Condensed ring compound as well as preparation method and application thereof

Abstract

The invention discloses a fused ring compound as well as a preparation method and application thereof. The invention provides a fused ring compound as shown in a formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof. The fused ring compound as shown in the formula I has relatively good inhibitory activity on SOS1; diseases related to SOS1 activity or expression quantity are expected to be treated and / or prevented; # imgabs0 #

Description

A condensed ring compound, preparation method thereof and application thereof

[0001] This application claims priority to Chinese Patent Application No. 2022109369139 filed on August 5, 2022, Chinese Patent Application No. 202211294374X filed on October 21, 2022, Chinese Patent Application No. 2022115292859 filed on November 30, 2022, and Chinese Patent Application No. 2023109135728 filed on July 24, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a condensed ring compound, a preparation method and application thereof. Background Art

[0003] RAS protein is a 21kDa guanine trinucleotide phosphate (GTP)-binding protein located on the cell membrane and 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 relatively weak GTPase hydrolysis function and a slow nucleotide exchange rate. Binding to GTPase activating proteins (GAPs) can enhance the GTP hydrolysis function of RAS protein, while guanine nucleotide exchange factors (GEFs) can catalyze the exchange of nucleotides (GTP for GDP). SOS1 (Son of Sevenless 1) is a RAS-specific GEF. SOS1 binding to RAS promotes the release of GDP from RAS and its binding to GTP, thereby activating RAS. Once activated, RAS can activate multiple downstream signaling pathways, including the MAPK and PI3K pathways, which play an important role in promoting cell differentiation, proliferation, and survival. RAS mutations are genetic drivers of many cancers, with 20%-30% of human tumors harboring RAS mutations, such as lung, colorectal, and pancreatic cancers.

[0004] The RAS gene family includes KRAS, NRAS, and HRAS. KRAS mutations are present in a variety of tumors, such as lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%). Among KRAS mutations, the most common 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 less frequent and primarily occur in cancers such as melanoma, leukemia, and thyroid cancer. In addition, abnormal activation of RAS proteins (such as gene mutations, amplification, and overexpression) is closely associated with 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.

[0005] SOS1 is a guanine nucleotide exchange factor of the RAS family that is involved in cancer-related signaling pathways. Reduced SOS1 expression can significantly inhibit the proliferation and survival of KRAS-mutant cancer cells. Because SOS1 is a common node for activating multiple RAS signaling pathways, and nearly all growth factor receptors initiate RAS signaling pathways through SOS1, SOS1 inhibitors have the potential to be broad-spectrum anticancer drugs. Signaling pathways activated by SOS1 also play a crucial role in other types of cancer with mutations. SOS1 can interact with the adaptor protein Grb2 to form the SOS1 / Grb2 complex, which binds to activated receptor tyrosine kinases (such as EGFR, HER2, ErbB4, TRKA, TRKB, TRKC, RET, and AXL). SOS1 can also be recruited to phosphorylated cell surface receptors, such as the T cell receptor, B cell receptor, and monocyte colony-stimulating factor receptor. SOS1's localization on the cell membrane allows it 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, which has been implicated in the pathogenesis of various human cancers and other diseases. Furthermore, SOS1 mutations have been found in lung adenocarcinoma, embryonal rhabdomyosarcoma, and cutaneous granular cell tumors, and SOS1 overexpression has been found in bladder and prostate cancers. Beyond cancer, inherited SOS1 mutations have also been implicated in the pathogenesis of RAS disorders, including Noonan syndrome, cardiofacial-cutaneous syndrome, and hereditary gingival fibromatosis type 1.

[0006] Currently, no SOS1 inhibitors have been approved for marketing, so new and effective SOS1 inhibitors need to be developed to meet clinical needs.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is that existing SOS1 inhibitors have defects such as a single structure. The present invention provides a fused ring compound, a preparation method and application thereof. This type of compound has good inhibitory activity against SOS1.

[0009] The present invention provides a fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof;

[0010] in:

[0011] Ring A is C 6-12 Aryl, 5-10 membered heteroaryl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic group;

[0012] Each R 1 are independently 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, one or more R 1a Substituted C 1-6 Alkyl, one or more R 1b Substituted C 1-6 Alkyl-O-, one or more R 1c Substituted C 2-6 Alkenyl, one or more R 1d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 1e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 1f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 1g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 1h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 1i Substituted C 3-7 Cycloalkenyl, -C(=O)-OR 9 、-OC(=O)-R 9 、-C(=O)-N(R 7 )2、-S(O)2-R 9 、-NR 8 -S(O)2-R9 、-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 ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, one or more R 1e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 1f Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 1i Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0013] Each R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f 、R 1g 、R 1h and R 1i are 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, one or more R 1-a Substituted C 1-6 Alkyl, one or more R 1-b Substituted C 1-6 Alkyl-O-, one or more R 1-c Substituted C 2-6 Alkenyl, one or more R 1-d Substituted C 2- 6 alkynyl, C 3-7 Cycloalkyl, C 3-7Cycloalkyl-O-, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl-O-, one or more R 1-e Substituted C 3-7 Cycloalkyl, one or more R 1-e Substituted C 3-7 Cycloalkyl-O-, one or more R 1-f substituted 3-7 membered heterocyclic group, one or more R 1-f Substituted 3-7 membered heterocyclyl-O-, C 6-12 Aryl, one or more R 1-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 1-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl-O-, one or more R 1-i Substituted C 3-7 Cycloalkenyl, 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;

[0014] 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-iare 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;

[0015] Ring D is C 6-12 Aryl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic group;

[0016] 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 membered heterocyclic group;

[0017] L is a linking bond, -C(=O)-, -C(=O)O-, or -C(=O)NR 8 -、-NR 8 -, -S-, -O-, -S(O)-, -S(O)2- or -(CH2) p -; When L is a connecting bond, it means R 3 Connect directly to the D ring;

[0018] R 3 For hydrogen, deuterium, C 1-6 Alkyl, one or more R 3a Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 3b Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 3c Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3f Substituted C 6-12Aryl, 5-10 membered heteroaryl, substituted by one or more R 3g Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0019] Each R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h are independently deuterium, hydroxyl, halogen, -N(R 7 )2, cyano, nitro, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 3-c Substituted C 2-6 Alkenyl, one or more R 3-d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 3-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 3-i Substituted C 3-7 Cycloalkenyl, 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-R9 、-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 ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3-i Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0020] 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 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 heterocyclic group, -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 ;

[0021] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-;

[0022] R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0023] Each R 4a and R 4b are each independently hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, amino protecting group, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0024] R 5 is absent, oxo, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, C 1-6 Alkyl, one or more R 5a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 5b Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 5c Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 5d Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0025] Each R 5a 、R 5b and R 5c Deuterium, C 1-6 alkyl, hydroxy, halogen, amino or cyano;

[0026] R 6 is hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl group or not present;

[0027] Each R 7 are independently hydrogen, C 1-6 Alkyl, one or more R 7b Substituted C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl or amino protecting group, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0028] Each R 7a and R 7b Deuterium, C 1-6 Alkyl, halogen, hydroxy, amino, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0029] 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;

[0030] R 10 For hydrogen, deuterium, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl;

[0031] R 11 For cyano, C 1-6 Alkyl or one or more R 11a Substituted C 1-6Alkyl; when there are multiple substituents, they may be the same or different;

[0032] Each R 11a are independently deuterium, halogen or hydroxyl;

[0033] m is 0, 1, 2, 3, 4 or 5;

[0034] p is 1, 2, 3, 4, 5, or 6;

[0035] 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, wherein the heteroatoms are independently selected from N, O and S";

[0036] The 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group substituted by a substituent are each independently a "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S".

[0037] The 5-6 membered heteroaryl group is a "5-6 membered heteroaryl group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0038] The amino protecting group is tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl or p-toluenesulfonyl;

[0039] When the carbon atom of * has chirality, the fused ring compound shown in Formula I is or a mixture thereof.

[0040] 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 (this paragraph is hereinafter referred to as "in a certain embodiment").

[0041] In one embodiment, when X is a connecting bond, R 4 C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different.

[0042] In one embodiment, X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-; when X is a linker, R 4 For cyano,

[0043] In one scenario, 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 -(CH2) p -; When L is a connecting bond, it means R 3 Directly connected to the D ring; R 3 For one or more R 3e Substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R 3e are independently deuterium, hydroxyl, halogen, -N(R 7 )2, cyano, nitro, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1- 6-alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 3-c Substituted C 2-6 Alkenyl, one or more R 3-d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 3-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 3-i Substituted C 3-7 Cycloalkenyl, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, -SR 9 、-C(=O)-OR9 、-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 may be the same or different.

[0044] In one scenario, R 6 is oxo; L is a connecting bond; when L is a connecting bond, it means R 3 Directly connected to the D ring; R 3 For one or more R 3e Substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R 3e are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 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.

[0045] In one plan, Not hydrogen.

[0046] In one scenario, R 1 、R 1a 、R 1b 、R1c 、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 11 In the C 1-6 Alkyl, C substituted by substituent 1-6 C in the alkyl group 1-6 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0047] In one scenario, 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 wherein the halogen is independently F, Cl, Br or I, for example, F.

[0048] In one scenario, 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 5 、R 6 、R 7a 、R 7b and R 10 In the C 1-6 Alkyl-O-, C substituted by substituent 1-6 C in alkyl-O- 1-6 Each alkyl-O- group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0049] In one scenario, 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 、R5 、R 6 、R 7a 、R 7b 、R 8 、R 9 and R 10 In the C 2-6 Alkenyl, C substituted by substituent 2-6 C in alkenyl 2-6 Each alkenyl group is independently 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, -CH=CH-CH-CH2-CH3, -CH=CH-CH(CH3)2, -CH2-CH=C(CH3)2 or -CH=CH-(CH2)3-CH3.

[0050] In one scenario, 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 In the C 2-6 Alkynyl, C substituted by substituent 2-6 C in alkynyl 2-6Each alkynyl group is independently 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-CH2-CH3, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -C≡C-CH(CH3)2, or -CH2C≡C-CH2-CH2-CH3.

[0051] In one embodiment, C in ring A 3-7 Cycloalkyl, R 1 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3- 7 cycloalkyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f 、R 1g 、R 1h and R 1i C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, C 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, C substituted by substituent 3- 7Cycloalkyl-O-C 3-7 Cycloalkyl, 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 R 2 C in 3-7 Cycloalkyl, R 3 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 3a 、R 3b 、R3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, C 3-7 C in cycloalkyl-O- 3- 7 cycloalkyl, C substituted by a substituent 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkyl 3-7 Cycloalkyl, 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 C in 3-7 Cycloalkyl, R 4 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3- 7 cycloalkyl, R 5 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 7 C in 3-7 Cycloalkyl, R 8 and R 9 C in 3-7 Cycloalkyl, each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or For example, cyclopropyl.

[0052] In one embodiment, C in ring A 3-7Cycloalkenyl, R 1 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3- 7-cycloalkenyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkenyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f 、R 1g 、R 1h and R 1i C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, C 3-7 C in cycloalkenyl-O- 3-7 Cycloalkenyl, C substituted by a substituent 3- 7Cycloalkenyl-O- 3-7 Cycloalkenyl, 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 R 2 C in 3-7 Cycloalkenyl, R 3 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, two R 3d , two R 3e , two R 3f , two R 3g or two R3h Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkenyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkenyl 3-7 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 R 3-j C in 3-7 Cycloalkenyl, R 5 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 7 、R 8 and R 9 C in 3-7 Cycloalkenyl, the C 3-7 Each cycloalkenyl group is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0053] In one embodiment, ring A, ring D, and 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 、R3f 、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 In the , the 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by a substituent, the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group-O-, and the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by a substituent are each independently a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spirocyclic system) heterocyclic group. Specifically, the monocyclic heterocyclic group can be pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, piperazinyl, azetidinyl, 1,2-dihydropyridinyl, tetrahydropyridinyl, etc.

[0054] In one scenario, R 3 wherein the 3-7 membered heterocyclic group is replaced by one or more R 3e The number of heteroatoms in the 3-7 membered heterocyclic group is independently 1 or 2; the 3-7 membered heterocyclic group, substituted by one or more R 3e The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or two of N and O; the 3-7 membered heterocyclic group, 3e The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 3-7 membered heterocyclic group in which the heteroatom species are independently selected from one or two of N and O, and the number of heteroatoms is 1 or 2"; further, the 3-7 membered heterocyclic group, substituted by one or more R 3e The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently a 4-7 membered heterocyclic group having 1 or 2 heteroatoms, the types of which are independently selected from N and O; 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; specifically, when R 3 When R is a 4-7 membered monocyclic heterocyclic group, the 4-7 membered monocyclic heterocyclic group may be a piperidinyl, tetrahydropyranyl, piperazinyl, azetidinyl, morpholinyl or pyrrolidinyl group; when R 3When it is a 5-7 membered bridged heterocyclic group, the 5-7 membered bridged heterocyclic group may be When R 3 When it is a 5-7 membered spiro heterocyclic group, the 5-7 membered spiro heterocyclic group may be For example,

[0055] In one scenario, R 4 wherein the 3-7 membered heterocyclic group is replaced by one or more R 4a The number of heteroatoms in the 3-7 membered heterocyclic group is independently 1, 2 or 3; the 3-7 membered heterocyclic group, replaced by one or more R 4a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or more of N, O and S; the 3-7 membered heterocyclic group, the one or more R 4a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 3-7 membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; further, the 3-7 membered heterocyclic group, substituted by one or more R 4a The number of heteroatoms in the 3-7 membered heterocyclic group is independently 1 or 2; the 3-7 membered heterocyclic group, substituted by one or more R 4a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or two of N and O; the 3-7 membered heterocyclic group, 4a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 4-7 membered heterocyclic group in which the heteroatom species are independently selected from one or two of N and O, and the number of heteroatoms is 1 or 2"; for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl or morpholinyl; for example For example

[0056] In one scenario, R 7 In the above two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The number of heteroatoms in the substituted 3-7 membered heterocyclic group is independently 1 or 2; the two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or two of N and O; the two R 7Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 4-7 membered heterocyclic group in which the heteroatom species are independently selected from one or two species of N and O, and the number of heteroatoms is 1 or 2"; for example: pyrrolidinyl, and for example

[0057] In one embodiment, in ring D, the 3-7 membered heterocyclic group is a "6-membered heterocyclic group wherein the heteroatom type is N and the number of heteroatoms is 1 or 2", for example, 1,2-dihydropyridyl, and for example "c" indicates that the atom is located at the meta position relative to the nitrogen atom of the B ring.

[0058] In one embodiment, ring A, ring D, and 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 In the C 6-12 Aryl, C substituted by substituent 6-12 C in aromatic groups 6-12 Each aryl group is independently phenyl or naphthyl; for example: phenyl.

[0059] In one embodiment, 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 3hIn the 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group substituted with a substituent, each independently represents a "5- to 8-membered heteroaryl group having 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S".

[0060] In a certain embodiment, in X, the -(C1-C4 alkylene)- and -O-(C1-C4 alkylene)- in the -(C1-C4 alkylene)- are each independently methylene, ethylene, n-propylene or isopropylene, for example: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH2CH3)- or -C(CH3)2-, preferably -CH2-, -CH2CH2-, -CH(CH3)- or -CH2CH2CH2-; further, in "-O-(C1-C4 alkylene)-", the "C1-C4 alkylene" and R 4 connected.

[0061] In one embodiment, in X, the -(C2-C4 alkenylene)- is independently vinylene, propenylene, allylene or butenylene, such as -CH=CH-, -CH=CH-CH2-; further, the -(C2-C4 alkenylene)- can be Where f end and R 4 connected.

[0062] In a certain embodiment, in X, the -(C2-C6 alkynylene)- is independently ethynylene, propynylene, propargylene, butynylene or pentynylene, such as -C≡C-, -CH2-C≡CH, -C≡C-CH2-, -C≡C-CH2-CH2-, -C≡C-CH(CH3)-CH2-, -C≡CC(CH3)2-, preferably -C≡C-, -C≡C-CH2- or -C≡CC(CH3)2-; further, the -(C2-C6 alkynylene)- may be -C≡C-*, -C≡C-CH2-* or -C≡CC(CH3)2-*, wherein the * end is aligned with R 4 connected.

[0063] In one embodiment, ring A is C 6-12 Aryl; preferably, Ring A is phenyl.

[0064] In one scheme, each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; preferably, each R 1 are independently halogen, C 1-6 Alkyl, cyano or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different.

[0065] In one scheme, each R 1a and R 1b are each independently halogen; preferably, each R 1a and R 1b are each independently F or Cl.

[0066] In a certain embodiment, m is 0, 1, 2 or 3; preferably, m is 2.

[0067] In one scenario, R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; preferably, R 2 For hydrogen.

[0068] In one embodiment, L is a linker.

[0069] In one scenario, R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; preferably, R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 More preferably, R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different.

[0070] In one scheme, each R3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; Further, each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 Preferably, each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O- or -C(=O)-R 9 ; Preferably, each R 3d 、R 3e and R 3h are each independently hydroxyl, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3- b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O- or -C(=O)-R 9 ; Further preferably, each R 3d 、R 3e and R 3h are independently hydroxy, halogen, C1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3- j Substituted C 3-7 Cycloalkyl-O- or -C(=O)-R 9 More preferably, each R 3d 、R 3e and R 3h are independently hydroxy, halogen, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they may be the same or different.

[0071] In one scheme, 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 R 3-b are each independently deuterium, hydroxyl, halogen or C 3-7 cycloalkyl; further, each R 3-b is independently deuterium, hydroxyl or halogen.

[0072] In one embodiment, X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 further, X is a connecting bond, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is connected to R 4 Preferably, X is -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is connected to R 4 connected.

[0073] In one scenario, R 4 For hydrogen, C 1-6 Alkyl, C 1-6Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; preferably, R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; more preferably, R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 )2. By one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; further preferably, R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; most preferably, R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group or one or more R 4a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different.

[0074] In one scheme, each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 Alkyl; preferably, each R 4a and R 4b are each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 Alkyl; More preferably, each R 4a and R 4b Each independently is C 1-6 Alkyl or amino; further preferably, each R 4a Independently C 1- 6 alkyl.

[0075] In one scenario, R5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 Alkyl; preferably, R 5 is hydrogen or C 1-6 Alkyl; More preferably, R 5 C 1-6 alkyl.

[0076] In one scenario, R 6 It is oxo (=O).

[0077] In one scheme, each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a substituted 3-7 membered heterocyclic group; further, each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; further, each R 7 are independently hydrogen or C 1-6 Alkyl; when there are multiple substituents, they may be the same or different.

[0078] In one scheme, each R 7b are independently deuterium, halogen, hydroxyl or cyano; preferably, each R 7b is independently deuterium or hydroxyl; more preferably, each R 7b independently deuterium.

[0079] In one scheme, each R 9 are independently hydrogen or C 1-6 Alkyl; preferably, each R 9 Independently C 1-6 alkyl.

[0080] In one embodiment, ring D is a 3-7 membered heterocyclic group.

[0081] In one scenario, R 10 C 1-6 Alkyl; preferably, R 10 It is a methyl group.

[0082] In one scenario, R 11 C 1-6 Alkyl; preferably, R 11 It is a methyl group.

[0083] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0084] Ring A is C 6-12 aryl;

[0085] Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different;

[0086] Each R 1a and R 1b are each independently halogen;

[0087] m is 0, 1, 2, or 3;

[0088] R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-;

[0089] L is the connecting key;

[0090] R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0091] Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0092] Each R 3-a 、R 3-b and R 3-j are each independently deuterium, hydroxyl, halogen or C 3-7 Cycloalkyl;

[0093] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C4 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected;

[0094] R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0095] Each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0096] R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl;

[0097] R 6 is oxo (=O);

[0098] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7aa substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0099] Each R 7a and R 7b are independently deuterium, halogen, hydroxyl or cyano;

[0100] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0101] Ring D is a 3-7 membered heterocyclic group;

[0102] R 10 C 1-6 alkyl;

[0103] R 11 C 1-6 alkyl;

[0104] in, Not hydrogen;

[0105] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0106] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0107] Ring A is C 6-12 aryl;

[0108] Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different;

[0109] Each R 1a and R 1b are each independently halogen;

[0110] m is 0, 1, 2, or 3;

[0111] R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C1-6 Alkyl-O-;

[0112] L is the connecting key;

[0113] R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0114] Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0115] Each R 3-a and R 3-b are each independently deuterium, hydroxyl or halogen;

[0116] X is a linker, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C4 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected;

[0117] R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0118] Each R4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0119] R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl;

[0120] R 6 is oxo (=O);

[0121] Each R 7 are independently hydrogen or C 1-6 alkyl;

[0122] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0123] Ring D is a 3-7 membered heterocyclic group;

[0124] R 10 C 1-6 alkyl;

[0125] R 11 C 1-6 alkyl.

[0126] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0127] Ring A is C 6-12 aryl;

[0128] Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different;

[0129] Each R 1a and R 1b are each independently halogen;

[0130] m is 0, 1, 2, or 3;

[0131] R 2For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-;

[0132] L is the connecting key;

[0133] R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0134] Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0135] Each R 3-a 、R 3-b and R 3-j are each independently deuterium, hydroxyl, halogen or C 3-7 Cycloalkyl;

[0136] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected;

[0137] R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0138] Each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0139] R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl;

[0140] R 6 is oxo (=O);

[0141] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0142] Each R 7a and R 7b are independently deuterium, halogen, hydroxyl or cyano;

[0143] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0144] Ring D is a 3-7 membered heterocyclic group;

[0145] R 10 C 1-6 alkyl;

[0146] R 11 C 1-6 alkyl;

[0147] in, Not hydrogen;

[0148] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0149] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0150] Ring A is C 6-12 aryl;

[0151] Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different;

[0152] Each R 1a and R 1b are each independently halogen;

[0153] m is 0, 1, 2, or 3;

[0154] R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-;

[0155] L is the connecting key;

[0156] R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0157] Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0158] Each R 3-a 、R 3-b and R 3-j are each independently deuterium, hydroxyl, halogen or C 3-7 Cycloalkyl;

[0159] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected;

[0160] R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0161] Each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0162] R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl;

[0163] R 6 is oxo (=O);

[0164] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7aa substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0165] Each R 7a and R 7b are independently deuterium, halogen, hydroxyl or cyano;

[0166] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0167] Ring D is a 3-7 membered heterocyclic group;

[0168] R 10 C 1-6 alkyl;

[0169] R 11 C 1-6 alkyl;

[0170] in, Not hydrogen;

[0171] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0172] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0173] Ring A is C 6-12 aryl;

[0174] Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different;

[0175] Each R 1a and R 1b are each independently halogen;

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

[0177] R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C1-6 Alkyl-O-;

[0178] L is the connecting key;

[0179] R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different;

[0180] Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0181] Each R 3-a 、R 3-b and R 3-j are each independently deuterium, hydroxyl, halogen or C 3-7 Cycloalkyl;

[0182] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected;

[0183] R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0184] Each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0185] R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl;

[0186] R 6 is oxo (=O);

[0187] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0188] Each R 7a and R 7b are independently deuterium, halogen, hydroxyl or cyano;

[0189] Each R 9 are independently hydrogen or C 1-6 alkyl;

[0190] Ring D is a 3-7 membered heterocyclic group;

[0191] R 10 C 1-6 alkyl;

[0192] R 11 C 1-6 alkyl;

[0193] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0194] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0195] Ring A is C 6-12 aryl;

[0196] Each R 1are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0197] Each R 1a are independently halogen;

[0198] m is 2;

[0199] R 2 is hydrogen;

[0200] L is the connecting key;

[0201] R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0202] Each R 3e are independently hydroxy, halogen, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3- 7-cycloalkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0203] Each R 3-b are independently deuterium, hydroxyl or halogen;

[0204] X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected;

[0205] R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0206] Each R 4a and R 4b are each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0207] R 5 is hydrogen or C 1-6 alkyl;

[0208] R 6 is oxo (=O);

[0209] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0210] Each R 7b are independently deuterium or hydroxyl;

[0211] Each R 9 Independently C 1-6 alkyl;

[0212] Ring D is a 3-7 membered heterocyclic group;

[0213] R 10 C 1-6 alkyl;

[0214] R 11 C 1-6 alkyl;

[0215] in, Not hydrogen;

[0216] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0217] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0218] Ring A is C 6-12 aryl;

[0219] Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0220] Each R 1a are independently halogen;

[0221] m is 2;

[0222] R 2 is hydrogen;

[0223] L is the connecting key;

[0224] R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0225] Each R 3e are independently hydroxy, halogen, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0226] Each R 3-b are independently deuterium or halogen;

[0227] X is a linker, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected;

[0228] R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 )2. By one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0229] Each R 4a and R 4b are each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl;

[0230] R 5 is hydrogen or C 1-6 alkyl;

[0231] R 6 is oxo (=O);

[0232] Each R 7 are independently hydrogen or C 1-6 alkyl;

[0233] Each R 9 Independently C1-6 alkyl;

[0234] Ring D is a 3-7 membered heterocyclic group;

[0235] R 10 C 1-6 alkyl;

[0236] R 11 C 1-6 alkyl.

[0237] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0238] Ring A is C 6-12 Aryl groups, e.g.

[0239] Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0240] Each R 1a are independently halogen;

[0241] m is 2;

[0242] R 2 is hydrogen;

[0243] L is the connecting key;

[0244] R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0245] Each R 3e are independently hydroxyl, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0246] Each R 3-b are independently deuterium, hydroxyl or halogen;

[0247] X is -(C1-C4 alkylene)-, -O-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected;

[0248] R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group or one or more R 4a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0249] Each R 4a Independently C 1-6 alkyl;

[0250] R 5 is hydrogen or C 1-6 alkyl;

[0251] R 6 is oxo (=O);

[0252] Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0253] Each R 7b are independently deuterium or hydroxyl;

[0254] Each R 9 Independently C 1-6 alkyl;

[0255] Ring D is a 3-7 membered heterocyclic group;

[0256] R 10 is methyl;

[0257] R 11 is methyl;

[0258] The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted with a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0259] In a certain embodiment, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof,

[0260] Ring A is C6-12 aryl;

[0261] Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0262] Each R 1a are independently halogen;

[0263] m is 2;

[0264] R 2 is hydrogen;

[0265] L is the connecting key;

[0266] R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0267] Each R 3e are independently hydroxyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different;

[0268] Each R 3-b independently for deuterium;

[0269] X is -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected;

[0270] R 4 -N(R 7 )2 or by one or more R 4a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different;

[0271] Each R 4a Independently C 1-6 alkyl;

[0272] R 5 is hydrogen or C 1-6 alkyl;

[0273] R 6 is oxo (=O);

[0274] Each R 7 are independently hydrogen or C 1-6 alkyl;

[0275] Each R 9 Independently C 1-6 alkyl;

[0276] Ring D is a 3-7 membered heterocyclic group;

[0277] R 10 is methyl;

[0278] R 11 It is a methyl group.

[0279] In one embodiment, Ring A is

[0280] In one scheme, each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl, when there are multiple substituents, they may be the same or different; for example: R 1 It is F, Cl, -CHF2, -CF3, cyano, -CH3 or -CF2CH3, preferably F, -CHF2, -CH3 or cyano.

[0281] In one scenario, R 2 For hydrogen.

[0282] In one scenario, R 5 is hydrogen or C 1-6 Alkyl groups, such as R 5 is hydrogen or methyl.

[0283] In one embodiment, X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected; for example: connecting key, Another example: connection key, Among them, the f end and R 4 connected.

[0284] In one plan, Can It can also be It can also be For example For example

[0285] In one embodiment, when ring D is a 3-7 membered heterocyclic group, ring D may be a 1,2-dihydropyridyl group, for example "c" indicates that the atom is located at the meta position relative to the nitrogen atom of the B ring.

[0286] In one plan, for "c" indicates that the atom is located at the meta position relative to the nitrogen atom of the B ring.

[0287] In one plan, Can It can also be For example:

[0288] In a certain scheme, when R 3 C 3-7 Cycloalkyl or one or more R 3d Substituted C 3-7 When cycloalkyl, the R 3 Can

[0289] In a certain scheme, when R 3 is a 3-7 membered heterocyclic group or is replaced by one or more R 3e When the 3-7 membered heterocyclic group is substituted, the R 3 Can It can also be For example For example For example Preferred

[0290] In one plan, Can It can also be For example For example For example Preferred

[0291] In one scenario, R 4 It can be hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH2, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -N(CD3)2, and hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH2, -NHCH3, -N(CH3)2,

[0292] In one plan, It can be methyl, methoxy, cyano, halogen, It can also be hydrogen, methyl, methoxy, cyano, halogen, For example, methyl, cyano, Preferred Also preferred

[0293] In one embodiment, the fused ring compound as shown in Formula I is

[0294] In one scenario, R 10 It is a methyl group.

[0295] In one scenario, R 11 It is a methyl group.

[0296] In a certain scheme, when R 4 When it is cyano, for

[0297] In one embodiment, the compound represented by formula I is any of the following compounds:

[0298] The present invention also provides a method for preparing the fused ring compound as shown in formula I, its stereoisomers or pharmaceutically acceptable salts thereof, wherein for When "c" represents that the atom is located at the meta position relative to the nitrogen atom of the B ring, the preparation method comprises the following steps: reacting the intermediate I-A1 with the raw material N-phenylbis(trifluoromethanesulfonyl)imide or trifluoromethanesulfonic anhydride to obtain the intermediate I-A2; then, I-A2 undergoes a coupling reaction with the raw material I-A3 to obtain the intermediate I-A4; and then, I-A4 undergoes a substitution reaction or a palladium-catalyzed Buchwald coupling reaction with the raw material I-A5 to obtain the compound of the general formula IA;

[0299] If I-A4 and I-A5 undergo a substitution reaction, it is carried out in the presence of a base, such as, but not limited to, cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like;

[0300] If I-A4 and I-A5 undergo a Buchwald coupling reaction, it is carried out 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., and the base includes but is not limited to cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc.;

[0301] Among them: 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 of the above options;

[0302] RG is hydrogen, -B(OH)2, -ZnBr or -ZnI.

[0303] The present invention also provides a compound as shown in Formula I-A1:

[0304] Among them, L, R 2 、R 3 、R 5 and R 10 is defined as in any of the above schemes.

[0305] In one embodiment, the compound represented by formula I-A1 is any one of the following compounds:

[0306] The present invention also provides a compound as shown in Formula I-A2:

[0307] Among them, L, R 2 、R 3 、R 5 and R 10 is defined as in any of the above schemes.

[0308] In one embodiment, the compound represented by formula I-A2 is any one of the following compounds:

[0309] The present invention also provides any of the following compounds:

[0310] The present invention provides a pharmaceutical composition comprising:

[0311] (1) (a therapeutically effective amount of) a substance Q, wherein the substance Q is a fused ring compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and

[0312] (2) Pharmaceutically acceptable excipients.

[0313] The present invention provides a use of a substance Q or the aforementioned pharmaceutical composition in the preparation of an SOS1 inhibitor, wherein the substance Q is a fused ring compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0314] In the above applications, preferably, the SOS1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of the compound in inhibiting SOS1.

[0315] The present invention provides a use of a substance Q or the pharmaceutical composition as described above in the preparation of a drug; the substance Q is a fused ring compound as shown in Formula I as described 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.

[0316] 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, skin granular cell tumor, liver cancer, rectal cancer, bladder cancer, pharyngeal 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, urinary tract cancer, These diseases include myelofibrosis, myelomonocytic leukemia, myelofibrosis, B-cell lymphoma, myelomonocytic monocytic leukemia, splenomegaly, polyeosinophilic syndrome, and multiple myeloma, as well as diseases associated with inherited mutations in SOS1, including but not limited to neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Kristen Stewart syndrome, Regis syndrome, and hereditary gingival fibromatosis type 1.

[0317] The present invention provides a use of a substance Q or the pharmaceutical composition as described above in the preparation of a drug; the substance Q is a fused ring compound as described above as shown in formula I, 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 granular cell tumor, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer 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, polycythemia vera syndrome and multiple myeloma, as well as neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Kristen Stewart syndrome, Regis syndrome and hereditary gingival fibroma type 1.

[0318] The present invention provides a method for inhibiting SOS1, comprising administering a therapeutically effective amount of substance Q or the pharmaceutical composition as described above to a patient (e.g., a human);

[0319] The substance Q is the fused ring compound represented by formula I as described above, its stereoisomers or pharmaceutically acceptable salts thereof.

[0320] The present invention provides a method for treating and / or preventing a disease, which comprises administering a therapeutically effective amount of substance Q or the pharmaceutical composition as described above to a patient (e.g., a human);

[0321] The substance Q is a fused ring compound as shown in Formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0322] The disease is a disease associated with SOS1 activity or expression.

[0323] In the method for treating and / or preventing a disease, 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 granular cell tumor, liver cancer, rectal cancer, bladder cancer, pharyngeal 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, Meningeal cancer, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, polycythemia vera syndrome, and multiple myeloma, as well as diseases associated with inherited mutations in SOS1, including but not limited to neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Kristen Stewart syndrome, Regis syndrome, and hereditary gingival fibromatosis type 1.

[0324] Unless otherwise specified, the terms used in this invention have the following meanings:

[0325] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0326] The term "alkyl" refers to a group consisting solely of carbon and hydrogen atoms, having a specified number of carbon atoms (e.g., C 1-10 , preferably C 1-6 , more preferably C 1-4 ) is a saturated straight or branched hydrocarbon group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl or n-hexyl.

[0327] The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated straight-chain or branched hydrocarbon group by removing two hydrogen atoms; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, n-propylene {including -CH2CH2CH2-}, isopropylene {including -CH(CH3)CH2-, -CH(CH2CH3)- or -C(CH3)2-}, and the like.

[0328] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting solely of carbon and hydrogen atoms, with a specified number of carbon atoms (e.g., C 2-10 , preferably C 2-6 , more preferably C 2-4 ) and is connected to the rest of the molecule by a single bond, including cis-trans or ZE isomers; for example, alkenyl includes but is not limited to ethenyl (-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, -CH=CH-CH-CH2-CH3, -CH=CH-CH(CH3)2, -CH2-CH=C(CH3)2, or -CH=CH-(CH2)3-CH3, etc.

[0329] The term "alkenylene" refers to an unsaturated divalent group derived from a straight or branched chain alkene molecule by removing two hydrogen atoms; that is, one of the hydrogen atoms in an alkenyl group is replaced, and the definition of alkenyl is as described above. Examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CH-CH2-, and the like.

[0330] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting solely of carbon and hydrogen atoms, with a specified number of carbon atoms (e.g., C 2-10 , preferably C 2-6 , more preferably C 2-4 ) and is attached 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(CH3)3, -C≡C-CH(CH3)2, or -CH2C≡C-CH2-CH2-CH3, etc.

[0331] The term "alkynylene" refers to an unsaturated divalent group derived from a straight-chain or branched alkyne molecule by removing two hydrogen atoms; that is, one of the hydrogen atoms in an alkynyl group is replaced, 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-, and -C≡C-C(CH3)2-.

[0332] The term "C 1-6 Alkyl-O-", C 1-6 The alkyl group is as defined above.

[0333] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged, fused or spirocyclic) carbocyclic substituent, which may be attached 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, 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.

[0334] The term "cycloalkenyl" means a non-aromatic cyclic hydrocarbon group having at least one double bond (e.g., a carbon-carbon double bond) which is monocyclic or polycyclic (e.g., a bicyclic, tricyclic, or more cyclic bridged, fused, or spirocyclic system) and which is attached 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, more preferably 3 to 7 ring carbon atoms; for example, C 3-7 Cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0335] The term "heterocyclyl" refers to a stable 3-20-membered (preferably 3-10-membered, further preferably 3-7-membered, even more 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 hydrocarbon group consisting 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)2; preferably a 3-7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and more preferably a 4-7-membered heterocyclyl wherein "the number of heteroatoms is 1 or 2, and the types of heteroatoms are independently selected from N and O", wherein the 4-7-membered heterocyclyl can be a 4-7-membered monocyclic heterocyclyl, a 5-7-membered bridged heterocyclyl or a 5-7-membered heterocyclyl. 5-7 membered spirocyclic heterocyclyl; Examples of 3-7 membered heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, oxiranyl, thietanyl, tetrahydrothienyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, tetrahydropyridinyl, azetidinyl, pyrrolidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2H-pyranyl, oxazepinyl, diazepinyl, thiazepinyl, azabicycloheptyl, thiazolinyl, dihydrofuranyl, imidazolinyl, imidazolidinyl, thiacyclohexyl, triazinyl, dithiolanyl, dithiolanyl, dioxane, 2,6-diazaspiro[3.3]heptyl, 1,2-dihydropyridinyl, homopiperazinyl, thiomorpholinyl, Thiapranyl, tetrahydrofuranyl, 4H-pyranyl or dihydropyrrolyl, for example:

[0336] The term "aryl" refers to an aromatic group comprising a conjugated hydrocarbon ring system consisting of carbon atoms that satisfies the 4n+2 rule, with each ring being aromatic. In one embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6-12) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0337] The term "heteroaryl" means a 5-20 membered (preferably 5-12 membered, more preferably 5-10 membered, even more preferably 5-8 membered, and most preferably 5-6 membered) conjugated ring system having 2 to 15 carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur within the ring. Unless otherwise specified in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or higher ring system, and may also be fused to a cycloalkyl, cycloalkenyl, or heterocyclyl group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via 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 groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl (e.g., ), benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthiazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl.

[0338] In the term "cycloalkyl-O-", the cycloalkyl group is as defined above.

[0339] In the term "cycloalkenyl-O-", the cycloalkenyl group is as defined above.

[0340] In the term "heterocyclyl-O-", the heterocyclyl group is as defined above.

[0341] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.

[0342] It is to be understood that as used herein, the singular forms, such as "a," "an," and the like, include plural referents unless otherwise specified.

[0343] The term "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0344] Unless otherwise stated, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0345] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some instances, standard techniques were used for chemical syntheses and chemical analyses.

[0346] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0347] It should be understood that, as used in the present invention, “the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3”, “the heteroatom species are independently selected from N, O and S” can be understood as “the heteroatom species are independently selected from one or more of N, O and S”. As 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”.

[0348] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0349] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0350] As used herein, the fused ring compound shown in Formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. 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 shown in Formula I contains more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. 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 of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation.

[0351] As mentioned above, the present invention provides compounds represented by the above-mentioned various structures, or their cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers, tautomers or mixtures thereof, wherein "their mixtures" include any mixtures of any of the aforementioned stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, atropisomers), tautomers and / or mixtures (meso-isomers, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereomer mixtures, mixtures of cis-trans isomers and tautomers, mixtures of atropisomers and diastereomer mixtures, etc.

[0352] The fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof are intended to encompass any isotopically labeled (or "radiolabeled") variants of the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof. Such variants may be fused ring compounds as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. 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 is often useful. For radiographic applications, 11 C or 18 F is often useful.

[0353] Certain isotopic variants of the compounds of the invention, particularly those into which one or more radioactive isotopes have been incorporated, can be useful, for example, in studying the mechanism of action or the distribution of the active ingredient in vivo; because of the relative ease of preparation and detectability, isotopic variants labeled with 3 H or 14 Compounds containing a C isotope are particularly suitable for this purpose. Furthermore, the incorporation of an isotope, such as deuterium, can provide particular therapeutic benefits due to improved metabolic stability of the compound, for example, by extending the half-life in vivo or reducing the required effective dose; thus, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention in some cases. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as those described below and in the working examples, by using corresponding isotopically modified specific reagents and / or starting compounds.

[0354] In the present invention, a "pharmaceutical composition" refers to a formulation comprising a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0355] 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.

[0356] The terms "pharmaceutical excipients", "pharmaceutically acceptable excipients" or "pharmaceutically acceptable carriers" refer to excipients and additives used in the production of drugs and the preparation of prescriptions, and are all substances contained in pharmaceutical preparations in addition to the active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the drug, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value 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, flavoring agents and sweeteners.

[0357] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0358] When used as a drug, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof can be administered in any form of a pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical field and can be administered in various ways, depending on the need for local or systemic treatment and the area to be treated. Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal or intranasal), oral (solid and liquid preparations) or parenteral administration. Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers. 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 administration, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be administered by continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, and the like may be necessary or desirable. Pharmaceutical compositions comprising the present invention may also be in the form of controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0359] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0360] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0361] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. 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.

[0362] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to 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, and humans, with humans being the most preferred.

[0363] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance 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 may 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.

[0364] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains a relatively acidic functional group, a base addition salt 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, and the like. When the compound contains a relatively basic functional group, an acid addition salt 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 acid includes 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).

[0365] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0366] The reagents and raw materials used in the present invention are commercially available.

[0367] The positive progress of the present invention is that the fused ring compound of Formula I has good inhibitory activity against SOS1 and is expected to treat and / or prevent diseases related to SOS1 activity or expression. DETAILED DESCRIPTION

[0368] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0369] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Nuclear magnetic resonance chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard. Mass spectrometry measurements were performed using an Agilent 1260-6125B single quadrupole liquid chromatography-mass spectrometer employing an electrospray ionization (ESI) source.

[0370] For silica gel column chromatography, a Biotage Selekt flash preparative chromatograph and a Biotage BK-SIL silica gel prepacked column or an Agela Claricep Flash silica gel prepacked column of appropriate specifications were used.

[0371] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of which is 0.15mm-0.20mm, and the specification of which is 0.4mm-0.5mm for preparative thin layer chromatography.

[0372] Preparative high-performance liquid chromatography (HPLC) was performed using a Waters AutoPurification LC system equipped with an ACQUITY QDa mass spectrometer. A SunFire C18 5μm 19x250mm OBD preparative column was used as the preparative column. Compounds were eluted using a gradient of water (containing 0.1% formic acid)-acetonitrile as the mobile phase.

[0373] The English abbreviations in the present invention are as follows:

[0374] Boc: tert-butyloxycarbonyl; TIPS: triisopropylsilyl; Bn: benzyl; DMSO: dimethyl sulfoxide; Tf: trifluoromethanesulfonyl; Ms: methanesulfonyl.

[0375] Example 1

[0376] 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) 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-naphthyridin-2(1H)-one (Compound 2)

[0377] Step 1: 4-Bromo-6-chloro-2-methylpyridin-3-ol

[0378] 6-Chloro-2-methylpyridin-3-ol (10 g, 69.6 mmol) was dissolved in acetonitrile (100 mL) and N-bromosuccinimide (13.6 g, 76.6 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. The reaction was 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 x 2). The organic phase was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried with ethanol (80 mL) to obtain the product 4-bromo-6-chloro-2-methylpyridin-3-ol as a yellow solid (14.0 g, yield 93%). ESI-MS m / z: 221.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.78(s,1H),2.40(s,3H).

[0379] Step 2: tert-Butyl (S)-2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0380] Dissolve 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) in tetrahydrofuran (50 mL). Under nitrogen, add triphenylphosphine (3.5 g, 13.5 mmol) and diisopropyl azodicarboxylate (2.7 g, 13.5 mmol) at 0°C. Warm the reaction mixture to room temperature and stir for 2 hours. Dilute with water (100 mL) and extract with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1, volume ratio) to afford tert-butyl (S)-2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate as a colorless oil (4.7 g, 86% yield). ESI-MS m / z: 405.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.38(s,1H),4.12(s,1H),4.05-3.75(m,2H),3.42(t,J =6.7Hz,2H),2.52(s,3H),2.36-2.22(m,1H),2.14-1.85(m,3H),1.46(s,9H).

[0381] Step 3: tert-Butyl (S)-2-((6-chloro-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0382] 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 dimethyl sulfoxide (20 mL), and 23% aqueous methylamine solution (30 mL) was added. The mixture was stirred at 105°C for 72 hours. The reaction mixture 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, as a colorless oil (4.4 g). The crude product was used directly in the next reaction. ESI-MS m / z: 356.2 [M+H] + .

[0383] Step 4: tert-Butyl (S)-2-((6-chloro-5-iodo-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0384] Tert-butyl (S)-2-((6-chloro-2-methyl-4-(methylamino)pyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (4.4 g, 12.4 mmol) was dissolved in acetic acid (20 mL), and N-iodosuccinimide (3.0 g, 13.3 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium sulfite solution (100 mL) was added for dilution, and saturated aqueous sodium bicarbonate solution was added for neutralization. The mixture was extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1, volume ratio) to obtain 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, 79% yield). ESI-MS m / z:482.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ5.44(brs,1H),4.01(s,1H),3.72(s,1H),3.63(t,J=11.2Hz,1H),3.27 (s,2H),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).

[0385] Step 5: 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

[0386] 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), palladium 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 and react at 90°C for 4 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to afford 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, 80% yield). ESI-MS m / z: 454.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.75(d,J=16.4Hz,1H),6.13(d,J=16.4Hz,1H),4.27(q,J=7.2Hz,2H),4.09(s,1H),3.95-3.80(m,2H),3.54-3. 35(m,2H),2.90(d,J=4.4Hz,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=7.2Hz,3H).

[0387] 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

[0388] 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 (2.4 g, 5.30 mmol) was dissolved in ethanol (20 mL), and sodium thiomethoxide (408 mg, 5.83 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was concentrated under reduced pressure, and 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, as a yellow oil (2.0 g, 92% yield). ESI-MS m / z:408.2[[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.03(d,J=9.8Hz,1H),6.75(d,J=9.8Hz,1H),4.18(s,1H),3.94(s,3H),3 .73(d,J=61.2Hz,2H),3.40(s,2H),2.60(s,3H),2.14(brs,2H),2.02-1.86(m,2H),1.45(s,9H)

[0389] 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

[0390] 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) was dissolved in acetic acid (30 mL), and N-bromosuccinimide (1.8 g, 9.83 mmol) was added. The reaction was stirred at 60°C for 5 hours. The mixture was diluted with saturated aqueous sodium sulfite (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to afford 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, 25% yield). ESI-MS m / z:486.1[M+H] + . 1 H NMR(400MHz, CDCl3)δ8.48(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).

[0391] Step 8: 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

[0392] 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) were dissolved in tetrahydrofuran (35 mL). Under nitrogen, samarium iodide (49.4 mL, 4.94 mmol, 0.1 M tetrahydrofuran solution) was added dropwise at -30°C. The reaction mixture was stirred at -30°C for 0.5 hours. Saturated aqueous ammonium chloride (100 mL) was added to dilute the mixture at -30°C, and the mixture was extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:15, volume ratio) to afford 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, 81% yield). ESI-MS m / z: 549.2 [M+H] + .

[0393] Step 9: 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

[0394] 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-dicyclohexylphosphine)-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 sodium tert-butoxide (288 mg, 3.0 mmol) were dissolved in toluene (15 mL), protected by nitrogen, and stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 25:1, volume ratio) to afford 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 as a yellow oil (350 mg, 50% yield). ESI-MS m / z: 702.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.67-7.57(m,1H),7.55-7.40(m,2H),7.15(td,J=7.6,2.0Hz,1H),6.92(t,J=55.2,1H),5.8 4(brs,1H),5.59(brs,1H),5.55-5.34(m,1H),4.61(d,J=13.2Hz,1H),3.91(d,J=7.2Hz,3H),3.76-3.56(m,4H),3. 52-3.40(m,1H),3.36(d,J=7.8Hz,2H),3.17(td,J=12.8,2.8Hz,1H),2.33(s,3H),2.28-2.18(m,1H),2.13(d,J=2 .8Hz,3H),2.09-2.05(m,1H),1.94(td,J=12.8,4.4Hz,3H),1.84-1.74(m,1H),1.62(d,J=7.0Hz,3H),1.44(s,9H).

[0395] 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

[0396] 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. The mixture was concentrated under reduced pressure to obtain crude 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, which was used directly in the next reaction. ESI-MS m / z:602.3[M+H] + .

[0397] 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)

[0398] 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) was added, followed by sodium triacetoxyborohydride (358 mg, 0.997 mmol), and stirred at room temperature for 0.5 hours. The mixture was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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, 55% yield). ESI-MS m / z:616.4[M+H] + . 1H NMR (400MHz, CDCl3) δ7.56(d,J=3.2Hz,1H),7.51(q,J=7.6Hz,1H),7.45(t,J=7.6Hz,1 H),7.16(t,J=7.6Hz,1H),6.92(t,J=55.2Hz,1H),5.77(d,J=5.6Hz,1H),5.59(p,J=6.8 Hz,1H),5.31(t,J=7.6Hz,1H),4.62(d,J=13.2Hz,1H),3.92(s,3H),3.71(d,J=8.5Hz, 2H),3.57(brs,1H),3.26(brs,1H),3.17(td,J=12.4,2.4Hz,1H),2.81(s,1H),2.57(s, 3H), 2.39 (s, 3H), 2.23 (dt, J = 13.2, 2.4Hz, 1H), 2.13 (d, J = 2.4Hz, 3H), 2.06 (dd, J = 13. 2,2.4Hz,2H),1.94(td,J=12.8,4.8Hz,2H),1.87-1.72(m,4H),1.63(d,J=7.0Hz,3H).

[0399] Step 12: (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 (Compound 59)

[0400] 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) under nitrogen protection. Diethylaminosulfur trifluoride (78 mg, 0.487 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Water (20 mL) was added to dilute the mixture, and ethyl acetate (50 mL) was added for extraction. 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 used directly in the next reaction. ESI-MS m / z: 618.3 [M+H] + .

[0401] 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)-one (Compound 2)

[0402] The crude (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 obtained in step 12 was dissolved in methanol (15 mL), and a 30% solution of sodium methoxide in methanol (455 mg, 2.44 mmol) was added. The reaction mixture was stirred at 40°C for 24 hours, concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford compound 2 as a white solid (26 mg, 17% yield). ESI-MS m / z: 630.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.70 (s, 1H), 7.51 (q, J = 6.4Hz, 1H), 7.45 (t, J = 7.2Hz, 1H), 7.16 (t, J = 7.6Hz, 1H), 6.91 (t, J = 55.1Hz, 1H),5.59(p,J=7.2Hz,1H),5.20(d,J=7.2Hz,1H),4.58(d,J=12.0Hz,1H),3.87(s,3H),3.76-3.63(m,2H),3.56-3.40(m,2 H),3.27(s,3H),3.12(t,J=7.2Hz,1H),2.93(q,J=10.0Hz,1H),2.72-2.49(m,4H),2.47(d,J=2.0Hz,3H),2.37(d,J=2.0Hz ,3H),2.30(q,J=9.2Hz,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=7.0Hz,3H). 13C NMR (101MHz, CDCl3) δ168.91,162.27,152.21,149.77,149.75,140.14,133. 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.

[0403] Example 2

[0404] 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 (Compound 3)

[0405] Compound 2 was prepared by the method of steps 2 to 13 in Example 1, wherein the starting material (S)-(-)-1-tert-butyloxycarbonyl-2-pyrrolidinemethanol in step 2 was replaced with (R)-(-)-1-tert-butyloxycarbonyl-2-pyrrolidinemethanol. ESI-MS m / z: 630.3 [M+H] + .

[0406] Example 3

[0407] (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)

[0408] Step 1: tert-Butyl (2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)ethyl)(methyl)carbamate

[0409] 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) were dissolved in tetrahydrofuran (400 mL). Triphenylphosphine (30 g, 114 mmol) and diisopropyl azodicarboxylate (23 g, 114 mmol) were added under nitrogen at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Water (400 mL) was added for dilution, and the mixture was extracted with ethyl acetate (800 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1, volume ratio) to obtain the product as a colorless oil (32 g, yield 89%). ESI-MS m / z: 379.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 4.01 (d, J = 16.7Hz, 2H), 3.62 (s, 2H), 3.03 (s, 3H), 2.49 (s, 3H), 1.45 (s, 9H).

[0410] Step 2: tert-Butyl (2-((6-chloro-2-methyl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate

[0411] Tert-butyl (2-((4-bromo-6-chloro-2-methylpyridin-3-yl)oxy)ethyl)(methyl)carbamate (32 g, 84.6 mmol) was dissolved in dimethyl sulfoxide (80 mL), and aqueous methylamine (80 mL, 23%) was added. The mixture was sealed and stirred at 120°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (600 mL). 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 (400MHz, CDCl3) δ6.32(s,1H),3.87(s,2H),3.55(t,J=4.9Hz,2H),2.98(s,3H),2.82(d,J=5.1Hz,3H),2.33(s,3H),1.45(s,9H).

[0412] Step 3: tert-Butyl (2-((6-chloro-5-iodo-yl-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate

[0413] 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), and N-iodosuccinimide (28.5 g, 126.9 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium sulfite solution (200 mL) was added for dilution, and saturated aqueous sodium bicarbonate solution (200 mL) was added for neutralization. The mixture was extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 (400MHz, CDCl3) δ4.62(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).

[0414] Step 4: Ethyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate

[0415] Tert-butyl (2-((6-chloro-5-iodo-4-(methylaminopyridin-3-yl)oxy)ethyl)(methyl)carbamate (28.1 g, 61.7 mmol), palladium acetate (1.38 mg, 6.17 mmol), tri(o-methylphenyl)phosphine (3.74 mg, 12.3 mmol), triethylamine (18.7 g, 185.1 mmol) and ethyl acrylate (30.8 g, 308.8 mmol) were 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 the mixture, and ethyl acetate (900 mL) was added to extract the mixture. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain the product as a yellow oil (24 g, yield 91%). ESI-MS m / z:428.1[M+1] + . 1H NMR (400MHz, CDCl3) δ7.74(d,J=16.2Hz,1H),6.12(d,J=16.3Hz,1H),4.26(q,J=7.1Hz,2H),3.89(s,2H),3 .58(t,J=5.0Hz,2H),3.00(s,3H),2.89(d,J=5.3Hz,3H),2.37(s,3H),1.46(s,9H),1.33(t,J=7.1Hz,3H).

[0416] Step 5: tert-Butyl (2-((5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl)oxy)ethyl (methyl)carbamate

[0417] Ethyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate (24 g, 56.2 mmol) was dissolved in ethanol (250 mL), sodium thiomethoxide (4.73 g, 67.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was dried, diluted with water (500 mL), and extracted with ethyl acetate (600 mL). 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 (400MHz, CDCl3) δ8.03(d,J=9.8Hz,1H),6.74(d,J=9.8Hz,1H),3.93(s,3H),3.85(d ,J=18.7Hz,2H),3.64(d,J=5.4Hz,2H),3.03(s,3H),2.56(s,3H),1.47(d,J=3.7Hz,9H).

[0418] 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

[0419] 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) was dissolved in acetic acid (120 mL), and dibromohydantoin (14.2 g, 49.6 mmol) was added. The reaction was stirred at 75°C for 5 hours. Saturated aqueous sodium sulfite solution (200 mL) was added for dilution, and the mixture was extracted with ethyl acetate (400 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow solid (6.5 mg, 85% yield). ESI-MS m / z: 460.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.46 (s, 1H), 3.99 (s, 3H), 3.84 (d, J = 21.1Hz, 2H), 3.64 (d, J = 5.5Hz, 2H), 3.03 (s, 3H), 2.55 (s, 3H), 1.47 (s, 9H).

[0420] Step 7: 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

[0421] 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) were dissolved in tetrahydrofuran (15 mL). Under nitrogen, samarium iodide (52 mL, 52 mmol, 0.1 M in THF) was added dropwise at -40°C. The reaction was stirred at -40°C for 0.5 h. Saturated aqueous ammonium chloride (100 mL) was added to the solution at -40°C for dilution and extraction with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:15, volume ratio) to afford the product as a yellow oil (500 mg, 73.7% yield). ESI-MS m / z: 523.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.93(s,1H),5.27(s,1H),4.62(d,J=10.4Hz,1H),3.97(s,3H),3.92–3.82(m,2H),3.76(dd,J=14.3,7.8Hz,2H),3. 65(t,J=5.4Hz,2H),3.19(d,J=18.2Hz,1H),3.04(s,3H),2.58(s,3H),2.14(d,J=9.9Hz,5H),1.87(td,J=12.9,5.1Hz,2H),1.48(s,9H).

[0422] 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

[0423] 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-dicyclohexylphosphine)-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 sodium tert-butoxide (275 mg, 2.87 mmol) were dissolved in toluene (10 mL), protected by nitrogen, and stirred at 90°C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 25:1, volume ratio) to obtain the product as a yellow oil (400 mg, yield 62%). ESI-MS m / z: 676.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.71(s,1H),7.55–7.40(m,2H),7.16(t,J=7.6Hz,1H),6.93(t,J=55.1Hz,1H),5.8 9(s,1H),5.62(dd,J=17.5,11.8Hz,2H),4.61(d,J=11.1Hz,1H),3.91(s,3H),3.71(d,J=8.9Hz,4H),3.5 6(t,J=5.2Hz,2H),3.24–3.08(m,1H),3.00(s,3H),2.32(d,J=0.9Hz,3H),2.23(d,J=13.3Hz,1H),2.13( d,J=5.4Hz,3H),2.05(d,J=12.9Hz,1H),1.98–1.78(m,2H),1.62(d,J=6.7Hz,3H),1.46(d,J=8.7Hz,9H).

[0424] 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

[0425] 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 the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 576.3 [M+1] + .

[0426] 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

[0427] The residue obtained in step 9 was dissolved in tetrahydrofuran (5 mL), and aqueous formaldehyde (1.5 mL, 30%) and sodium triacetoxyborohydride (566 mg, 2.67 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a 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 (400MHz, CDCl3) δ7.69 (d, J=3.7Hz, 1H), 7.58–7.41 (m, 2H), 7.16 (dd, J=7.6, 6.3Hz, 1H), 6.93 (t, J= 55.1Hz,1H),5.88(s,1H),5.61(d,J=7.3Hz,2H),4.61(d,J=12.3Hz,1H),3.92(s,3H),3.79–3.68(m,4H) ,3.17(td,J=12.7,2.5Hz,1H),2.81(s,2H),2.43(s,6H),2.37(d,J=0.7Hz,3H),2.26–2.19(m,1H),2.1 3(d,J=5.1Hz,3H),2.05(d,J=12.4Hz,1H),1.99–1.89(m,1H),1.87–1.75(m,1H),1.62(d,J=6.0Hz,3H).

[0428] 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

[0429] (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) under nitrogen protection. Diethylaminosulfur trifluoride (70 mg, 0.447 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. Water (20 mL) was added to dilute the mixture and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used directly in the next reaction. ESI-MS m / z: 592.3 [M+1] + .

[0430] 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

[0431] The residue from step 11 was dissolved in methanol (15 mL) and a methanol solution of sodium methoxide (455 mg, 2.44 mmol, 30% w / v in MeOH) was added. The reaction mixture was stirred at 40°C for 24 hours, concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford compound 4 as a white solid (25 mg, 19% yield). ESI-MS m / z: 604.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.55–7.42(m,2H),7.17(t,J=7.7Hz,1H),6.91(t,J=55.1Hz,1H),5.68 –5.51(m,1H),5.20(d,J=6.8Hz,1H),4.58(d,J=11.0Hz,1H),4.15(s,2H),3.85(s,3H),3.73(dd,J=18.4,1 2.4Hz,3H),3.54–3.40(m,1H),3.27(s,3H),2.99–2.86(m,1H),2.82(t,J=6.0Hz,2H),2.42(s,6H),2.37( d,J=1.6Hz,3H),2.13(s,3H),2.04(d,J=14.1Hz,1H),1.90(dd,J=18.5,6.9Hz,1H),1.64(d,J=7.0Hz,3H).

[0432] Example 4

[0433] (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)

[0434] 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 by referring to Steps 11 and 12 of Example 3. ESI-MS m / z: 590.3 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),7.69(s,1H),7.46(dd,J=18.7,11.7Hz,2H),7.17(s,1H),6.90(t,J=55.1Hz,1H ),5.66–5.54(m,1H),5.25(s,1H),4.57(d,J=11.5Hz,1H),3.83(s,5H),3.70(d,J=13.8Hz,1H),3.48(dd,J=23.0,1 0.3Hz,1H),3.27(s,3H),3.16(d,J=4.8Hz,2H),2.99–2.86(m,1H),2.64(d,J=13.0Hz,3H),2.51(ddd,J=31.6,13.8 ,4.5Hz,2H),2.37(d,J=1.3Hz,3H),2.13(s,3H),2.08–1.98(m,1H),1.89(t,J=11.2Hz,1H),1.64(d,J=7.0Hz,3H).

[0435] Example 5

[0436] (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)

[0437] Step 1: 3-(Benzyloxy)-4-bromo-6-chloro-2-methylpyridine

[0438] 4-Bromo-6-chloro-2-methylpyridin-3-ol (14.0 g, 62.9 mmol) was dissolved in N,N-dimethylformamide (50 mL), and benzyl bromide (14.0 g, 81.8 mmol) was added. The reaction was stirred at room temperature for 16 hours. Water (300 mL) was added for dilution, and methyl tert-butyl ether (250 mL x 2) was added 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 slurried with ethanol to obtain the product as a white solid (17.5 g, yield 89%). ESI-MS m / z: 312.0 [M+H] + .

[0439] Step 2: 3-(Benzyloxy)-6-chloro-N,2-dimethylpyridin-4-amine

[0440] 3-(Benzyloxy)-4-bromo-6-chloro-2-methylpyridine (17.5 g, 56.0 mmol) was dissolved in dimethyl sulfoxide (150 mL), and a 25% aqueous methylamine solution (80 mL) was added. The mixture was stirred at 105°C for 5 hours. After cooling to room temperature, the mixture was diluted with saturated aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated aqueous sodium chloride (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1, volume ratio) to afford the product as a white solid (8.0 g, 54% yield). ESI-MS m / z: 263.1 [M+H] + .

[0441] Step 3: 3-(Benzyloxy)-6-chloro-5-iodo-N,2-dimethylpyridin-4-amine

[0442] 3-(Benzyloxy)-6-chloro-N,2-dimethylpyridin-4-amine (8.0 g, 30.5 mmol) was dissolved in acetic acid (40 mL), and N-iodosuccinimide (8.2 g, 36.6 mmol) was added. The mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium sulfite solution (200 mL) was added for dilution, and saturated aqueous sodium bicarbonate solution (400 mL) was added for neutralization. The mixture was extracted with ethyl acetate (200 mL x 2). 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to afford the product as a white solid (8.3 g, 73% yield). ESI-MS m / z: 389.0 [M+H] + .

[0443] Step 4: Ethyl 3-(5-(benzyloxy)-2-chloro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate

[0444] 3-(Benzyloxy)-6-chloro-5-iodo-N,2-dimethylpyridin-4-amine (8.3 g, 21.4 mmol), palladium 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) were dissolved in N,N-dimethylformamide (120 mL). Stir and react at 95°C under nitrogen for 6 hours. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1, volume ratio) to afford the product as a white solid (5.8 g, 75% yield). ESI-MS m / z: 361.1 [M+H] + .

[0445] Step 5: 8-(Benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0446] 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) and sodium thiomethoxide (0.77 g, 11.1 mmol) was added. The mixture was stirred at room temperature for 2 hours. TLC indicated 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 combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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 (400MHz, CDCl3) δ8.05(d,J=9.8Hz,1H),7.46-7.35(m,5H),6.75(d,J=9.8Hz,1H),4.79(s,2H),3.89(s,3H),2.59(s,3H).

[0447] Step 6: 8-(Benzyloxy)-3-bromo-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0448] 8-(Benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (8.0 g, 25.4 mmol) was dissolved in N,N-dimethylformamide (120 mL), and dibromohydantoin (36.3 g, 127 mmol) was added. The mixture was stirred at 70°C in the dark for 5 hours. Saturated aqueous sodium sulfite solution (200 mL) was added for dilution, and the mixture was extracted with ethyl acetate (400 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to afford the product as a pale yellow solid (7 g, 70% yield). ESI-MS m / z: 393.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),7.47-7.29(m,5H),4.79(s,2H),3.96(s,3H),2.58(s,3H).

[0449] Step 7: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0450] To a 2L three-necked flask, 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) were added to completely dissolve the mixture. Under nitrogen protection, the reaction solution was cooled to -40°C and 0.1 mol / L samarium diiodide tetrahydrofuran solution (500 mL) was added dropwise. After the addition was completed, the reaction was continued at -40°C for 0.5 hours. The reaction was quenched by adding saturated ammonium chloride (300 mL), followed by extraction with ethyl acetate (400 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 3:1, volume ratio) to afford 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (6.6 g, 76% yield) as an off-white solid. ESI-MS m / z: 456.3 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.94(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).

[0451] 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

[0452] To a 250 mL round-bottom flask were added 3-(1-acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-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-dicyclohexylphosphino)-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)ethan-1-amine (6.0 g, 31.64 mmol), and the mixture was stirred at 80°C under nitrogen protection for 1 hour. The reaction mixture was cooled to room temperature, extracted with water and ethyl acetate, and the layers were separated. The organic phase was washed once with 10% citric acid solution (300 mL) and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, volume ratio) to obtain (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, 70% yield) as a pale yellow solid. ESI-MS m / z: 609.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.64-7.55(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=55.0,3.4Hz,1H),5.82-5.60(m,J =50.7Hz,2H),4.73-4.53(m,3H),3.88(s,3H),3.73-3.64(m,2H),3.16(t,J=12.7Hz,1H),2 .42(s,2H),2.33–2.25(m,3H),2.13(d,J=7.9Hz,3H),2.06-1.98(m,1H),1.75-1.60(m,4H).

[0453] Step 9: (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

[0454] To a 250 mL round-bottom flask was added (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), and 10% palladium on carbon (1.5 g). The reaction was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, volume ratio) to afford (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 (1.4 g, 80% yield) as a pale yellow solid. ESI-MS m / z: 519.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.52 (q, J = 7.8Hz, 1H), 7.43 (t, J = 7.2Hz, 1H), 7.17-7.11 (m, 1H),6.91(t,J=55.1Hz,1H),5.93(s,1H),5.63-5.51(m,1H),5.49-5.3(m,1H),4.51(d,J=13.4H z,1H),3.95(s,3H),3.71–3.59(m,2H),3.10(td,J=12.8,2.9Hz,1H),2.35(s,2H),2.23–2.12( m,1H),2.08(d,J=2.2Hz,3H),1.99(d,J=12.7Hz,2H),1.90–1.75(m,3H),1.61(d,J=6.9Hz,3H).

[0455] 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

[0456] To a solution of (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) was added N-phenylbis(trifluoromethanesulfonyl)imide (270 mg, 0.75 mmol). The reaction was stirred at room temperature for 1.5 hours. Dichloromethane and water were added for extraction and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 20:1, volume ratio) to give the product as a yellow solid (340 mg, yield 90%). ESI-MS m / z: 651[M+H] + .

[0457] Step 11: (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

[0458] (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 (38 mg, 0.058 mmol) was dissolved in dry N,N-dimethylformamide (5 mL), and tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol), zinc cyanide (68 mg, 0.58 mmol) and 4-nitropropene were added. 1), under nitrogen protection, the reaction solution was stirred at 110°C for 1 hour, cooled to room temperature, filtered through celite, washed with ethyl acetate (20 ml), extracted with ethyl acetate (100 mL), washed with water (20 ml), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to obtain a crude product, which was then purified by preparative HPLC to obtain compound 6 as a white solid (4 mg, yield 13%). ESI-MS m / z: 528.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.08(d,J=8.6Hz,1H),7.57–7.45(m,2H),7.36–7.28(m, 1H),7.20(t,J=7.6Hz,1H),6.93(t,J=55.0Hz,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=33.5Hz,3H),2.04–1.80(m,3H),1.67–1.62(m,3H).

[0459] Example 6

[0460] (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 (Compound 7)

[0461] (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), tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) and potassium phosphate (106 mg, 0.5 mmol) were added, and trimethylcyclotrifluoromethanesulfonate was added under nitrogen protection. Boroxane (0.14 ml, 1 mmol) was added, and the reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, filtered through celite, washed with ethyl acetate (20 ml), extracted with ethyl acetate (100 mL), washed with water (20 ml), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain a crude product, which was then purified by preparative HPLC to obtain compound 7 as a white solid (2.5 mg, 4.8% yield). ESI-MS m / z: 517.2 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.59(d,J=3.8Hz,1H),7.58–7.50(m,1H),7.47(t,J=7.2Hz,1H),7.22–7.15( m,1H),6.95(t,J=55.1Hz,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),2.1 6(d,J=3.4Hz,3H),2.12–2.06(m,1H),2.00–1.91(m,1H),1.82–1.76(m,1H),1.66(d,J=7.0Hz,3H).

[0462] Example 7

[0463] (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 (Compound 8)

[0464] 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

[0465] 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 triisopropylsilyl acetylene (110 mg, 0.6 mmol) in tetrahydrofuran (5 mL) were added tetrakistriphenylphosphine palladium (10 mg, 0.009 mmol), cuprous iodide (5 mg, 0.03 mmol), and triethylamine (1 mL). After argon substitution three times, the reaction was stirred at 60°C for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 20:1, volume ratio) to afford the product as a yellow solid (30 mg). ESI-MS m / z: 683.4 [M+H] + .

[0466] Step 2: (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

[0467] 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 twice with water (30 mL × 2), and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give compound 8 as a white solid (15 mg). ESI-MS m / z: 527.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.49–8.41(m,1H),8.07(d,J=7.1Hz,1H),7.66(t,J=7.4Hz,1H),7.46(t ,J=7.1Hz,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=11.8Hz,1H),3.50–3.44(m,1H),2.92(t,J=12.8Hz,1H),2.38(s,3H),2 .35-2.29(m,1H),2.03(s,3H),1.57(d,J=7.1Hz,3H),1.50(d,J=13.1Hz,1H),1.26–1.20(m,1H).

[0468] Example 8

[0469] (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 (Compound 9)

[0470] 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

[0471] Compound 6 (70 mg, 0.13 mmol) was dissolved in dry dichloromethane (8 mL) under nitrogen protection and cooled to 0°C. Diethylaminosulfur trifluoride (42 mg, 0.26 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. Water (20 mL) was added to quench the reaction, and then extracted with ethyl acetate (100 mL x 2). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by 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]+.

[0472] 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

[0473] (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. A methanol solution of sodium methoxide (5N 0.36 ml, 1.78 mmol) was added. The reaction solution was stirred at room temperature for 12 hours, quenched by the addition of water (20 ml), and extracted with ethyl acetate (100 mL x 2). The product was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a crude product, which was purified by preparative HPLC to give compound 9 as a white solid (13 mg, yield 27%). ESI-MS m / z: 542.2[M+H]+. 1H NMR (400MHz, CDCl3) δ7.71(s,1H),7.49(t,J=7.2Hz,2H),7.20(t,J=7.7Hz,1H),6.89(t,J =55.0Hz,1H),6.05(d,J=5.7Hz,1H),5.77–5.68(m,1H),4.58(d,J=12.1Hz,1H),3.99(s,3 H),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=7.2Hz,3H).

[0474] Example 9

[0475] (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 (Compound 10)

[0476] Compound 10 was prepared from compound 8 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 541.2 [M+1] + .

[0477] Example 10

[0478] (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)

[0479] 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

[0480] (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), and triethylamine (2 mL) were added under nitrogen protection. The reaction solution was stirred at 60°C for 3 hours, cooled to room temperature, filtered with suction from celite, washed with ethyl acetate (20 mL), and then added with ethyl acetate (100 mL x 10 mL). 2) Extraction, washing with water (20 ml), washing with saturated brine (20 ml), drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (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] + .

[0481] 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

[0482] 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 (59 mg, 0.086 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 2 hours, diluted with dichloromethane (20 mL), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by 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] + .

[0483] Example 11

[0484] (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)

[0485] Compound 12 was prepared 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 starting material 2-methyl-3-butyn-2-ol according to Step 1 of Example 10. ESI-MS m / z: 585.3 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ8.42(d,J=1.8Hz,1H),8.00(d,J=7.1Hz,1H),7.66(t, J=7.5Hz,1H),7.46(t,J=7.0Hz,1H),7.37–7.07(m,3H),5.75–5.64(m,1H),5.5 1(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=12.7Hz,1H),2.36(s,3H),2.03(s,3H),1.63–1.58(m, 1H),1.56(d,J=7.1Hz,3H),1.53–1.48(m,1H),1.44(s,6H),1.06(t,J=7.2Hz,1H).

[0486] Example 12

[0487] 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)

[0488] Step 1: 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

[0489] (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 (150 mg, 0.23 mmol) and tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate (180 mg, 13.5 mmol), cuprous iodide (13 mg, 0.07 mmol), tetrakistriphenylphosphine palladium (27 mg, 0.02 mmol), and triethylamine (3.5 mL) were dissolved in tetrahydrofuran (15 mL). After nitrogen substitution, the reaction was heated at 60 ° C and stirred for 10 hours. The solid was filtered off 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] + .

[0490] 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

[0491] 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), and trifluoroacetic acid (0.5 mL) was added. 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 as a yellow oil (77 mg), which was used directly in the next reaction. ESI-MS m / z: 596.2 [M+1] + .

[0492] 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

[0493] The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% aqueous formaldehyde solution (3 mL) was added, followed by sodium triacetoxyborohydride (360 mg, 1 mmol), and stirred at room temperature for 0.5 hours. Saturated aqueous sodium bicarbonate solution (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield compound 13 as a yellow solid (5 mg). ESI-MS m / z: 610.3 [M+H] + .

[0494] Example 13

[0495] 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 (Compound 14)

[0496] Compound 14 was prepared 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 tert-butyl (R)-2-ethynylpyrrolidine-1-carboxylate, according to Example 12. ESI-MS m / z: 610.3 [M+1]+.

[0497] Example 14

[0498] (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)

[0499] Compound 15 was prepared 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 starting material N,N-dimethylpropargylamine according to Step 1 of Example 10. ESI-MS m / z: 584.3 [M+1] + .

[0500] Example 15

[0501] (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 (Compound 16)

[0502] Step 1: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0503] 3-(1-Acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(benzyloxy)-1,6-naphthyridin-2(1H)-one (2.4 g, 5.27 mmol) was dissolved in dichloromethane (24 mL) under nitrogen protection. Boron trichloride (53 mL, 52.7 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was added dropwise to cold methanol (200 mL) and concentrated under reduced pressure. The residue was dissolved in methanol (50 mL) and a saturated methanolic solution of ammonia (3 mL) was added. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to obtain the product as a white foamy solid (1 g, yield 52%). ESI-MS m / z: 366.1 [M+H] + .

[0504] Step 2: 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

[0505] 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 purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to obtain the product (1 g, yield 72%). ESI-MS m / z: 498.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.96(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=13.0,5.0Hz,2H).

[0506] Step 3: 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

[0507] 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), tetrakistriphenylphosphine palladium (91 mg, 0.08 mmol), and triethylamine (1 mL) were dissolved in tetrahydrofuran (10 mL). The reaction was stirred at 40°C under nitrogen for 10 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, volume ratio) to obtain the product (420 mg, 99% yield). ESI-MS m / z: 531.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 4.58 (t, J = 20.8Hz, 1H), 4.14 (s, 3H), 3.75–3.67 (m, 2H), 3.16 (td,J=12.8,2.3Hz,1H),2.74(s,3H),2.15(s,3H),1.95–1.75(m,4H),1.68(s,6H),1.46(s,9H).

[0508] 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

[0509] 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-dicyclohexylphosphino)-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) were dissolved in toluene (10 mL). The reaction was stirred at 80°C under nitrogen for 50 minutes. After the reaction was cooled to room temperature, water (50 mL) was added to dilute it and ethyl acetate (50 mL) was added to extract it. 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] + .

[0510] Step 5: (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

[0511] 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 give compound 16 as a white solid (11 mg, yield 52%). ESI-MS m / z: 555.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.24(d,J=27.6Hz,1H),7.69(t,J=7.1Hz,1H),7.49(t,J=14. 6Hz,1H),7.31–7.21(m,1H),4.00(s,3H),3.85(d,J=11.8Hz,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),1.9 2–1.88(m,1H),1.86(s,3H),1.85-1.75(m,1H),1.72(s,6H),1.57(d,J=7.0Hz,3H).

[0512] Example 16

[0513] (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)

[0514] Compound 17 was prepared according to steps 3 to 5 of Example 15, except that the starting material in step 3, tert-butyl (2-methylbut-3-yn-2-yl)carbamate, was replaced with tert-butyl (1-ethynylcyclopropyl)carbamate, and the starting material in step 4, (R)-3-(1-aminoethyl)-2-methylbenzonitrile, was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine. ESI-MS m / z: 582.3 [M+1] + .

[0515] Example 17

[0516] (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 (Compound 18)

[0517] Step 1: 3-(1-acetyl-4-methoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0518] 3-(1-Acetyl-4-hydroxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (5 g, 10.96 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydroxide (2.19 g, 54.8 mmol) was added at 0°C. After stirring for 5 minutes, iodomethane (6.2 g, 43.84 mmol) was added and the mixture was stirred at 0°C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to afford the product as a yellow solid (4.0 g, 78% yield). ESI-MS m / z: 470.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),7.40(s,5H),4.79(s,2H),4.58(d,J=12.9Hz,1H),3.88(s,3H),3.70(dd,J=11.1,4.7Hz,1H),3.49(d dd,J=13.0,9.1,3.7Hz,1H),3.28(s,3H),2.94(dd,J=14.6,9.5Hz,1H),2.59(s,3H),2.55–2.38(m,2H),2.13(s,3H),2.09–1.93(m,2H).

[0519] Step 2: 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0520] 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 under a hydrogen balloon at room temperature for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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] + . 1H NMR (400MHz, DMSO-d6) δ9.44(s,1H),7.93(s,1H),4.30(d,J=12.7Hz,1H),3.86(s,3H),3.68(d,J=1.8Hz,1H),3.33–3 .26(m,1H),3.18(s,3H),2.76(dd,J=13.3,11.3Hz,1H),2.44(s,3H),2.30(dq,J=8.3,4.7Hz,2H),2.02(s,4H),1.89– 1.76(m,2H).

[0521] Step 3: 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

[0522] 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). 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 reaction 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 as a white solid (2.2 g, 90% yield). ESI-MS m / z: 512.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),4.59(d,J=10.9Hz,1H),3.75(s,3H),3.70(s,1H),3.51(d,J=11.0Hz,1H),3 .30(s,3H),2.93(dd,J=21.1,9.3Hz,1H),2.68(s,3H),2.48(d,J=12.7Hz,2H),2.15(s,3H),2.02–1.90(m,2H).

[0523] 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

[0524] 3-(1-Acetyl-4-methoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (510 mg, 1.0 mmol), N,N-dimethylpropargylamine (250 mg, 3.0 mmol), cuprous iodide (57 mg, 0.3 mmol), and tetrakistriphenylphosphine palladium (115 mg, 0.1 mmol) were dissolved in tetrahydrofuran (5 mL) and triethylamine (1 mL) under nitrogen atmosphere at 55°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to afford the product as a white solid (370 mg, 83% yield). ESI-MS m / z: 445.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),4.60–4.50(m,1H),4.08(s,3H),3.72(s,2H),3.68(d,J=2.1Hz,1H),3.48(td,J= 13.1,2.5Hz,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).

[0525] 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-naphthyridin-2(1H)-one

[0526] 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 (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) were dissolved in 1,4-dioxane (5 mL) and stirred at 80°C under nitrogen protection for 1 hour. After cooling to room temperature, the mixture 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 give compound 18 as a white solid (100 mg, yield 42%). ESI-MS m / z: 598.1 [[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=1.4Hz,1H),8.01(d,J=7.0Hz,1H),7.64(s,1H),7.45(t,J= 7.0Hz,1H),7.24(dt,J=64.5,41.7Hz,2H),5.68(p,J=7.0Hz,1H),4.32(d,J=11.4Hz,1H),3.8 7(s,3H),3.70(d,J=13.7Hz,1H),3.48(s,2H),3.42–3.29(m,3H),3.10(d,J=2.9Hz,3H),2.82 (t,J=12.4Hz,1H),2.38(s,3H),2.28–2.11(m,8H),2.11–1.95(m,4H),1.57(d,J=7.1Hz,3H).

[0527] Example 18

[0528] 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 (Compound 19)

[0529] Compound 19 was prepared from compound 13 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 624.3 [M+1] + . 1H NMR (400MHz, CD3OD) δ8.17(s,1H),7.56(t,J=7.2Hz,1H),7.42(t,J=6.8Hz,1H),7.18(t,J=7.7 Hz,1H),6.99(t,J=54.9Hz,1H),5.71(q,J=6.8Hz,1H),4.44(d,J=11.9Hz,1H),4.01(s,3H),3.81(d,J=13.4Hz,1H),3.53(dd,J=17.4,10.2Hz, 2H),3.16(s,3H),3.09–2.91(m,2H),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=7.1Hz,3H).

[0530] Example 19

[0531] 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)

[0532] Compound 20 was prepared from compound 14 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 624.3 [M+1] + .

[0533] Example 20

[0534] (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 (Compound 21)

[0535] Compound 20 was prepared from compound 11 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 598.3 [M+1] + .

[0536] Example 21

[0537] (R)-3-(1-acetyl-4-(methoxy-d3)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 (Compound 22)

[0538] Step 1: 3-(1-acetyl-4-(methoxy-d3)piperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0539] 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. 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. Dilute with water (100 mL), 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to give the product 3-(1-acetyl-4-(methoxy-d3)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(400MHz, CDCl3)δ8.13(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).

[0540] Step 2: 3-(1-acetyl-4-(methoxy-d3)piperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0541] 3-(1-acetyl-4-(methoxy-d3)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), and platinum dioxide (160 mg) was added. The mixture was hydrogenated with a hydrogen balloon at room temperature for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the product as a white solid (600 mg, 93% yield). It was used directly in the next reaction. ESI-MS m / z: 383.1 [M+1] + .

[0542] Step 3: 3-(1-acetyl-4-(methoxy-d3)piperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

[0543] 3-(1-acetyl-4-(methoxy-d3)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 product was concentrated at low temperature, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to afford 3-(1-acetyl-4-(methoxy-d3)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, 83% yield). ESI-MS m / z: 515.1 [M+1] + . 1 H NMR(400MHz, CDCl3)δ8.14(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).

[0544] Step 4: tert-Butyl (4-(3-(1-acetyl-4-(methoxy-d3)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

[0545] 3-(1-acetyl-4-(methoxy-d3)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), tetrakistriphenylphosphine palladium (78 mg, 0.068 mmol), and triethylamine (1 mL) were dissolved in tetrahydrofuran (10 mL). The reaction was stirred at 50°C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to obtain the product (300 mg, 81% yield). ESI-MS m / z: 548.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.13(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).

[0546] Step 5: Tert-butyl (R)-(4-(3-(1-acetyl-4-(methoxy-d3)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

[0547] Tert-butyl(4-(3-(1-acetyl-4-(methoxy-d3)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 sodium tert-butoxide (120 mg, 1.25 mmol) were 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 it and ethyl acetate (50 mL) was added to extract it. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product (400 mg). It was used directly in the next reaction. ESI-MS m / z: 701.4 [M+H] + .

[0548] Step 6: (R)-3-(1-acetyl-4-(methoxy-d3)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

[0549] Tert-butyl (R)-(4-(3-(1-acetyl-4-(methoxy-d3)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), 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 give compound 22 as a white solid (30 mg, 9% yield). ESI-MS m / z: 601.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.19(s,1H),7.56(t,J=7.4Hz,1H),7.43(t,J=6.9Hz,1H),7 .19(t,J=7.7Hz,1H),6.99(t,J=54.9Hz,1H),5.72(q,J=6.9Hz,1H),4.44(d,J=13 .3Hz,1H),3.98(s,3H),3.81(d,J=12.1Hz,1H),3.54(td,J=13.1,2.5Hz,1H),3.0 3(dd,J=12.8,10.3Hz,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).

[0550] Example 22

[0551] (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 (Compound 23)

[0552] Compound 23 was prepared from compound 16 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 569.3 [M+1] + . 1 H NMR (400MHz, CD3OD) δ8.18(s,1H),7.70(d,J=7.9Hz,1H),7.51(d,J=7.5Hz,1H),7. 27(t,J=7.8Hz,1H),5.62(q,J=7.0Hz,1H),4.44(d,J=12.8Hz,1H),3.99(s,3H),3.8 1(d,J=13.6Hz,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=7.0Hz,3H).

[0553] Example 23

[0554] (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)

[0555] Compound 24 was prepared from compound 17 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 596.3 [M+1] + .

[0556] Example 24

[0557] 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 (Compound 25)

[0558] Compound 13 (20 mg, 0.03 mmol) was dissolved in tetrahydrofuran (5 mL), and 10% palladium on carbon (5 mg) was added. The mixture was hydrogenated using a hydrogen balloon at room temperature for 4 hours. The product was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford compound 25 as a white solid (1.74 mg, 9% yield). ESI-MS m / z: 612.2 [M+H] + .

[0559] Example 25

[0560] (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)

[0561] Starting from compound 18, compound 26 was obtained according to the method of Example 24. ESI-MS m / z: 600.3 [M+1] + .

[0562] Example 26

[0563] 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)

[0564] Starting from compound 19, compound 27 was obtained according to the method of Example 24. ESI-MS m / z: 626.3 [M+1] + . 1 H NMR (400MHz, CD3OD) δ8.21(s,1H),7.57(d,J=5.5Hz,1H),7.40(t,J=6.8Hz,1H),7.15(dd,J=14.5,6.8Hz,1H),7.13–6.81(m,2H),5.78-5.55(m,2H),4 .44(d,J=11.3Hz,1H),3.81(d,J=12.9Hz,1H),3.67–3.43(m,2H),3.39(s,2 H),3.16(s,3H),3.11–2.92(m,2H),2.63–1.90(m,14H),1.88–1.45(m,9H).

[0565] Example 27

[0566] 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 (Compound 28)

[0567] Starting from compound 20, compound 28 was obtained according to the method of Example 24. ESI-MS m / z: 626.3 [M+1] + . 1H NMR (400MHz, CD3OD) δ8.22(s,1H),7.56(d,J=6.9Hz,1H),7.41(t,J=7.0Hz,1H),7.16(t,J=7.6Hz,1H),7.15-6.80(m,2H),5.66(dt,J=20.0,8.9Hz,2H ),4.44(d,J=12.8Hz,1H),3.88–3.73(m,1H),3.65–3.46(m,2H),3.38(m,2 H),3.16(s,3H),3.11–2.86(m,2H),2.69–1.90(m,14H),1.90–1.45(m,9H).

[0568] Example 28

[0569] 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 (Compound 29)

[0570] 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 at 60°C using a hydrogen balloon for 5 hours. The product was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 29. ESI-MS m / z: 614.2 [M+H] + .

[0571] Example 29

[0572] (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 (Compound 30)

[0573] Starting from compound 15, compound 30 was obtained according to the method of Example 28. ESI-MS m / z: 588.3 [M+1] + .

[0574] Example 30

[0575] (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)

[0576] Compound 31 was prepared from compound 30 by referring to steps 1 and 2 of Example 8. ESI-MS m / z: 602.3 [M+1] + .

[0577] Example 31

[0578] 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)

[0579] Starting from compound 28, compound 32 was obtained according to the method of Example 28. ESI-MS m / z: 628.3 [M+1] + .

[0580] Example 32

[0581] 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)

[0582] Starting from compound 27, compound 33 was obtained according to the method of Example 28. ESI-MS m / z: 628.3 [M+1] + .

[0583] Example 33

[0584] (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 (Compound 34)

[0585] Compound 34 was prepared according to step 5 of Example 17, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-methylbenzonitrile. ESI-MS m / z: 569.3 [M+1] + .

[0586] Example 34

[0587] (R)-3-(1-((3-(1-acetyl-4-(methoxy-d3)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 (Compound 35)

[0588] Compound 35 was prepared according to steps 5 and 6 of Example 21, wherein the starting material in step 5, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine, was replaced with (R)-3-(1-aminoethyl)-2-methylbenzonitrile. ESI-MS m / z: 572.3 [M+1] + .

[0589] Example 35

[0590] (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 (Compound 63)

[0591] Step 1: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(benzyloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0592] 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 hydroxide (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 with water and extracted with ethyl acetate. The product was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:1, volume ratio) to obtain the product as a yellow solid (8.0 g, 86% yield). ESI-MS m / z: 484.1 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.39(s,5H),4.77(s,2H),4.57(ddt,J=13.2,4.8,2.2Hz,1H),3.86(s,3H),3.69(ddq,J=8.9,4.7,2.1 Hz,1H),3.50(td,J=13.0,2.7Hz,1H),3.45–3.36(m,2H),2.93(td,J=13.0,2.7H z,1H),2.62–2.48(m,5H),2.12(s,3H),1.94–1.83(m,2H),1.36(t,J=6.9Hz,3H).

[0593] Step 2: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0594] 3-(1-acetyl-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), and platinum dioxide (1.6 g) was added. The mixture was stirred at room temperature for 30 minutes under a hydrogen balloon atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by 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] + . 1H NMR(400MHz,DMSO-d6)δ9.44(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=13.6,4.8Hz,1H),2.03(s,3H),1.79–1.68(m,2H),1.27(t,J=6.9Hz,3H).

[0595] Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate

[0596] 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (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 reaction was cooled to 0°C, and phenylbis(trifluoromethanesulfonyl)imide (3.49 g, 9.77 mmol) was added. The reaction was continued at 0°C for 30 minutes. The reaction 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 as a white solid (3.7 g, 87% yield). ESI-MS m / z: 526.1 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.18(s,1H),4.60(ddt,J=13.2,4.6,2.1Hz,1H),3.76(s,3H),3.71(dt,J=4.5,2.1Hz,1H),3.56–3.3 8(m,3H),2.96(td,J=13.0,2.8Hz,1H),2.63–2.48(m,2H),2.15(s,3H),1.89(ddq,J=30.9,14.2,2.7Hz,2H),1.38(t,J=6.9Hz,3H)

[0597] 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

[0598] 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), tetrakistriphenylphosphine palladium (231 mg, 0.2 mmol), and triethylamine (3 mL) were dissolved in tetrahydrofuran (15 mL). The mixture was reacted at 55°C under nitrogen for 1 hour. The reaction 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 as a white solid (800 mg, 83.6% yield). ESI-MS m / z: 459.1 [M+1] + . 1 H NMR(400MHz, CDCl3)δ8.16(s,1H),4.62–4.50(m,1H),4.07(s,3H),3.68(dd t,J=13.2,4.5,2.2Hz,1H),3.61(s,2H),3.48(td,J=13.1,2.7Hz,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=6.9Hz,3H).

[0599] 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-naphthyridin-2(1H)-one

[0600] 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 (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)ethan-1-amine (743 mg, 3.93 mmol), and sodium tert-butoxide (377 mg, 3.93 mmol) were dissolved in toluene (12 mL). The reaction was stirred at 80°C under nitrogen protection for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5, volume ratio) to obtain the product as a white solid (500 mg, yield 62.5%). ESI-MS m / z: 612.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.17–8.11(m,1H),7.97(dd,J=7.1,2.3Hz,1H),7.65(q,J=6.7,6 .1Hz,1H),7.45(t,J=7.1Hz,1H),7.36–7.04(m,2H),5.65(t,J=7.1Hz,1H),4.37–4.26(m, 1H),3.86(s,3H),3.69(d,J=13.2Hz,1H),3.47(s,2H),3.41–3.28(m,3H),3.21(dtt,J=13.5,8.9,4.4Hz,2H),2.84(tt,J=12 .9,3.1Hz,1H),2.38(s,3H),2.20(s,6H),2.16–2.11(m,1H),2.02(s,4H),1.55(d,J=7.1Hz,3H),1.18(td,J=7.0,1.7Hz,3H).

[0601] Example 36

[0602] (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)

[0603] 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 (400 mg, 0.873 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-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-dioxane (8 mL). The reaction was stirred at 80°C under nitrogen protection for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5, volume ratio) to obtain the product as an off-white solid (310 mg, yield 60.6%). ESI-MS m / z: 587.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.00(d,J=6.9Hz,1H),7.78(dt,J=18.6,6.0Hz,2H),7.34(t ,J=7.7Hz,1H),5.57(t,J=7.0Hz,1H),4.32(d,J=12.5Hz,1H),3.86(s,3H),3.70(d,J=13.4Hz,1H ),3.48(s,2H),3.42–3.33(m,3H),3.22(dq,J=15.4,7.8Hz,2H),2.84(d,J=11.0Hz,1H),2.38(s, 3H),2.21(s,6H),2.12(d,J=15.9Hz,1H),2.03(s,4H),1.56(d,J=7.1Hz,3H),1.22–1.17(m,3H).

[0604] Example 37

[0605] (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)

[0606] Compound 65 was prepared according to Example 36, wherein the starting material (R)-3-(1-aminoethyl)-2-fluorobenzonitrile was replaced with (R)-3-(1-aminoethyl)-2-methylbenzonitrile. ESI-MS m / z: 583.3 [M+1] + .

[0607] Example 38

[0608] (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 (Compound 66)

[0609] 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)

[0610] (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 was heated to room temperature and stirred for 12 hours. Saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used directly in the next reaction. ESI-MS m / z: 586.3 [M+1] + .

[0611] 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

[0612] (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 reaction 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(400MHz, DMSO-d6)δ8.42–8.05(m,2H),7.74(q,J=7.7Hz,1H),7.45(t,J= 7.1Hz,1H),7.38–7.05(m,2H),5.67(h,J=7.3Hz,1H),4.67(s,1H),4.19(d,J= 10.2Hz,1H),3.87(d,J=2.7Hz,3H),3.46–3.27(m,7H),3.08(s,3H),2.47–2.3 4(m,4H),2.20(s,7H),2.00(s,3H),1.89–1.72(m,2H),1.59(t,J=6.7Hz,3H).

[0613] Example 39

[0614] (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)

[0615] (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% ethylamine in ethanol (2.5 mL), and triethylamine (0.5 mL) were dissolved in ethanol (5 mL). The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the product as a white solid (40 mg). ESI-MS m / z: 611.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.98(d,J=1.5Hz,1H),7.92(t,J=6.3Hz,1H),7.63(q,J=6.8 Hz,1H),7.46(t,J=7.1Hz,1H),7.36–7.07(m,2H),5.66(p,J=7.3Hz,1H),4.14(t,J=12.0Hz,2H),3 .90(s,3H),3.59(d,J=10.6Hz,2H),3.50(s,2H),3.15(p,J=9.4,7.8Hz,1H),2.37(d,J=1.6Hz,3H) ,2.22(s,9H),2.03–1.97(m,3H),1.86–1.72(m,2H),1.57(d,J=7.1Hz,3H),0.95(t,J=7.0Hz,3H).

[0616] Example 40

[0617] (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)

[0618] (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 a reaction system of sodium hydroxide (136 mg, 3.4 mmol) and 2,2,2-trifluoroethanol (5 mL). The mixture was 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 (15 mg, 13.2% yield). ESI-MS m / z: 666.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.14(d,J=1.7Hz,1H),7.90(t,J=6.5Hz,1H),7.64(q,J=7. 1Hz,1H),7.47(d,J=7.3Hz,1H),7.37–7.07(m,2H),5.72–5.59(m,1H),4.33(d,J=10 .5Hz,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=12.6Hz,1H),2.38(d,J=1.2Hz,4H),2.21(s,6H),2.03(s,5H),1.60–1.53(m,3H).

[0619] Example 41

[0620] (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)

[0621] Compound 69 was prepared according to the method of Example 40, wherein the starting material 2,2,2-trifluoroethanol was replaced by 2,2-difluoroethanol. ESI-MS m / z: 648.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.90(t,J=5.9Hz,1H),7.63(q,J=6.7Hz,1H),7.46(t,J =7.1Hz,1H),7.37–7.06(m,2H),6.33–6.01(m,1H),5.65(p,J=7.0Hz,1H),4.31(d,J=11.8Hz ,1H),3.87(s,3H),3.71(d,J=13.3Hz,1H),3.47(s,2H),3.37(t,J=12.4Hz,3H),2.87(t,J=1 2.4Hz,1H),2.37(s,4H),2.20(s,7H),2.13–2.05(m,2H),2.03(s,3H),1.56(d,J=7.1Hz,3H).

[0622] Example 42

[0623] (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)

[0624] 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 (400MHz, Methanol-d4) δ8.71–8.63(m,1H),7.57(t,J=7.4Hz,1H),7.44(t,J=7.0Hz,1H),7. 20(t,J=7.7Hz,1H),7.02(t,J=54.9Hz,1H),5.70(q,J=7.1Hz,1H),4.55–4.43(m,1H),4.02(s,3H ),3.96–3.88(m,2H),3.84(d,J=13.7Hz,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=4.4Hz,9H),2.17(s,3H),2.05–1.88(m,2H),1.62(d,J=7.1Hz,3H).

[0625] Example 43

[0626] (R)-3-(1-acetyl-4-cyclopropyloxypiperidin-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)

[0627] (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] + .

[0628] Example 44

[0629] (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 (Compound 72)

[0630] 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] + .

[0631] Example 45

[0632] (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 (Compound 73)

[0633] 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

[0634] 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) was dissolved in tetrahydrofuran (10 mL). N,N-diethylpropargylamine (63 mg, 0.57 mmol), iodide (10 mg, 0.048 mmol), tetrakistriphenylphosphine palladium (100 mg, 0.1 mmol), and triethylamine (1 mL) were added. The mixture was stirred at 40°C for 30 minutes under a nitrogen atmosphere. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with dichloromethane / methanol = 100 to 100:6) to obtain the product (225 mg, 70% yield). ESI-MS m / z:487.3[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.17(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=27.3,13.9,2.7Hz,2H),1.37(t,J=7.0Hz,9H).

[0635] 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

[0636] To a 50 mL round-bottom flask were added 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 (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), and the mixture was reacted at 90°C for 1 hour under nitrogen protection. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product (30 mg). ESI-MS m / z: 640.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.98(d,J=7.2Hz,1H),7.64(t,J=6.3Hz,1H),7.46(t,J=7.3Hz,1H),7 .36–7.08(m,2H),5.65(t,J=7.1Hz,1H),4.32(d,J=12.8Hz,1H),3.87(s,3H),3.71(d,J=13.4Hz,1H),3.65 (s,2H),3.25–3.18(m,4H),2.85(t,J=12.9Hz,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=7.0Hz,3H),1.19(td,J=7.0,2.1Hz,3H),1.00(t,J=7.1Hz,6H).

[0637] Example 46

[0638] (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)

[0639] Step 1: 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

[0640] 3-(1-Acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-8-yl trifluoromethanesulfonate (392 mg, 0.75 mmol) was dissolved in tetrahydrofuran (15 mL). 1-(Propan-2-yn-1-yl)pyrrolidine (97 mg, 0.89 mmol), iodide (14 mg, 0.074 mmol), tetrakistriphenylphosphine palladium (172 mg, 0.15 mmol), and triethylamine (1.2 mL) were added. The mixture was stirred at 40°C for 30 minutes under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 to 100:6) to obtain the product (210 mg, 58% yield). ESI-MS m / z: 485.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.16(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=4.2Hz,1H),3.49(td,J=13.2,2. 7Hz,2H),3.43–3.32(m,2H),2.93(td,J=13.1,2.8Hz,2H),2.74(d,J=4.1Hz ,3H),2.59–2.46(m,3H),2.12(s,3H),1.90–1.81(m,4H),1.40–1.32(m,4H).

[0641] 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

[0642] To a 50 mL round-bottom flask was 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-dicyclohexylphosphine)-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)ethan-1-amine (200 mg, 1.05 mmol), and the mixture was reacted at 90°C under nitrogen protection for 1 hour. The reaction mixture was added with ethyl acetate (150 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a light yellow solid (68 mg). ESI-MS m / z: 638.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=1.5Hz,1H),7.98(dd,J=7.0,2.2Hz,1H),7.65(q,J=6.6Hz,1H),7.46(t,J=7.1Hz,1H),7.3 8–7.06(m,2H),5.65(p,J=7.0Hz,1H),4.32(d,J=12.6Hz,1H),3.86(s,3H),3.69(dd,J=13.6,9.5Hz,1H),3.63(s,2H),3.42– 3.31(m,2H),3.21(qd,J=8.9,4.0Hz,2H),2.85(ddd,J=13.3,10.0,3.3Hz,1H),2.54(d,J=6.1Hz,4H),2.37(s,3H),2.19(dtd ,J=30.4,13.2,12.8,4.2Hz,3H),2.03(s,3H),1.69(q,J=3.4,3.0Hz,4H),1.56(d,J=7.0Hz,3H),1.19(td,J=7.0,2.0Hz,3H).

[0643] Example 47

[0644] (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 (Compound 75)

[0645] 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

[0646] 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), tetrakistriphenylphosphine palladium (231 mg, 0.2 mmol), and triethylamine (3 mL) were dissolved in tetrahydrofuran (15 mL) and reacted at 55°C under nitrogen for 60 minutes. The reaction 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 as a brown solid (460 mg, 53% yield). ESI-MS m / z: 432.1 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),4.59(s,2H),4.54(d,J=12.0Hz,1H),4.06(d,J=4.7Hz,3H),3.68(d,J=13.6Hz,1H),3.55–3.43(m,1H),3 .38(p,J=7.9Hz,2H),2.97–2.87(m,1H),2.73(s,3H),2.51(ddt,J=17.9,1 3.4, 6.5Hz, 2H), 2.12 (s, 3H), 1.86 (dd, J = 26.9, 13.9Hz, 2H), 1.35 (s, 3H).

[0647] Step 2: 3-(3-(1-acetyl-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

[0648] 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 (460 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (321 mg, 3.18 mmol) and methanesulfonyl chloride (241 mg, 2.12 mmol) were added at 0°C, and the reaction was stirred at 0°C for 30 minutes. The reaction was diluted with water, extracted with dichloromethane, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by 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(400MHz,Chloroform-d)δ8.17(s,1H),5.15(s,2H),4.57(d,J=14.0Hz,1H),4.04(s,3H),3.70(d,J=16.1Hz,1H),3.57–3.45(m,1H),3.39 (t,J=7.2Hz,2H),3.12(s,3H),3.01–2.91(m,1H),2.75(s,3H),2.52(d,J=13.5Hz,2H),2.15(s,3H),1.97–1.80(m,2H),1.35(t,J=6.9Hz,3H).

[0649] Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d3)amino)prop-1-yn-1-yl)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0650] 3-(3-(1-acetyl-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-dimethylacetamide (60 mL). Dimethyl-d6-amine hydrochloride (102 mg, 1.17 mmol) was added and reacted at 50°C for 1 hour. The mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5, volume ratio) to obtain the product as a light yellow solid (160 mg, yield 58.6%). ESI-MS m / z: 465.1 [M+1] + . 1H NMR(400MHz,Chloroform-d)δ8.17(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=13.1,2.6Hz,1H),3.39(q d,J=8.7,4.4Hz,2H),2.98–2.89(m,1H),2.75(s,3H),2.53(dtd,J=18.3, 13.4, 4.8Hz, 2H), 2.12 (s, 3H), 1.94–1.86 (m, 2H), 1.35 (t, J = 6.9Hz, 3H).

[0651] Step 4: (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

[0652] 3-(1-Acetyl-4-ethoxypiperidin-4-yl)-8-(3-(bis(methyl-d3)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) were dissolved in toluene (5 mL), protected by nitrogen, and stirred at 80°C for 1 hour. After the reaction 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 purified by silica gel column chromatography (dichloromethane / methanol = 95:5, volume ratio) to obtain the product as a white solid (170 mg, yield 80.5%). ESI-MS m / z: 618.1 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ8.14(s,1H),7.97(dd,J=7.2,2.3Hz,1H),7.65(q,J=6.4,6.0Hz,1H),7.4 6(t,J=7.1Hz,1H),7.36–7.06(m,2H),5.65(p,J=7.0Hz,1H),4.36–4.27(m,1H),3.86(s,3H),3.70 (d,J=13.3Hz,1H),3.47(s,2H),3.21(dtt,J=13.3,8.7,4.3Hz,2H),2.84(tt,J=12.8,3.1Hz,1H) ,2.38(s,3H),2.26–2.09(m,3H),2.02(s,5H),1.55(d,J=7.1Hz,3H),1.17(dd,J=6.9,1.9Hz,3H).

[0653] Example 48

[0654] (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 (Compound 76)

[0655] Compound 76 was prepared according to step 4 of Example 47, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile. ESI-MS m / z: 593.3 [M+1] + .

[0656] Example 49

[0657] (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 (Compound 77)

[0658] Compound 77 was prepared according to step 4 of Example 47, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-methylbenzonitrile. ESI-MS m / z: 589.4 [M+1] + .

[0659] Example 50

[0660] (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)

[0661] 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

[0662] 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-butyloxycarbonyl-4-hydroxypiperidine (519 mg, 3.0 mmol), and triphenylphosphine (1.05 g, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen, diisopropyl azodicarboxylate (909 mg, 4.5 mmol) was added at 0°C and stirred for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:2, volume ratio) to afford the product as a yellow solid (540 mg, 93% yield). ESI-MS m / z: 577.1 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),4.56(d,J=13.0Hz,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=2 3.9,13.8Hz,4H),1.68–1.57(m,2H),1.44(s,9H),1.35(t,J=6.9Hz,3H).

[0663] Step 2: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(piperidin-4-yloxy)-1,6-naphthyridin-2(1H)-one

[0664] 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 reaction mixture was concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 477.1 [M+1] + .

[0665] 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

[0666] The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% aqueous formaldehyde solution (1 mL) and sodium triacetoxyborohydride (1.82 g, 9.03 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed sequentially with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by 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(400MHz,Chloroform-d)δ8.11(s,1H),4.55(ddt,J=13.1,4.6,2.1Hz,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=6.9Hz,3H).

[0667] 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

[0668] 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-dicyclohexylphosphine)-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), protected by nitrogen, and stirred at 80°C for 1 hour. After the reaction 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 purified by silica gel column chromatography (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(400MHz, DMSO-d6)δ8.12(s,1H),7.67(q,J=6.1,5.2Hz,1H),7.51–7.39(m,2H),7.36–7.07(m,2H),5.56(t ,J=7.1Hz,1H),4.41–4.26(m,1H),3.69(d,J=12.8Hz,1H),3.63(s,3H),3.47(dt,J=10.0,4.5Hz,2H),3.43–3. 32(m,3H),3.28–3.16(m,2H),2.84(dddd,J=13.3,10.7,6.8,3.7Hz,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=7.1Hz,3H),1.20(dd,J=7.0,1.6Hz,3H).

[0669] Example 51

[0670] (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylazetidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one (Compound 79)

[0671] 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)azetidine-1-carboxylate

[0672] 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-butyloxycarbonyl-3-hydroxyazetidine (519 mg, 3.0 mmol), and triphenylphosphine (1.05 g, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen, diisopropyl azodicarboxylate (909 mg, 4.5 mmol) was added at 0°C and stirred for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99:2, volume ratio) to afford the product as a yellow solid (280 mg, 51% yield). ESI-MS m / z: 549.1 [M+1] + .

[0673] Step 2: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-8-(azetidin-3-yloxy)-5-chloro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

[0674] 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)azetidine-1-carboxylate (260 mg, 0.474 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2 mL) was added and stirred at room temperature for 15 minutes. The reaction was concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 449.1 [M+1] + .

[0675] Step 3: 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylazetidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one

[0676] 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 reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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(400MHz,Chloroform-d)δ8.12(s,1H),4.62–4.52(m,1H),4.31(p,J=6.1Hz,1H),3.80(s,3H),3.75–3.65(m,3H),3.53–3.34(m,3H),3.27 (td,J=6.2,2.0Hz,2H),2.92(td,J=13.1,2.8Hz,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=6.9Hz,3H).

[0677] Step 4: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,7-dimethyl-8-((1-methylazetidin-3-yl)oxy)-1,6-naphthyridin-2(1H)-one

[0678] 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-((1-methylazetidin-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) were dissolved in toluene (5 mL), protected by nitrogen, and stirred at 80°C for 1 hour. After the reaction 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 purified by silica gel column chromatography (dichloromethane / methanol = 95:5, volume ratio) to obtain the product as a white solid (150 mg, yield 68%). ESI-MS m / z: 616.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.67(q,J=6.5,5.7Hz,1H),7.54(dd,J=7.3,2.3Hz,1H),7.44(t,J=7.1Hz,1 H),7.35–7.07(m,2H),5.56(p,J=7.1Hz,1H),4.31(d,J=12.6Hz,1H),4.17(p,J=5.9Hz,1H),3.69(d,J=14.3Hz,1 H),3.62(s,3H),3.59–3.53(m,2H),3.36(tt,J=13.0,3.3Hz,2H),3.27–3.17(m,2H),3.09(d,J=7.0Hz,2H),2.85 (ddt,J=13.9,10.0,4.1Hz,1H),2.26(s,3H),2.17(s,3H),2.03(s,5H),1.52(d,J=7.1Hz,3H),1.21–1.17(m,3H).

[0679] Example 52

[0680] (R)-3-(1-((3-(1-acetyl-4-ethoxypiperidin-4-yl)-1,7-dimethyl-8-((1-methylazetidin-3-yl)oxy)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)amino)ethyl)-2-fluorobenzonitrile (Compound 80)

[0681] Compound 80 was prepared according to step 4 of Example 51, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile. ESI-MS m / z: 591.3 [M+1] + .

[0682] Example 53

[0683] 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 (Compound 81)

[0684] Step 1: tert-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

[0685] To a 50 mL round-bottom flask were added 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-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). The reaction solution was cooled to 0°C under nitrogen protection, and diisopropyl azodicarboxylate (616 mg, 3.05 mmol) was added. 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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 to 100:5) to obtain the product as a yellow solid (526 mg, 60%). ESI-MS m / z: 577.3 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.12(d,J=3.5Hz,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= 4.4Hz,3H),2.00–1.84(m,4H),1.44–1.42(m,4H),1.39–1.22(m,10H).

[0686] Step 2: (S)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(pyrrolidin-2-ylmethoxy)-1,6-naphthyridin-2(1H)-one

[0687] To a 50 mL round-bottom flask was added tert-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 (500 mg, 0.86 mmol), dichloromethane (6 mL), and trifluoroacetic acid (3 mL). The mixture was reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give a crude product, which was used directly in the next reaction. ESI-MS m / z: 477.2 [M+1] + .

[0688] 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

[0689] The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% aqueous formaldehyde 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 reaction, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane / methanol = 95:5, volume ratio) to obtain the product (383 mg, yield 90%). ESI-MS m / z: 491.2 [M+1] + . 1H NMR(400MHz,Chloroform-d)δ8.14(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=13.1,2.6Hz,1H),3.45–3.3 6(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=6.9Hz,3H).

[0690] 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-naphthyridin-2(1H)-one

[0691] To a 50 mL round-bottom flask was 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), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (68 mg, 0.075 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (429 mg, 2.26 mmol), and the mixture was reacted at 90°C for 1 hour under nitrogen protection. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture was 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 = 95:5, volume ratio) to obtain the product (371 mg, yield 76%). ESI-MS m / z: 644.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.66(d,J=8.9Hz,1H),7.53–7.41(m,2H),7.37–7.07(m,2H),5.58(p,J=7.1Hz ,1H),4.32(d,J=12.5Hz,1H),3.75(s,3H),3.71(d,J=13.6Hz,1H),3.57(dd,J=9.2,5.3Hz,1H),3.46–3.40(m,2H), 3.30–3.17(m,2H),2.95(dd,J=9.2,4.9Hz,1H),2.85(t,J=12.6Hz,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=7.1Hz,3H),1.27–1.17(m,5H).

[0692] Example 54

[0693] 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 (Compound 82)

[0694] Compound 82 was prepared according to step 4 of Example 53, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile. ESI-MS m / z: 619.3 [M+1] + .

[0695] Example 55

[0696] 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 (Compound 83)

[0697] Step 1: 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

[0698] To a 50 mL round-bottom flask was added 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)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (356 mg, 1.91 mmol), anhydrous tetrahydrofuran (8 mL) and triphenylphosphine (833 mg, 3.18 mmol). The reaction solution was cooled to 0°C under nitrogen protection, and diisopropyl azodicarboxylate (513 mg, 2.54 mmol) was added dropwise. After the addition, the reaction was continued at 0°C for 2 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction mixture, 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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 to 100:5) to obtain the product. ESI-MS m / z: 563.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),4.59(s,1H),4.51–4.40(m,2H),3.81(s,3H),3.63(dd,J=34.3,8. 9Hz,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=6.9Hz,3H).

[0699] Step 2: (R)-3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(pyrrolidin-3-yloxy)-1,6-naphthyridin-2(1H)-one

[0700] To a 50 mL round-bottom flask was added 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). The mixture was reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give a crude product, which was used directly in the next reaction. ESI-MS m / z: 463.2 [M+1] + .

[0701] 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

[0702] The crude product obtained in step 2 was dissolved in tetrahydrofuran (10 mL), and 30% aqueous formaldehyde 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 reaction, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (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(400MHz,Chloroform-d)δ8.13(d,J=0.9Hz,1H),4.58(d,J=13.2Hz,1H),4.46(s,1H),3.85(s,3H),3.69(d,J=13.8Hz,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),2.1 3(s,3H),2.07(d,J=6.6Hz,1H),1.96–1.80(m,3H),1.36(t,J=6.9Hz,3H).

[0703] Step 4: 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

[0704] To a 50 mL round-bottom flask was added (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)ethan-1-amine (136 mg, 0.72 mmol), and the mixture was reacted at 90°C for 1 hour under nitrogen protection. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture was 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 = 95:5, volume ratio) to obtain the product (120 mg, yield 79%). ESI-MS m / z: 630.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.13(d,J=1.5Hz,1H),7.71–7.65(m,1H),7.54–7.41(m,2H),7.39–7.06(m,2H),5.57(p ,J=7.0Hz,1H),4.32(d,J=12.7Hz,1H),4.26(td,J=5.4,2.5Hz,1H),3.72(s,1H),3.68(s,3H),3.37(qd,J=12.4, 11.5,4.9Hz,2H),3.29–3.17(m,3H),2.88–2.79(m,2H),2.66(d,J=10.8Hz,1H),2.23(d,J=6.1Hz,6H),2.21–2.0 9(m,4H),2.04(s,3H),1.91(s,1H),1.83–1.74(m,1H),1.53(d,J=7.0Hz,3H),1.20(ddd,J=9.0,5.8,2.3Hz,3H).

[0705] Example 56

[0706] 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 (Compound 84)

[0707] Compound 84 was prepared according to the method of Example 55, wherein the starting material in step 1, (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, was replaced with (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. ESI-MS m / z: 630.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.12(s,1H),7.68(q,J=6.8,6.4Hz,1H),7.53–7.42(m,2H),7.39–7.07(m,2H),5.58(p,J=7.0Hz,1H),4.33 (d,J=12.7Hz,1H),4.26(d,J=6.7Hz,1H),3.72(d,J=6.7Hz,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=5.2Hz,6H),2.19–2.07(m,3H),2.04(s,3H),1.87–1.78(m,1H),1.53(d,J=7.1Hz,3H),1.24–1.16(m,4H).

[0708] Example 57

[0709] (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)

[0710] 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

[0711] To a 50 mL round-bottom flask were added 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-8-hydroxy-1,7-dimethyl-1,6-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). The reaction mixture was reacted at 60°C for 2 hours under a nitrogen atmosphere. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The organic phase was separated, 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 to 100:5) to afford the product as a yellow solid (81 mg, 65%). ESI-MS m / z: 491.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),4.58(d,J=13.0Hz,1H),4.09(s,2H),3.88(s,3H),3.70(d,J=13.1Hz,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=6.9Hz,3H).

[0712] 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

[0713] To a 50 mL round-bottom flask were added 3-(1-acetyl-4-ethoxypiperidin-4-yl)-5-chloro-1,7-dimethyl-8-(2-(pyrrolidin-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), protected by nitrogen, and reacted at 90°C for 1 hour. The reaction mixture was added with ethyl acetate (150 mL), 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 = 95:5, volume ratio) to obtain the product (66 mg, yield 70%). ESI-MS m / z: 644.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.68(s,1H),7.54–7.41(m,2H),7.38–7.07(m,2H),5.57(p,J=7.1Hz,1 H),4.31(dd,J=11.6,8.4Hz,1H),3.73(s,3H),3.67(q,J=6.9,6.0Hz,3H),3.30–3.18(m,2H),2.85(ddd,J=1 3.2,10.0,3.8Hz,1H),2.71(t,J=5.9Hz,2H),2.43(q,J=3.8Hz,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=7.1Hz,3H),1.34(d,J=6.1Hz,1H),1.24–1.17(m,5H).

[0714] Example 58

[0715] (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)

[0716] Compound 86 was prepared according to step 2 of Example 57, wherein the starting material (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was replaced with (R)-3-(1-aminoethyl)-2-fluorobenzonitrile. ESI-MS m / z: 619.3 [M+1] + .

[0717] Example 59

[0718] 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)

[0719] Compound 87 was prepared according to the method of Example 53, wherein 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] + .

[0720] Example 60

[0721] 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 (Compound 88)

[0722] Compound 88 was prepared according to the method of Example 53, wherein the starting material in step 1, (S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, was replaced with (R)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, and the starting material in step 4, (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] + .

[0723] Biological Test Examples

[0724] Example A: Inhibitory effect of the compound on the cell growth of NCI-H358 and MIA PaCa-2 tumor cell lines under 3D culture conditions.

[0725] Cell sources: NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., Ltd.; MIA PaCa-2 was purchased from Shanghai Dio Biotechnology Co., Ltd.

[0726] Logarithmically growing cells were seeded in ultra-low attachment 96-well plates (4,000 NCI-H358 and 2,000 MIA PaCa-2 cells per well, respectively, at 180 μl / well). Cells were incubated at 37°C, 5% CO₂, and allowed to aggregate and form microspheres. After one day, a serial dilution of the test compound was added. Specifically, a 10 mM stock solution of the compound, previously dissolved in DMSO, was diluted four-fold to a total of 10 concentrations. This was then diluted to 10-fold the target concentration in culture medium in a separate 96-well plate. Then, 20 μl / well of the compound solution was added to the 96-well plate seeded with cells to achieve the target concentrations (10,000, 2,500, 625, 156, 39, 10, 2.5, 0.6, 0.15, and 0.04 nM). Three replicates were performed for each concentration, and a blank control was included. After culturing for 6 days at 37°C and 5% CO2, 50 μl CellTiter- 3D reagent (luciferase ATP bioluminescence detection reagent for detecting 3D cell microspheres, purchased from Promega, catalog number G9683), shake for 10 minutes, incubate at room temperature for 20 minutes, and then measure the fluorescence intensity (light collection time is 100ms). Calculate the activity inhibition rate of each concentration of compound on 3D cell microspheres, cell activity inhibition rate (%) = [(luminescence intensity of the control group containing cell culture medium for 6 days - luminescence intensity of 6 days)] 天化合物组 ) / (luminescence intensity of the control group containing cell culture medium for 6 days – luminescence intensity of the control group without cell culture medium for 6 days) × 100%. Data were analyzed using GraphPad Prism 8.3 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 The results are shown in Table 1.

[0727] Table 1

[0728] “--” in the table means not tested.

[0729] Among them, BI-3406 is a SOS1 inhibitor reported in the literature (Cancer Discovery 2021(11)142-157), and its structure is:

[0730] The results showed that the compound of the present invention exhibited good cell growth inhibition effect on NCI-H358 and MIA PaCa-2 tumor cell lines.

[0731] Example B: Pharmacokinetics test in rats

[0732] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention after oral administration and intravenous injection in rats.

[0733] Oral administration group: Three female SD rats were fasted for 12 hours and then gavaged with the test compound (5 mg / kg, 10 mL / kg, 10% DMSO / 10% Solutol / 80% saline). Sampling was performed at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration. [Solutol refers to polyethylene glycol (15)-hydroxystearate.]

[0734] Intravenous administration group: Three female SD rats were fasted for 12 hours and intravenously administered with the test compound (1 mg / kg, 5 mL / kg, 10% DMSO / 10% Solutol / 80% saline). Sampling time points were 5 minutes, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration.

[0735] At the above set time points, 0.2 mL of venous blood was collected from the retroorbital venous plexus of rats, placed in a K2-EDTA (dipotassium ethylenediaminetetraacetic acid) test tube, centrifuged at 6800 g for 6 min at 4°C, and the plasma was separated and stored at -80°C.

[0736] 20 μL of plasma sample was taken, 200 μL of methanol (containing 10 ng / mL internal standard verapamil) was added, and the mixture was vortexed for 1 min and centrifuged at 18,000 g for 7 min. 200 μL of the supernatant was transferred to a 96-well plate. The concentration of the compound in plasma was determined by liquid chromatography-tandem mass spectrometry, and the main pharmacokinetic parameters of the compound were calculated using WinNonlin 7.0 software. The results are shown in Table 2.

[0737] Table 2

[0738] AUC: plasma exposure; C max : maximum plasma concentration; V: apparent volume of distribution; CL: clearance; F: oral bioavailability.

[0739] The results showed that the pharmacokinetic properties of the compounds of the present invention, such as plasma exposure AUC and maximum blood concentration C max All performed well.

Claims

1. A fused ring compound as shown in Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: Ring A is C 6-12 Aryl, 5-10 membered heteroaryl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic group; Each R 1 are independently deuterium, hydroxyl, halogen, -N(R 7 )2、-SR 9 , cyano, oxo, nitro, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl, one or more R 1b Substituted C 1-6 Alkyl-O-, one or more R 1c Substituted C 2-6 Alkenyl, one or more R 1d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 1e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 1f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 1g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 1h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 1i Substituted C 3-7 Cycloalkenyl, -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 ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, one or more R 1e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 1f Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 1i Substituted 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 are 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, one or more R 1-a Substituted C 1-6 Alkyl, one or more R 1-b Substituted C 1-6 Alkyl-O-, one or more R 1-c Substituted C 2-6 Alkenyl, one or more R 1-d Substituted C 2- 6 alkynyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-O-, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl-O-, one or more R 1-e Substituted C 3-7 Cycloalkyl, one or more R 1-e Substituted C 3-7 Cycloalkyl-O-, one or more R 1-f substituted 3-7 membered heterocyclic group, one or more R 1-f Substituted 3-7 membered heterocyclyl-O-, C 6-12 Aryl, one or more R 1-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 1-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl-O-, one or more R 1-i Substituted C 3-7 Cycloalkenyl, 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 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 heterocyclic group; 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 membered heterocyclic group; L is a linking bond, -C(=O)-, -C(=O)O-, or -C(=O)NR 8 -、-NR 8 -, -S-, -O-, -S(O)-, -S(O)2- or -(CH2) p -; When L is a connecting bond, it means R 3 Connect directly to the D ring; R 3 For hydrogen, deuterium, C 1-6 Alkyl, one or more R 3a Substituted C 1-6 Alkyl, C 2-6 Alkenyl, one or more R 3b Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 3c Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3f Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 3g Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h are independently deuterium, hydroxyl, halogen, -N(R 7 )2, cyano, nitro, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 3-c Substituted C 2-6 Alkenyl, one or more R 3-d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 3-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 3-i Substituted C 3-7 Cycloalkenyl, 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 ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or 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 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 heterocyclic group, -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 linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-; R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or 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 each independently hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, amino protecting group, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is absent, oxo, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, C 1-6 Alkyl, one or more R 5a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 5b Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 5c Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 5d Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 5a 、R 5b and R 5c Deuterium, C 1-6 alkyl, hydroxy, halogen, amino or cyano; R 6 For hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl group or not present; Each R 7 are independently hydrogen, C 1-6 Alkyl, one or more R 7b Substituted C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl or amino protecting group, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 7a and R 7b Deuterium, C 1-6 Alkyl, halogen, hydroxy, amino, 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 For 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 For cyano, C 1-6 Alkyl or one or more R 11a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; Each R 11a are independently deuterium, halogen or hydroxyl; m is 0, 1, 2, 3, 4 or 5; p is 1, 2, 3, 4, 5, or 6; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; The 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group substituted by a substituent are each independently a "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S"; The 5-6 membered heteroaryl group is a "5-6 membered heteroaryl group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; The amino protecting group is tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl or p-toluenesulfonyl; When the carbon atom of * has chirality, the fused ring compound shown in Formula I is or a mixture thereof.

2. The fused ring compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: When X is a connecting bond, R 4 C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; when there are multiple substituents, they may be the same or different.

3. The fused ring compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: X is a linking bond, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-; when X is a linking bond, R 4 For cyano, 4. The fused ring compound of formula I according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: 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 -(CH2) p -; When L is a connecting bond, it means R 3 Directly connected to the D ring; R 3 For one or more R 3e Substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R 3e are independently deuterium, hydroxyl, halogen, -N(R 7 )2, cyano, nitro, C 1- 6 alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2- 6 alkenyl, C 2-6 Alkynyl, one or more R 3-c Substituted C 2-6 Alkenyl, one or more R 3-d Substituted C 2-6 Alkynyl, C 3-7 Cycloalkyl, one or more R 3-e Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3-f Substituted 3-7 membered heterocyclic group, C 6-12 Aryl, one or more R 3-g Substituted C 6-12 Aryl, 5-10 membered heteroaryl, substituted by one or more R 3-h Substituted 5-10 membered heteroaryl, C 3-7 Cycloalkenyl, one or more R 3-i Substituted C 3-7 Cycloalkenyl, 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 ; 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 R 3 Directly connected to the D ring; R 3 For one or more R 3e Substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; each R 3e are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 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.

5. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: It meets 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 11 In the C 1-6 Alkyl, C substituted by substituent 1-6 C in the alkyl group 1-6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-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 wherein the halogen is independently F, Cl, Br or I, for example, 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 、R 5 、R 6 、R 7a 、R 7b and R 10 In the C 1-6 Alkyl-O-, C substituted by substituent 1-6 C in alkyl-O- 1-6 Alkyl-O- is each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; (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 3e 、R 3f 、R 3g 、R 3h 、R 5 、R 6 、R 7a 、R 7b 、R 8 、R 9 and R 10 In the C 2-6 Alkenyl, C substituted by substituent 2-6 C in alkenyl 2-6 each alkenyl group is independently -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH2-CH2-CH3, -CH2-CH=CH-CH2-CH3, -CH=CH-CH(CH3)2, -CH2-CH=C(CH3)2, or -CH=CH-(CH2)3-CH3; (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 In the C 2-6 Alkynyl, C substituted by substituent 2-6 C in alkynyl 2-6 Each alkynyl group is independently -C≡CH, -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≡C-C(CH3)3, -C≡C-CH(CH3)2, or -CH2C≡C-CH2-CH2-CH3; (6) C in ring A 3-7 Cycloalkyl, R 1 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f 、R 1g 、R 1h and R 1i C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, C 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, 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 R 2 C in 3-7 Cycloalkyl, R 3 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, C 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl-O- 3-7 Cycloalkyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkyl 3-7 Cycloalkyl, 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 C in 3-7 Cycloalkyl, R 4 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 5 C in 3-7 Cycloalkyl, C substituted by substituent 3-7 C in cycloalkyl 3-7 Cycloalkyl, R 7 C in 3-7 Cycloalkyl, R 8 and R 9 C in 3-7 Cycloalkyl, each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or For example, cyclopropyl; (7) C in ring A 3-7 Cycloalkenyl, R 1 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkenyl, two R 1 Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f 、R 1g 、R 1h and R 1i C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, C 3-7 C in cycloalkenyl-O- 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl-O- 3-7 Cycloalkenyl, 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 R 2 C in 3-7 Cycloalkenyl, R 3 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g and R 3h C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 Cycloalkenyl, two R 3d , two R 3e , two R 3f , two R 3g or two R 3h Together with the ring atoms to which it is attached, it forms a C 3-7 C in cycloalkenyl 3-7 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 R 3-j C in 3-7 Cycloalkenyl, R 5 C in 3-7 Cycloalkenyl, C substituted by a substituent 3-7 C in cycloalkenyl 3-7 Cycloalkenyl, R 7 、R 8 and R 9 C in 3-7 Cycloalkenyl, the C 3-7 Each cycloalkenyl group is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl; (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 wherein the 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by a substituent, the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group-O-, and the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by a substituent are each independently a saturated or partially unsaturated non-aromatic monocyclic or polycyclic heterocyclic group. Specifically, the monocyclic heterocyclic group may be pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, piperazinyl, azetidinyl, 1,2-dihydropyridinyl, tetrahydropyridinyl, etc., and the polycyclic ring may be a bridged ring, a condensed ring or a spiro ring; (9)R 3 wherein the 3-7 membered heterocyclic group is replaced by one or more R 3e The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 3-7 membered heterocyclic group in which the heteroatom species are independently selected from one or two of N and O, and the number of heteroatoms is 1 or 2"; further, the 3-7 membered heterocyclic group, substituted by one or more R 3e The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently a 4-7 membered heterocyclic group having 1 or 2 heteroatoms, the types of which are independently selected from N and O; 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; specifically, when R 3 When it is a 4-7 membered monocyclic heterocyclic group, the 4-7 membered monocyclic heterocyclic group may be piperidinyl, tetrahydropyranyl, piperazinyl, azetidinyl, morpholinyl or pyrrolidinyl; when R 3 When it is a 5-7 membered bridged heterocyclic group, the 5-7 membered bridged heterocyclic group may be When R 3 When it is a 5-7 membered spiro heterocyclic group, the 5-7 membered spiro heterocyclic group may be For example, (10)R 4 wherein the 3-7 membered heterocyclic group is replaced by one or more R 4a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 3-7 membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; further, the 3-7 membered heterocyclic group, substituted by one or more R 4a The 3- to 7-membered heterocyclic groups in the substituted 3- to 7-membered heterocyclic groups are each independently "a 4- to 7-membered heterocyclic group in which the heteroatom species are independently selected from one or two of N and O, and the number of heteroatoms is 1 or 2"; for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl or morpholinyl; for example For example (11)R 7 In the above two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The number of heteroatoms in the substituted 3-7 membered heterocyclic group is independently 1 or 2; the two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or two of N and O; the two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic groups are each independently "a 4-7 membered heterocyclic group in which the heteroatom species are independently selected from one or two of N and O, and the number of heteroatoms is 1 or 2"; for example: pyrrolidinyl, and for example (12) In ring D, the 3- to 7-membered heterocyclic group is a "6-membered heterocyclic group in which the heteroatom species is N and the number of heteroatoms is 1 or 2", for example, 1,2-dihydropyridyl, and for example "c" indicates that the atom is located in the meta position relative to the N atom of the B ring; (13) 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 In the C 6-12 Aryl, C substituted by substituent 6-12 C in aromatic groups 6-12 Each aryl group is independently phenyl or naphthyl; for example: phenyl; (14) 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 wherein the 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group substituted by a substituent are each independently a "5-8 membered heteroaryl group having 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S"; (15) In X, the -(C1-C4 alkylene)- and -O-(C1-C4 alkylene)- are each independently methylene, ethylene, n-propylene or isopropylene, for example: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH2CH3)- or -C(CH3)2-, preferably -CH2-, -CH2CH2-, -CH(CH3)- or -CH2CH2CH2-; further, the "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" and R 4 connected; (16) In X, the -(C2-C4 alkenylene)- is independently vinylene, propenylene, allylene or butenylene, for example, -CH=CH-, -CH=CH-CH2-; further, the -(C2-C4 alkenylene)- can be Where f end and R 4 connected; and (17) In X, the -(C2-C6 alkynylene)- is independently ethynylene, propynylene, propargylene, butynylene or pentynylene, for example, -C≡C-, -CH2-C≡CH, -C≡C-CH2-, -C≡C-CH2-CH2-, -C≡C-CH(CH3)-CH2-, -C≡CC(CH3)2-, preferably -C≡C-, -C≡C-CH2- or -C≡CC(CH3)2-; further, the -(C2-C6 alkynylene)- can be -C≡C-*, -C≡C-CH2-* or -C≡CC(CH3)2-*, wherein the * end is aligned with R 4 connected.

6. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: It meets one or more of the following conditions: (1)R 3 wherein the 3-7 membered heterocyclic group is replaced by one or more R 3e The number of heteroatoms in the 3-7 membered heterocyclic group of the substituted 3-7 membered heterocyclic group is independently 1 or 2; (2)R 3 wherein the 3-7 membered heterocyclic group is replaced by one or more R 3e The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or both of N and O; (3)R 3 wherein the 3-7 membered heterocyclic group is replaced by one or more R 3e The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic group are each independently a 4-7 membered heterocyclic group; (4)R 4 wherein the 3-7 membered heterocyclic group is replaced by one or more R 4a The number of heteroatoms of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group is independently 1, 2 or 3; further, the 3-7 membered heterocyclic group, substituted by one or more R 4a The number of heteroatoms in the 3-7 membered heterocyclic group of the substituted 3-7 membered heterocyclic group is independently 1 or 2; (5)R 4 wherein the 3-7 membered heterocyclic group is replaced by one or more R 4a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or more of N, O and S; further, the 3-7 membered heterocyclic group, substituted by one or more R 4a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or both of N and O; (6)R 4 wherein the 3-7 membered heterocyclic group is replaced by one or more R 4a The 3-7 membered heterocyclic groups in the substituted 3-7 membered heterocyclic group are each independently a 4-7 membered heterocyclic group; (7)R 7 In the above two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The number of heteroatoms in the 3-7 membered heterocyclic group of the substituted 3-7 membered heterocyclic group is independently 1 or 2; (8)R 7 In the above two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a The heteroatom species of the 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group are independently selected from one or both of N and O; (9)R 7 In the above two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group, which is supported by one or more R 7a Substituted 3- The 3- to 7-membered heterocyclic groups in the 7-membered heterocyclic group are each independently a 4- to 7-membered heterocyclic group; (10) In ring D, the heteroatom species of the 3-7 membered heterocyclic group is N; (11) In ring D, the number of heteroatoms in the 3-7 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.

7. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: It meets one or more of the following conditions: (1) Ring A is C 6-12 Aryl; preferably, ring A is phenyl; (2) Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; preferably, each R 1 are independently halogen, C 1-6 Alkyl, cyano or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; (3) Each R 1a and R 1b are each independently halogen; preferably, each R 1a and R 1b are each independently F or Cl; (4) m is 0, 1, 2 or 3; preferably, m is 2; (5)R 2 For 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 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; preferably, R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 More preferably, R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; (8) Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3- a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; Further, each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 Preferably, each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O- or -C(=O)-R 9 ; Preferably, each R 3d 、R 3e and R 3h are each independently hydroxyl, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O- or -C(=O)-R 9 ; Further preferably, each R 3d 、R 3e and R 3h are independently hydroxy, halogen, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O- or -C(=O)-R 9 More preferably, each R 3d 、R 3e and R 3h are independently hydroxy, halogen, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O- or -C(=O)-R 9 ; When there are multiple substituents, they are the same or different; (9) 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 R 3-b are each independently deuterium, hydroxyl, halogen or C 3-7 cycloalkyl; further, each R 3-b are independently deuterium, hydroxyl or halogen; (10) X is a linking bond, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is identical to R 4 further, X is a connecting bond, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, -O-(C1-C4 alkylene)-"C1-C4 alkylene" and R 4 Preferably, X is -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 Alkyne)-; preferably, "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected; (11)R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; preferably, R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; more preferably, R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 )2. By one or more R 4a substituted 3-7 membered heterocyclic group or one or more R 4b Substituted C 3-7 Cycloalkyl; further preferably, R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or one or more R 4b Substituted C 3-7 Cycloalkyl; most preferably, R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group or one or more R 4a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; (12) Each R 4a and R 4b Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 Alkyl; preferably, each R 4a and R 4b are each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 Alkyl; More preferably, each R 4a and R 4b Each independently is C 1-6 Alkyl or amino; further preferably, each R 4a Independently C 1-6 alkyl; (13)R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 Alkyl; preferably, R 5 is hydrogen or C 1-6 Alkyl; more preferably, R 5 C 1-6 alkyl; (14)R 6 For oxygen; (15) Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a substituted 3-7 membered heterocyclic group; further, each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; further, each R 7 are independently hydrogen or C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; (16) Each R 7b are independently deuterium, halogen, hydroxyl or cyano; preferably, each R 7b is independently deuterium or hydroxyl; more preferably, each R 7b independently for deuterium; (17) Each R 9 are independently hydrogen or C 1-6 Alkyl; preferably, each R 9 Independently C 1-6 alkyl; (18) Ring D is a 3-7 membered heterocyclic group; (19)R 10 C 1-6 Alkyl; preferably, R 10 is methyl; (20)R 11 C 1-6 Alkyl; preferably, R 11 is methyl; and (21) Not hydrogen.

8. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: Ring A is C 6-12 aryl; Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different; Each R 1a and R 1b are each independently halogen; m is 0, 1, 2, or 3; R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; L is the connecting key; R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are 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 linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C4 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected; R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or 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 Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl; R 6 For oxygen; Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 7a and R 7b are each independently deuterium, halogen, hydroxyl or cyano; Each R 9 are independently hydrogen or C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; Further, Ring A is C 6-12 aryl; Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; Each R 1a are independently halogen; m is 2; R 2 is hydrogen; L is the connecting key; R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 3e are independently hydroxy, halogen, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, 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 are independently deuterium, hydroxyl or halogen; X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected; R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a substituted 3-7 membered heterocyclic group or 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 each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen or C 1-6 alkyl; R 6 For oxygen; Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 7b are independently deuterium or hydroxyl; Each R 9 Independently C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; Going further, Ring A is C 6-12 Aryl (e.g., )； Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; Each R 1a are independently halogen; m is 2; R 2 is hydrogen; L is the connecting key; R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 3e are independently hydroxyl, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, 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 are independently deuterium, hydroxyl or halogen; X is -(C1-C4 alkylene)-, -O-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected; R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group or one or more R 4a a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 4a Independently C 1-6 alkyl; R 5 is hydrogen or C 1-6 alkyl; R 6 For oxygen; Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 7b are independently deuterium or hydroxyl; Each R 9 Independently C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 is methyl; R 11 is methyl; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently a "3- to 7-membered heterocyclic group wherein the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3".

9. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: The fused ring compound shown in Formula I is the following Scheme 1, Scheme 2, Scheme 3 or Scheme 4: Scheme 1: The fused ring compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, Ring A is C 6-12 aryl; Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different; Each R 1a and R 1b are each independently halogen; m is 0, 1, 2, or 3; R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; L is the connecting key; R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are 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 linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected; R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or 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 Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl; R 6 is oxo (=O); Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 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 are independently hydrogen or C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; in, Not hydrogen; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; Scheme 2: In the fused ring compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, Ring A is C 6-12 aryl; Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; Each R 1a are independently halogen; m is 2; R 2 is hydrogen; L is the connecting key; R 3 For one or more R 3e a substituted 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 3e are independently hydroxy, halogen, -N(R 7 )2、C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, 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 are independently deuterium, hydroxyl or halogen; X is a linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is the same as R 4 connected; R 4 For hydrogen, C 1-6 Alkyl, cyano, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a substituted 3-7 membered heterocyclic group or 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 each independently amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen or C 1-6 alkyl; R 6 is oxo (=O); Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic group; when there are multiple substituents, they may be the same or different; Each R 7b are independently deuterium or hydroxyl; Each R 9 Independently C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; in, Not hydrogen; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; Scheme 3: In the fused ring compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, Ring A is C 6-12 aryl; Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different; Each R 1a and R 1b are each independently halogen; m is 0, 1, 2, or 3; R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; L is the connecting key; R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are 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 linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected; R 4 For hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-O-, cyano, halogen, hydroxyl, -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or 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 Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl; R 6 is oxo (=O); Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 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 are independently hydrogen or C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; in, Not hydrogen; The 3- to 7-membered heterocyclic group and the 3- to 7-membered heterocyclic group substituted by a substituent are each independently "a 3- to 7-membered heterocyclic group in which the heteroatom species are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; Scheme 4: In the fused ring compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, Ring A is C 6-12 aryl; Each R 1 are independently halogen, hydroxy, -N(R 7 )2、C 1-6 Alkyl, cyano, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, one or more R 1a Substituted C 1-6 Alkyl or one or more R 1b Substituted C 1-6 Alkyl-O-; when there are multiple substituents, they may be the same or different; Each R 1a and R 1b are each independently halogen; m is 0, 1, 2, or 3; R 2 For hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; L is the connecting key; R 3 C 3-7 Cycloalkyl, one or more R 3d Substituted C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, one or more R 3e Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkenyl or one or more R 3h Substituted C 3-7 Cycloalkenyl; when there are multiple substituents, they may be the same or different; Each R 3d 、R 3e and R 3h are each independently hydroxy, halogen, -N(R 7 )2, cyano, C 1-6 Alkyl, one or more R 3-a Substituted C 1-6 Alkyl, C 1-6 Alkyl-O-, one or more R 3-b Substituted C 1-6 Alkyl-O-, C 3-7 Cycloalkyl-O-, one or more R 3-j Substituted C 3-7 Cycloalkyl-O-, C 2-6 Alkynyl or -C(=O)-R 9 ; When there are multiple substituents, they are 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 linker, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)- or -(C2-C6 alkynylene)-; preferably, the "C1-C4 alkylene" in -O-(C1-C4 alkylene)- is the same as R 4 connected; R 4 -N(R 7 ) 2, 3-7 membered heterocyclic group, one or more R 4a Substituted 3-7 membered heterocyclic group, C 3-7 Cycloalkyl or 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 Each independently represents hydroxyl, halogen, amino, C 1-6 Alkyl or C substituted by one or more deuterium 1-6 alkyl; R 5 is hydrogen, hydroxy, halogen, amino, cyano or C 1-6 alkyl; R 6 is oxo (=O); Each R 7 are independently hydrogen, C 1-6 Alkyl or one or more R 7b Substituted C 1-6 Alkyl, or two R 7 Together with the nitrogen atom to which it is connected, it forms a 3-7 membered heterocyclic group or is replaced by one or more R 7a a substituted 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 are independently hydrogen or C 1-6 alkyl; Ring D is a 3-7 membered heterocyclic group; R 10 C 1-6 alkyl; R 11 C 1-6 alkyl; The 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by a substituent are each independently "heteroatom species only"; A 3-7 membered heterocyclic group independently selected from N, O and S, with 1, 2 or 3 heteroatoms.

10. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: It meets one or more of the following conditions: (1) Ring A is (2) Each R 1 are independently halogen, cyano, C 1-6 Alkyl or one or more R 1a Substituted C 1-6 Alkyl, when there are multiple substituents, they may be the same or different; for example: R 1 is F, Cl, -CHF2, -CF3, cyano, -CH3 or -CF2CH3, preferably F, -CHF2, -CH3 or cyano; (3)R 2 is hydrogen; (4)R 5 is hydrogen or C 1-6 Alkyl groups, such as R 5 is hydrogen or methyl; (5) X is a linking bond, -O-, -(C1-C4 alkylene)-, -O-(C1-C4 alkylene)-, -(C2-C4 alkenylene)-, or -(C2-C6 alkynylene)-, where "C1-C4 alkylene" in "-O-(C1-C4 alkylene)-" is identical to R 4 connected; for example: connecting key, Another example: connection key, Among them, the f end and R 4 connected; (6) When ring D is a 3-7 membered heterocyclic group, ring D is a 1,2-dihydropyridyl group, for example "c" indicates that the atom is located in the meta position relative to the N atom of the B ring; (7) When R 3 C 3-7 Cycloalkyl or one or more R 3d Substituted C 3-7 When cycloalkyl, the R 3 for (8) When R 3 is a 3-7 membered heterocyclic group or is replaced by one or more R 3e When the 3-7 membered heterocyclic group is substituted, the R 3 for Also for For example For example For example Preferred (9)R 4 is hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH2, -NHCH3, -N(CH3)2, -N(CD3)2, -N(CH2CH3)2, and hydrogen, methyl, methoxy, cyano, halogen, hydroxyl, -NH2, -NHCH3, -N(CH3)2, (10)R 10 is methyl; (11)R 11 is methyl; (12) When R 4 When it is cyano, for Preferably, the fused ring compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof meet one or more of the following conditions: (1A) for It can also be It can also be For example For example (1B) for Also for For example For example For example Preferred (1C) for "c" indicates that the atom is located in the meta position relative to the N atom of the B ring; (1D) is methyl, methoxy, cyano, halogen, It can also be hydrogen, methyl, methoxy, cyano, halogen, For example, methyl, cyano, Preferred Also preferred More preferably, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof meet the following conditions: for For example: Specifically, the fused ring compound as shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof are 11. The fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to 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:

12. A method for preparing the fused ring compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized in that: in, when for When "c" represents that the atom is located at the meta position relative to the nitrogen atom of the B ring, the preparation method comprises the following steps: reacting the intermediate I-A1 with the raw material N-phenylbis(trifluoromethanesulfonyl)imide or trifluoromethanesulfonic anhydride to obtain the intermediate I-A2; then coupling reaction of I-A2 with the raw material I-A3 to obtain the intermediate I-A4; and then substitution reaction or palladium-catalyzed Buchwald coupling reaction of I-A4 with the raw material I-A5 to obtain the compound of the general formula IA; If I-A4 and I-A5 undergo a substitution reaction, it is carried out in the presence of a base, wherein the base is cesium carbonate, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine; If I-A4 and I-A5 undergo a Buchwald coupling reaction, it is carried out in the presence of a catalyst and a base. 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. Among them: Ring A, m, X, L, R 1 、R 2 、R 3 、R 4 、R 5 、R 10 and R 11 The definition as set forth in any one of claims 1 to 11; RG is hydrogen, -B(OH)2, -ZnBr or -ZnI.

13. A compound of formula I-A1 or formula I-A2, characterized in that: Where: L, R 2 、R 3 、R 5 and R 10 The definition as described in any one of claims 1 to 11.

14. The compound according to claim 13, wherein: (1) The compound represented by formula I-A1 is any one of the following compounds: (2) The compound represented by formula I-A2 is any one of the following compounds:

15. Any of the following compounds:

16. A pharmaceutical composition, characterized in that It includes: (1) a substance Q, wherein the substance Q is a fused ring compound represented by formula I according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

17. Use of a substance Q or the pharmaceutical composition according to claim 16 in the preparation of an SOS1 inhibitor, characterized in that: The substance Q is a fused ring compound represented by formula I according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

18. Use of a substance Q or the pharmaceutical composition according to claim 16 in preparing a drug; characterized in that: The substance Q is a fused ring compound as shown in Formula I according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; the drug may be a drug for treating and / or preventing diseases related to SOS1 activity or expression; 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, skin granular cell tumor, liver cancer, rectal cancer, bladder cancer, pharyngeal 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, urinary tract cancer, Epithelial cancers, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, polyeosinophilic syndrome, and multiple myeloma, as well as diseases associated with inherited mutations in SOS1, such as neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Kristen Stewart syndrome, Regis syndrome, and hereditary gingival fibromatosis type 1.

19. Use of a substance Q or the pharmaceutical composition according to claim 16 in preparing a drug; characterized in that: The substance Q is a fused ring compound as shown in formula I according to 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 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, granular cell tumor of the skin, liver cancer, rectal cancer, bladder cancer, laryngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer 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, polycythemia vera syndrome and multiple myeloma, as well as neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentiginous features, capillary malformation-arteriovenous malformation syndrome, cardiofacial-cutaneous syndrome, Kristen Stewart syndrome, Regis syndrome and hereditary gingival fibroma type 1.

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