , the R ³ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and for , , , , , , , , , , , , , , , , , or ,For example , , , , , , , , , , , , , , or , another example , , , , , , , , , , or , another example , , or , preferred , , , , , , , , or ; (9) R ⁴ is hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CD ₃ ) ₂ , -N( CH ₂ CH ₃ ) ₂ , , , , , , , , , , , , , or ; Also hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , , , , , , , , or ; (10) R ¹⁰ is methyl; (11) R ¹¹ is methyl; (12) When R ⁴ is cyano, for ; Preferably, the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt satisfies one or more of the following conditions: (1A) for , and can also be , , , , , , , or , can also be , , , , , , or ,For example , or , another example or ; (1B) for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and for , , , , , , , , , , , , , , , , , , , , , , , , , or ,For example , , , , , , , , , , , , , , or , another example , , , , , , , , , , or , another example , , or , preferred , , , , , , , , or ; (1C) for or , "c" means that the atom is located in the meta position of the N atom of the B ring; (1D) For methyl, methoxy, cyano, halogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , and can be hydrogen, methyl, methoxy, cyano, halogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , such as methyl, cyano, , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , preferred , , , , , , , , , , , , , , , , , , , , , , , , , or , also preferred , , , , , , , , , , , , , , or ; More preferably, the fused ring compound shown in Formula I, its stereoisomer or its pharmaceutically acceptable salt satisfies the following conditions: for or ;For example: or ; Specifically, the fused ring compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt is or . A fused ring compound as shown in formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, wherein the fused ring compound as shown in formula I is selected from any one of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . A method for preparing a fused ring compound as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, wherein, when for , "c" indicates that the atom is located at the meta position of the N atom of the B ring, and the preparation method comprises the following steps: intermediate I-A1 reacts with raw material N-phenylbis(trifluoromethanesulfonyl)imide or trifluoromethanesulfonic anhydride to obtain intermediate I-A2, I-A2 is then coupled with raw material I-A3 to obtain intermediate I-A4, I-A4 is then subjected to substitution reaction or palladium-catalyzed Buchwald coupling reaction with raw material I-A5 to obtain a compound of general formula IA; If I-A4 and I-A5 undergo a substitution reaction, the reaction is carried out in the presence of a base, and the base is cesium carbonate, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine; If I-A4 and I-A5 undergo a Buchwald coupling reaction, the reaction is carried out in the presence of a catalyst and a base, and the catalyst is RuPhos Pd G3, BrettPhos Pd G3, XPhos Pd G3, XantPhos Pd G3, RuPhos Pd G4 or BrettPhos Pd G4, and the base is cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide or sodium tert-butoxide; wherein ring A, m, X, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ is defined as in any one of claim 1 to 11; RG is hydrogen, -B(OH) ₂ , , , -ZnBr or -ZnI. A compound represented by formula I-A1, a compound represented by formula I-A2, wherein, , ; Wherein, L, R ² , R ³ , R ⁵ and R ¹⁰ are as defined in any one of claims 1 to 11. The compound according to claim 13, wherein (1) the compound represented by formula I-A1 is any of the following compounds: , , , ; (2) The compound represented by formula I-A2 is any of the following compounds: , , , . A compound that is any of the following: , , , , , , , , , , , , , , , , , , , , , , , . A pharmaceutical composition, wherein it contains: (1) Substance Q , which is a fused ring compound represented by formula I according to any one of claims 1 to 11, its stereoisomer or its Pharmaceutically acceptable salts, and (2) pharmaceutically acceptable excipients. The use of a substance Q or a pharmaceutical composition as described in claim 16 in the preparation of SOS1 inhibitors, wherein the substance Q is a fused ring represented by formula I as described in any one of claims 1 to 11 compound, its stereoisomers or its pharmaceutically acceptable salts. The use of a substance Q or a pharmaceutical composition as described in claim 16 in the preparation of medicines; wherein the substance Q is a fused ring compound represented by formula I as described in any one of claims 1 to 11 , its stereoisomer or its pharmaceutically acceptable salt; the drug can be a drug for treating and/or preventing diseases related to SOS1 activity or expression amount; Preferably, the drug is related to SOS1 activity or expression amount The disease is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, liver cancer, rectal cancer, bladder cancer , throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer , urothelial carcinoma, acute skeletal leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic syndrome and multiple myeloid carcinoma, as well as associated with SOS1 inherited mutations Diseases such as neurofibromatosis type 1, Noonan syndrome, multiple lentigo-like Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, cardio-facial-cutaneous syndrome, Costello syndrome, Regis syndrome Syndrome and hereditary gingival fibroma type 1. A use of a substance Q or a pharmaceutical composition as described in claim 16 in the preparation of a drug; wherein the substance Q is a fused ring compound as shown in formula I as described in any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the drug is a drug for treating and/or preventing the following diseases; the diseases are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granuloma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, neurofibromatosis ovarian cancer, squamous cell carcinoma of the head and neck, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic syndrome and multiple myeloma, as well as neurofibroma type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Costillo syndrome, Regis syndrome and hereditary gingival fibroma type 1.