A condensed ring compound, a method for preparing the same, and use thereof

Abstract

The application discloses a fused ring compound, a preparation method thereof and application thereof. The application provides a fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate of the fused ring compound or the solvate of the pharmaceutically acceptable salt thereof. The fused ring compound as shown in formula I of the application has good inhibitory activity on SOS1; is expected to treat and / or prevent diseases related to SOS1 activity or expression amount; (I).

Description

[0001] This application claims priority to Chinese patent application 2021111465322, filed on September 28, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a fused-ring compound, its preparation method, and its applications. Background Technology

[0003] RAS protein is a 21 kDa guanine trinucleotide phosphate (GTP)-binding protein located on the cell membrane, composed of 188 or 189 amino acids. The activity of RAS protein is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When bound to GDP, it is in an "inactive" state; when bound to GTP, it is in an "activated" state. RAS protein itself has relatively weak GTPase hydrolytic function and a slow nucleotide exchange rate. Binding to GTPase activating proteins (GAPs) can enhance the GTP hydrolytic function of RAS protein, while guanine nucleotide exchange factors (GEFs) can catalyze the exchange of nucleotides (GTP to GDP). SOS1 (Son of Sevenless 1) is a RAS-specific GEF. Binding of SOS1 to RAS promotes the release of GDP from RAS, which then binds to GTP, thereby activating RAS. Once activated, the RAS can activate multiple downstream signaling pathways, including the MAPK and PI3K signaling pathways, which play important roles in promoting cell differentiation, proliferation, and survival. RAS mutations are a genetic driver of many cancers, present in 20%-30% of human tumors, such as lung cancer, colorectal cancer, and pancreatic cancer.

[0004] The RAS gene family includes KRAS, NRAS, and HRAS. KRAS mutations are present in various tumors, such as lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%). G12 mutations at codon 12 are the most common KRAS mutations; for example, in KRAS-mutant 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 mainly occur in melanoma, leukemia, and thyroid cancer. Furthermore, abnormal activation of RAS proteins (such as gene mutations, amplification, and overexpression) is closely related to resistance to some antitumor drugs, such as EGFR monoclonal antibodies and EGFR small molecule inhibitors. Therefore, RAS-related signaling pathways have become important antitumor targets.

[0005] SOS1 is the main guanine nucleotide exchanger in the RAS family involved in cancer-related signaling pathways. Reducing SOS1 expression can significantly inhibit the proliferation and survival of KRAS-mutant cancer cells. Since SOS1 is a common node in multiple RAS signaling pathways, and almost all growth factor receptors initiate RAS signaling through SOS1, SOS1 inhibitors have the potential to become broad-spectrum anticancer drugs. The signaling pathways activated by SOS1 also play important roles in other types of cancer with different 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 T-cell receptors, B-cell receptors, and monocyte colony-stimulating factor receptors. The localization of SOS1 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 is also associated with the pathogenesis of various human cancers and other diseases. In addition, SOS1 mutations have been found in lung adenocarcinoma, embryonal rhabdomyosarcoma, and cutaneous granulosa cell tumors, while SOS1 overexpression has been found in bladder and prostate cancer. Besides cancer, hereditary SOS1 mutations are also associated with the pathogenesis of RAS disorders, including Noonan syndrome, cardiofacial-skin syndrome, and hereditary gingival fibroma type 1.

[0006] Currently, no SOS1 inhibitors have been approved for marketing, therefore, there is a need to develop new SOS1 inhibitors with good efficacy to meet clinical needs. Summary of the Invention

[0007] The technical problem this invention aims to solve is the deficiency of existing SOS1 inhibitors, such as their simple structures. This invention provides a fused-ring compound, its preparation method, and its applications. This type of compound exhibits good inhibitory activity against SOS1.

[0008] The present invention provides a fused ring compound as shown in Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts;

[0009]

[0010] in:

[0011] X and Y are independently -O-, -S-, -NH- or -CH2-;

[0012] Z is -CR 10 Or N;

[0013] L represents a single bond, -C(=O)-, -C(=O)O-, -C(=O)NR 8 -、-NR 8 -、-S-、-O-、-S(O)-、-S(O)2- or -(CH2) p -;

[0014] Ring A is C 6-12 Aryl, 5-10 heteroaryl, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic groups;

[0015] Each R 1 Independently deuterium, hydroxyl group, 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 group, with one or more R 1a Replacement C 1-6 Alkyl, with one or more R 1b Replacement C 1-6 Alkyl-O-, with one or more R 1c Replacement C 2-6 alkenyl, with one or more R 1d Replacement C 2-6 alkynyl group, C 3-7 cycloalkyl, with one or more R 1e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 1f Substituted 3-7 membered heterocyclic groups, C 6-12 aryl, with one or more R 1g Replacement C 6-12 aryl, 5-10 heteroaryl, with one or more R 1h Substituted 5-10 heteroaryl groups, C 3-7 Cycloalkenyl, with one or more R 1i Replacement 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(R7 )2、-S(O)-N(R 7 )2、-S(O)-R 9 -NR 8 -S(O)-R 9 -NR 8 -S(O)-N(R 7 )2、-C(=O)-R 9 -NR 8 C(=O)-R 9 or -NR 8 C(=O)-OR 9 , or two R 1 Together with the attached ring atoms, they form C 3-7 cycloalkyl, with one or more R 1e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 1f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 1i Replacement C 3-7 Cycloalkenyl;

[0016] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each is 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 group, with one or more R 1-a Replacement C 1-6 Alkyl, with one or more R 1-b Replacement C 1-6 Alkyl-O-, with one or more R 1-c Replacement C 2-6 alkenyl, with one or more R 1-d Replacement C 2-6 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkyl-O-, 3-7 membered heterocyclic, 3-7 membered heterocyclic-O-, with one or more R 1-e Replacement C 3-7 cycloalkyl or C 3-7Cycloalkyl-O-, with one or more R 1-f Substituted 3-7 membered heterocyclic groups or 3-7 membered heterocyclic groups -O-, C 6-12 aryl, with one or more R 1-g Replacement C 6-12 aryl, 5-10 heteroaryl, with one or more R 1-h Substituted 5-10 heteroaryl groups, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl-O-, with one or more R 1-i Replacement C 3-7 Cycloalkenyl or 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 ;

[0017] 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 Each is 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 group, C 3-7 cycloalkyl, C 3-7Cycloalkenyl or 3-7 membered heterocyclic groups;

[0018] Ring D is C 6-12 Aryl, 5-6 quinone heteroaryl, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic groups;

[0019] R 2 The following are not present: 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 group, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic groups;

[0020] R 3 For hydrogen, deuterium, C 1-6 Alkyl, with one or more R 3a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 3b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 3c Replacement C 2-6 alkynyl group, C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 6-12 aryl, with one or more R 3f Replacement C 6-12 aryl, 5-10 heteroaryl, with one or more R 3g Substituted 5-10 heteroaryl groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl;

[0021] Each R 3a R 3b R 3c R 3d R 3e R 3f R 3g and R 3h Each is independently deuterium, hydroxyl, halogen, -N(R) 7 2. Cyano, Nitro, C 1-6 Alkyl, with one or more R 3-a Replacement C1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 3-c Replacement C 2-6 alkenyl, with one or more R 3-d Replacement C 2-6 alkynyl group, C 3-7 cycloalkyl, with one or more R 3-e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3-f Substituted 3-7 membered heterocyclic groups, C 6-12 aryl, with one or more R 3-g Replacement C 6-12 aryl, 5-10 heteroaryl, with one or more R 3-h Substituted 5-10 heteroaryl groups, C 3-7 Cycloalkenyl, with one or more R 3-i Replacement C 3-7 Cycloalkenyl, -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 Rs 3e Two Rs 3f Two Rs 3g Or two Rs 3h Together with the attached ring atoms, they form C 3-7cycloalkyl, with one or more R 3-e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3-f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3-i Replacement C 3-7 Cycloalkenyl;

[0022] 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 and R 3-i Each is 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 groups, -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 ;

[0023] Each R 4 Independently deuterium, hydroxyl group, halogen, -N(R) 7 2. Cyano, Oxide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-4 Alkylene-N(R) 7 2. By one or more R 4a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 4b Replacement C1-6 Alkyl-O-, C 3-7 cycloalkyl, with one or more R 4c Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 4d Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 4e Replacement C 3-7 Cycloalkenyl, or two R 4 Together with the atoms they are attached to, they form C. 3-7 cycloalkyl, with one or more R 4c Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 4d Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 4e Replacement C 3-7 Cycloalkenyl;

[0024] (R 4 Can be connected to the ring Any valence is allowed on ring atoms, for example, attached to ring atoms. (on the X, Y, or any methylene group);

[0025] Each R 4a R 4b R 4c and R 4d Each is independently a deuterium, hydroxyl, halogen, amino, cyano, or C group. 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl or C 2-6 alkynyl group;

[0026] R 5 The following are not present: oxidized, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, C 1-6 Alkyl, with one or more R 5a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, with one or more R 5b Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 5c Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 5d Replacement C 3-7 Cycloalkenyl;

[0027] Each R 5a R 5b and R 5c Each independently constitutes deuterium and C. 1-6 Alkyl, hydroxyl, halogen, amino, or cyano groups;

[0028] R 6 It can be hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo, or C. 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 The alkynyl group may not be present;

[0029] Each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Cycloalkenyl, or two R 7 Together with the attached nitrogen atom, it forms a 3-7 membered heterocyclic group or is surrounded by one or more R atoms. 7a Substituted 3-7 membered heterocyclic groups;

[0030] Each R 7a Independent of deuterium and C 1-6 Alkyl, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl-O-, C 2-6 alkenyl or C 2-6 alkynyl group;

[0031] Each R 8 and R 9 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic groups;

[0032] R 10 It can be hydrogen, deuterium, hydroxyl, halogen, amino, cyano, or C. 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl or 3-7 membered heterocyclic groups;

[0033] R 11 It is hydrogen, deuterium, cyano, C 1-6 Alkyl or with one or more R 11a Replacement C 1-6 alkyl;

[0034] Each R 11aIndependently, it can be deuterium, halogen, or hydroxyl;

[0035] m can be 0, 1, 2, 3, 4, or 5;

[0036] n is 0, 1, 2, 3, 4, 5, or 6;

[0037] p is 1, 2, 3, 4, 5 or 6;

[0038] The 3-7 membered heterocyclic groups are each independently selected from N, O, and S as the type of heteroatom, and are 3-7 membered heterocyclic groups with 1, 2, or 3 heteroatoms (the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group -O-, a 3-7 membered heterocyclic group substituted with a substituent, and a 3-7 membered heterocyclic group -O- substituted with a substituent; that is, the "ring A, 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 , ring D, 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 4 R 5 R 8 R 9 and R 10 The 3-7 membered heterocyclic group substituted by the substituent in the middle; the 3-7 membered heterocyclic group; two R 1The ring atoms connected to it form a ring with one or more R atoms. 1f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 3d Two Rs 3e Two Rs 3f Two Rs 3g Or two Rs 3h The ring atoms connected to it form a ring with one or more R atoms. 3-f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 4 The atoms connected together form a group of one or more R 4d The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 7 The nitrogen atom attached to it forms a structure with one or more R atoms. 7a The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i In which one or more R 1-f The 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group-O- is replaced by the 3-7-membered heterocyclic group in the 3-7-membered heterocyclic group-O-);

[0039] The 5-10 membered heteroaryl groups are each independently selected from N, O, and S as heteroatoms, and the number of heteroatoms is 1, 2, or 3 (the 5-10 membered heteroaryl group includes both 5-10 membered heteroaryl groups and 5-10 membered heteroaryl groups substituted by substituents; that is, the "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"5-10 heteroaryl groups substituted by substituents in the 5-10 heteroaryl group (5-10 heteroaryl group);

[0040] The 5-6 membered heteroaryl group is a 5-6 membered heteroaryl group whose heteroatom species are independently selected from N, O and S, and whose number of heteroatoms is 1, 2 or 3;

[0041] When the carbon atom of * is chiral, the fused ring compound shown in Formula I is: Or a mixture thereof.

[0042] In one embodiment, certain groups in the fused-ring compound represented by Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment"): X and Y are each independently -O-, -NH-, or -CH2-; for example, X and Y are each independently -O- or -CH2-.

[0043] In a certain scheme, Z is N.

[0044] In one scheme, L represents a single bond.

[0045] In one possible solution, ring A is C. 6-12 Aryl or 5-10 membered heteroaryl; for example, ring A is C. 6-12 Aryl.

[0046] In a certain scheme, each R 1 Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 1a Replacement C 1-6 Alkyl, with one or more R 1b Replacement C 1-6 Alkyl-O-, or two R 1 Together with the attached ring atoms, they form C 3-7 cycloalkyl, with one or more R 1e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 1f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 1i Replacement C 3-7 Cycloalkenyl; for example, each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C1-6 alkyl.

[0047] In a certain scheme, each R 1a R 1b R 1e R 1f and R 1i Each is independently a hydroxyl group, halogen, or -N(R) 7 2. C 1-6 Alkyl or with one or more R 1-a Replacement C 1-6 Alkyl groups; for example, each R 1a It is a halogen on its own.

[0048] In a certain scheme, each R 1-a Independently for C 1-6 Alkyl or halogen.

[0049] In one scheme, ring D is a 3-7 membered heterocyclic group; for example, ring D is a six-membered heterocyclic group with N as the type of heteroatom and one or two heteroatoms, another example is 1,2-dihydropyridyl, and yet another example is... “c” indicates that the atom is located at the meta position of the Z atom in the B ring.

[0050] In one particular scheme, R 2 It is hydrogen.

[0051] In one particular scheme, R 3 For hydrogen, C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl; for example, R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups.

[0052] In a certain scheme, each R 3d R 3e and R 3h Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Cyano group, C 1-6 Alkyl, with one or more R 3-a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkenyl, C2-6 alkynyl group, with one or more R 3-c Replacement C 2-6 alkenyl, with one or more R 3-d Replacement C 2-6 Alkyne group, -C(=O)-R 9 -NR 8 C(=O)-R 9 , or two R 3d Two Rs 3e Or two Rs 3h Together with the attached ring atoms, they form C 3-7 cycloalkyl, with one or more R 3-e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3-f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3-i Replacement C 3-7 Cycloalkenyl; for example, each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 Alkyne group or -C(=O)-R 9 For example, each R 3e Independently hydroxyl, C 1-6 Alkyl-O- or -C(=O)-R 9 .

[0053] In a certain scheme, each R 3-a R 3-b R 3-c R 3-d R 3-e R 3-f and R 3-i Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Nitro, Cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-; for example, each R 3-b It can be hydroxyl or halogen independently.

[0054] In a certain scheme, each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 2. By one or more R 4a Replacement C 1-6Alkyl, 3-7 membered heterocyclic group or with one or more R 4d Substituted 3-7 membered heterocyclic groups; for example, each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups.

[0055] In a certain scheme, each R 4a and R 4d Each independently is C 1-6 Alkyl or halogen; for example, each R 4d Independently for C 1-6 Alkyl or halogen.

[0056] In one particular scheme, R 5 It is hydrogen or C 1-6 alkyl.

[0057] In one particular scheme, R 6 It is oxygenated.

[0058] In a certain scheme, each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Cycloalkenyl; or two R 7 Together with the attached nitrogen atom, it forms a 3-7 membered heterocyclic group or is surrounded by one or more R atoms. 7a Substituted 3-7 membered heterocyclic groups; for example, each R 7 Independent hydrogen or C 1-6 alkyl.

[0059] In a certain scheme, each R 7a Independently for C 1-6 Alkyl or halogen.

[0060] In a certain scheme, each R 8 and R 9 Each is independently hydrogen or C 1-6 Alkyl groups; for example, each R 9 Independently hydrogen or C 1-6 alkyl.

[0061] In one particular scheme, R 11 C 1-6 alkyl.

[0062] In a given scheme, m can be 0, 1, 2, or 3; for example, m can be 1, 2, or 3.

[0063] In a given scheme, n is 0, 1, 2, or 3; for example, n is 0, 1, or 2.

[0064] In a given scheme, p is 1, 2, or 3.

[0065] In one embodiment, the 3-7 membered heterocyclic groups are each independently selected from N, O, and S as the type of heteroatom, and the number of heteroatoms is 1, 2, or 3 (the 3-7 membered heterocyclic group includes both 3-7 membered heterocyclic groups and 3-7 membered heterocyclic groups substituted by substituents). That is, the R... 3 and R 4 The 3-7 membered heterocyclic group substituted by the substituent in the ring D; the 3-7 membered heterocyclic group in the ring D; the two R groups. 1 The ring atoms connected to it form a ring with one or more R atoms. 1f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 3d Two Rs 3e Or two Rs 3h The ring atoms connected to it form a ring with one or more R atoms. 3-f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 7 The nitrogen atom attached to it forms a structure with one or more R atoms. 7a The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group (3-7 membered heterocyclic group).

[0066] In one embodiment, the 5-10 heteroaryl group is a 5-10 heteroaryl group whose heteroatom species are independently selected from N, O, and S, and whose number of heteroatoms is 1, 2, or 3.

[0067] In one embodiment, in the fused-ring compound represented by Formula I,

[0068] X and Y are independently -O-, -NH-, or -CH2-;

[0069] Z is N;

[0070] L represents a single bond;

[0071] Ring A is C 6-12 Aryl or 5-10 heteroaryl groups;

[0072] Each R 1 Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 1a Replacement C 1-6 Alkyl, with one or more R 1b Replacement C 1-6Alkyl-O-, or, two Rs 1 Together with the attached ring atoms, they form C 3-7 cycloalkyl, with one or more R 1e Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 1f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 1i Replacement C 3-7 Cycloalkenyl;

[0073] Each R 1a R 1b R 1e R 1f and R 1i Each is independently a hydroxyl group, halogen, or -N(R) 7 2. C 1-6 Alkyl or with one or more R 1-a Replacement C 1-6 alkyl;

[0074] Each R 1-a Independently for C 1-6 Alkyl or halogen;

[0075] Ring D is a 3-7 membered heterocyclic group;

[0076] R 2 It is hydrogen;

[0077] R 3 For hydrogen, C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl;

[0078] Each R 3d R 3e and R 3h Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Cyano group, C 1-6 Alkyl, with one or more R 3-a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R3-c Replacement C 2-6 alkenyl, with one or more R 3-d Replacement C 2-6 Alkyne group, -C(=O)-R 9 -NR 8 C(=O)-R 9 , or two R 3d Two Rs 3e Or two Rs 3h Together with the attached ring atoms, they form C 3-7 cycloalkyl, with one or more R 3-e Replacement C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or with one or more R 3-f Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3-i Replacement C 3-7 Cycloalkenyl;

[0079] Each R 3-a R 3-b R 3-c R 3-d R 3-e R 3-f and R 3-i Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Nitro, Cyano, C 1-6 Alkyl or C 1-6 Alkyl-O-;

[0080] Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 2. By one or more R 4a Replacement C 1-6 Alkyl, 3-7 membered heterocyclic group or with one or more R 4d Substituted 3-7 membered heterocyclic groups;

[0081] Each R 4a and R 4d Each independently is C 1-6 Alkyl or halogen;

[0082] R 5 It is hydrogen or C 1-6 alkyl;

[0083] R 6 For oxygenation;

[0084] Each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-7cycloalkyl or C 3-7 Cycloalkenyl; or two R 7 Together with the attached nitrogen atom, it forms a 3-7 membered heterocyclic group or is surrounded by one or more R atoms. 7a Substituted 3-7 membered heterocyclic groups;

[0085] Each R 7a Independently C 1-6 Alkyl or halogen;

[0086] Each R 8 and R 9 Each is independently hydrogen or C 1-6 alkyl;

[0087] R 11 C 1-6 alkyl;

[0088] m can be 0, 1, 2, or 3;

[0089] n is 0, 1, 2, or 3;

[0090] p is 1, 2, or 3;

[0091] The 3-7 membered heterocyclic groups are each independently selected from N, O, and S as the type of heteroatom, and are 3-7 membered heterocyclic groups with 1, 2, or 3 heteroatoms (the 3-7 membered heterocyclic group includes both 3-7 membered heterocyclic groups and 3-7 membered heterocyclic groups substituted by substituents). That is, the R... 3 and R 4 The 3-7 membered heterocyclic group substituted by the substituent in the ring D; the 3-7 membered heterocyclic group in the ring D; the two R groups. 1 The ring atoms connected to it form a ring with one or more R atoms. 1f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 3d Two Rs 3e Or two Rs 3h The ring atoms connected to it form a ring with one or more R atoms. 3-f The 3-7 membered heterocyclic group in the substituted 3-7 membered heterocyclic group; two R 7 The nitrogen atom attached to it forms a structure with one or more R atoms. 7a The 3-7 membered heterocyclic group that is replaced in the 3-7 membered heterocyclic group (3-7 membered heterocyclic group);

[0092] The 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group whose heteroatom types are independently selected from N, O and S, and whose number of heteroatoms is 1, 2 or 3.

[0093] In one embodiment, in the fused-ring compound represented by Formula I,

[0094] X and Y are each independently -O-;

[0095] Each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0096] Each R 1a Halogens are independent of each other;

[0097] Ring A is C 6-12 Aryl;

[0098] for

[0099] L represents a single bond;

[0100] R 2 It is hydrogen;

[0101] R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups;

[0102] Each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkyne group or -C(=O)-R 9 ;

[0103] R 5 It is hydrogen or C 1-6 alkyl;

[0104] Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups;

[0105] Each R 4d Independently for C 1-6 Alkyl or halogen;

[0106] Each R 7 Independent hydrogen or C 1-6 alkyl;

[0107] Each R 9 Independently hydrogen or C 1-6 alkyl;

[0108] R 11 C 1-6 alkyl;

[0109] m is 1, 2, or 3;

[0110] n is 0, 1, or 2.

[0111] In one embodiment, in the fused-ring compound represented by Formula I,

[0112] X and Y are each independently -O- or -CH2-;

[0113] Each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0114] Each R 1a Halogens are independent of each other;

[0115] Ring A is C 6-12 Aryl;

[0116] Ring D is a six-membered heterocyclic group with N as the type of heteroatom and one or two heteroatoms, such as 1,2-dihydropyridyl, or more specifically... “c” indicates that the atom is located at the meta position of atom Z in ring B; Z is N;

[0117] L represents a single bond;

[0118] R 2 It is hydrogen;

[0119] R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups;

[0120] Each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 Alkyne group or -C(=O)-R 9 ;

[0121] Each R 3-b Independently hydroxyl or halogen;

[0122] R 5 It is hydrogen or C 1-6 alkyl;

[0123] R6 For oxygenation;

[0124] Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups;

[0125] Each R 4d Independently for C 1-6 Alkyl or halogen;

[0126] Each R 7 Independent hydrogen or C 1-6 alkyl;

[0127] Each R 9 Independently hydrogen or C 1-6 alkyl;

[0128] R 11 C 1-6 alkyl;

[0129] m is 1, 2, or 3;

[0130] n is 0, 1, or 2.

[0131] In one embodiment, in the fused-ring compound represented by Formula I,

[0132] for

[0133] for

[0134] L represents a single bond;

[0135] R 3 for

[0136] R 11 It is a methyl group.

[0137] In one embodiment, in the fused-ring compound represented by Formula I,

[0138] for

[0139] for

[0140] L represents a single bond;

[0141] R3 for

[0142] R 11 It is a methyl group.

[0143] In a certain scheme, when ring A is C 6-12 When aryl, the C 6-12 The aryl group is phenyl or naphthyl, for example, phenyl.

[0144] In one embodiment, when ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group with N heteroatom type and one or two heteroatoms, for example...

[0145] In a certain scheme, when R 1 For one or more R 1a Replacement C 1-6 When alkyl, the substance is subjected to one or more R 1a Replacement C 1-6 The alkyl group is -CHF2, -CF3, -CF2CH3, -CF2CH2OH or -CF2C(CH3)2OH.

[0146] In a certain scheme, when two R 1 Together with the attached ring atoms, they form C 3-7 Cycloalkenyl or with one or more R 1i Replacement C 3-7 When cycloalkenyl, the C 3-7 The cycloalkenyl group can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, for example, cyclopentenyl.

[0147] In a certain scheme, when two R 1 Together with the attached ring atom, it forms a 3-7 membered heterocyclic group or is bound by one or more R atoms. 1f When a 3-7 membered heterocyclic group is substituted, the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group in which the heteroatoms are independently selected from O, N, and S, and the number of heteroatoms is 1 or 2, for example, “a” indicates that this part is connected to ring A in parallel.

[0148] In one embodiment, when ring D is a 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group is a six-membered heterocyclic group with N as the type of heteroatom and one or two heteroatoms, for example, 1,2-dihydropyridyl, and another example is... “c” indicates that the atom is located at the meta position of the Z atom in the B ring.

[0149] In a certain scheme, when R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3eWhen a 3-7 membered heterocyclic group is substituted, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group whose heteroatom species are independently selected from N and O, and whose number of heteroatoms is 1 or 2, for example,

[0150] In a certain scheme, when R 3 C 3-7 cycloalkyl or with one or more R 3d Replacement C 3-7 When cycloalkyl, the C 3-7 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or...

[0151] In a certain scheme, when each R 3d and R 3e C independently 2-6 When alkynyl group is used, the C 2-6 The alkynyl group is either ethynyl or propynyl.

[0152] In a certain scheme, when R 4 -C 1-4 Alkylene-N(R) 7 At time 2, the two Rs 7 Together with the attached nitrogen atom, it forms a 3-7 membered heterocyclic group or is surrounded by one or more R atoms. 7a When the 3-7 membered heterocyclic group is substituted, for example, the -C 1-4 Alkylene-N(R) 7 )2 is

[0153] In a certain scheme, when R 4 -C 1-4 Alkylene-N(R) 7 When )2, the R 7 Independently for C 1-6 Alkyl groups; for example, the -C 1-4 Alkylene-N(R) 7 )2 is

[0154] In a certain scheme, when R 4 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 4d The substituted 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group in which the heteroatom type is N and the number of heteroatoms is 1 or 2, for example,

[0155] In one scheme, two R 7 Together with the attached nitrogen atom, it forms a 3-7 membered heterocyclic group or is surrounded by one or more R atoms. 7aWhen replacing a 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group in which the heteroatom type is N and the number of heteroatoms is 1 or 2, for example,

[0156] In a certain scheme, when R 1 R 1a R 1b R 1e R 1f R 1i R 1-a R 3d R 3e R 3h R 3-a R 3-b R 3-c R 3-d R 3-e R 3-f R 3-i R 4 R 4a R 4d R 5 R 7 R 7a R 8 R 9 Or R 11 C 1-6 Alkyl or substituent C 1-6 When alkyl, the C 1-6 Each alkyl group is independently C10. 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and again, methyl, ethyl, or isobutyl.

[0157] In a certain scheme, when R 1 R 1a R 1b R 1e R 1f R 1i R 1-a R 3d R 3e R 3h R 3-a R 3-b R 3-c R 3-d R 3-e R 3-f R 3-i R 4a R 4d Or R 7a When the halogen is halogen, each halogen is independently F, Cl, Br or I, for example F or Cl.

[0158] In a certain scheme, when R 1 R 3d R 3e R 3h R 3-a R 3-b R 3-c R 3-d R 3-e R 3-f Or R 3-i C 1-6 Alkyl-O- or C-substituted with a substituent 1-6 When alkyl-O-, the C 1-6 Alkyl groups -O- are each independently C 1-4 Alkyl-O-, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, further for example, methoxy, ethoxy or isopropoxy, and even further for example, methoxy or ethoxy.

[0159] In one possible solution, ring A is...

[0160] In one particular scheme, R 1 For F, Cl, -CN, -CHF2, -CF3, -CH3, -CF2CH2OH, -CF2CH3, -NH2 or -CF2C(CH3)2OH; or two Rs 1 Together with the attached ring atoms, they form “a” indicates that this part is connected to ring A in parallel.

[0161] In one of the solutions, for For example,

[0162] In one particular scheme, R 3 for For example,

[0163] In one particular scheme, R 3 for

[0164] In one of the solutions, for For example,

[0165] In one particular scheme, R 4-CH3,

[0166] In one of the solutions, for For example, The b-end is connected to the Z atom.

[0167] In one of the solutions, for For example,

[0168] In one of the solutions, for For example,

[0169] In one of the solutions, for For example,

[0170] In one of the solutions, for For example,

[0171] In one embodiment, the fused ring compound as shown in Formula I is or

[0172] In one particular scheme, R 11 It is a methyl group.

[0173] In one embodiment, the fused-ring compound represented by Formula I is selected from any of the following compounds:

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] The present invention also provides a method for preparing a fused-ring compound as shown in Formula I as described above, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts, comprising the following steps:

[0198] Option 1: When the fused ring compound shown in Formula I is compound Ia, compound Ia-6 and Compound Ia was obtained via a Buchwald-Hartwig coupling reaction;

[0199]

[0200] Option 2: When the fused-ring compound shown in Formula I is compound Ib, compound Ib-3 and... Compound Ib was obtained via a Buchwald-Hartwig coupling reaction;

[0201]

[0202] Preferably, in the preparation method, in Scheme 1 or Scheme 2, the Buchwald-Hartwig coupling reaction is carried out in the presence of a catalyst and a base; the catalyst is conventional in the art, such as RuPhos Pd G3 (methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)), BrettPhos Pd G3 (methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)), XPhos Pd G3 (methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)), XantPhos Pd G3 (methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphoxanthracene)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)), RuPhosPd G4 (methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)) and BrettPhos Pd G4 (one or more of methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)); the base is conventional in the art, for example, one or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

[0203] Preferably, in the preparation method, Scheme 1 further includes the following steps:

[0204]

[0205] The compound I-1 and R 5 -NH2 undergoes a substitution reaction to give compound Ia-1;

[0206] The compound Ia-1 was reacted with an iodination reagent (such as N-iodosuccinimide, I2) via an iodination reaction to obtain compound Ia-2;

[0207] The compound Ia-2 and Compound Ia-3 was obtained via Heck coupling reaction;

[0208] The compound Ia-3 under alkaline conditions under a cyclization reaction yielded compound Ia-4;

[0209] The compound Ia-4 was reacted with a brominating reagent via a bromination reaction to yield compound Ia-5;

[0210] The compound Ia-5 reacts with the corresponding substituted ketones, amines, and borate ester derivatives to give compound Ia-6;

[0211] Preferably, in the iodination reaction, the iodination reagent is conventional in the art, such as N-iodosuccinimide and / or I2.

[0212] Preferably, in the ring-closing reaction, the base is conventional in the art, such as one or more of sodium methanethiol, sodium methoxide, and sodium ethoxide;

[0213] Preferably, in the bromination reaction, the brominating agent is conventional in the art, such as N-bromosuccinimide and / or Br2.

[0214] Preferably, in the preparation method, the second embodiment further includes the following steps:

[0215]

[0216] Where R 12 It is methyl or ethyl;

[0217] The compound I-1 underwent an acylation reaction under the action of a strong base to give compound Ib-1;

[0218] Compound Ib-1 reacts with malonate and undergoes decarboxylation to give compound Ib-2;

[0219] Compound Ib-2 and H2N-LR 3 A ring-closing reaction occurs to give compound Ib-3;

[0220] Preferably, in the acylation reaction, the strong base is conventional in the art, for example, lithium diisopropylamino.

[0221] Preferably, the malonic ester is conventional in the art, such as methyl malonate or ethyl malonate.

[0222] This invention provides a pharmaceutical composition; the pharmaceutical composition comprises:

[0223] (1) Substance X, wherein substance X is a fused-ring compound as described above in Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts, and

[0224] (2) Pharmaceutically acceptable excipients.

[0225] This invention provides the use of substance X or a pharmaceutical composition as described above in the preparation of an SOS1 inhibitor, wherein substance X is a fused-ring compound as shown in Formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0226] In the aforementioned applications, preferably, the SOS1 inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the compound's effect in inhibiting SOS1.

[0227] This invention provides the use of substance X or a pharmaceutical composition as described above in the preparation of a medicament; said substance X is a fused-ring compound as described above, represented by Formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof; said medicament may be a medicament for treating and / or preventing diseases related to SOS1 activity or expression levels.

[0228] In the aforementioned applications, preferably, the diseases associated with SOS1 activity or expression levels 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, granulosa cell tumors of the skin, 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, and urinary tract cancer. Roadside skin cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic leukocytosis and multiple myeloma, as well as diseases associated with SOS1 hereditary mutations, including but not limited to neurofibromatosis type I, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, cardiofacial-skin syndrome, Kristilo syndrome, Regigigas syndrome and hereditary gingival fibroma type I.

[0229] This invention provides the use of substance X or a pharmaceutical composition as described above in the preparation of a medicament; said substance X is a fused-ring compound as described above, represented by Formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof; said medicament is a medicament for treating and / or preventing the following diseases; said 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, granular cell tumor of the skin, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, and anterior Prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic leukocytosis syndrome, and multiple myeloma, as well as neurofibroma type I, Noonan syndrome, Noonan syndrome with multiple freckles, capillary malformation-arteriovenous malformation syndrome, cardiofacial-skin syndrome, Kristilo syndrome, Regigigas syndrome, and hereditary gingival fibroma type I.

[0230] This invention provides a method for inhibiting SOS1, comprising administering to a patient (e.g., a human) a therapeutically effective amount of substance X or a pharmaceutical composition as described above;

[0231] The substance X is a fused-ring compound as described above in Formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0232] The present invention provides a method for treating and / or preventing disease, comprising administering to a patient (e.g., a human) a therapeutically effective amount of substance X or a pharmaceutical composition as described above;

[0233] The substance X is a fused-ring compound as shown in Formula I as described above, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0234] The disease in question is one related to SOS1 activity or expression levels.

[0235] In the methods for treating and / or preventing diseases, preferably, the diseases associated with SOS1 activity or expression 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, granulosa cell tumors of the skin, 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, and endometrial cancer. Membrane carcinoma, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic leukocytosis and multiple myeloma, as well as diseases associated with SOS1 hereditary mutations, including but not limited to neurofibromatosis type I, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, cardiofacial-skin syndrome, Kristilo syndrome, Regigigas syndrome and hereditary gingival fibroma type I.

[0236] Unless otherwise specified, the terms used in this invention have the following meanings:

[0237] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0238] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C70, C60, C60, C70, C60, C70, C60 1-10 C is preferred 1-6 C is preferred 1-4 Alkyl groups are straight-chain or branched alkyl groups. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, or n-hexyl.

[0239] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group; that is, one hydrogen atom in the alkyl group is replaced, as defined above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, etc.

[0240] The term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group having at least one double bond, consisting only of carbon and hydrogen atoms, and having a specified carbon atom (e.g., C). 2-10 C is preferred 2-6 C is preferred 2-4 It is connected to the rest of the molecule by single bonds, such as alkenyl groups including but not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl or n-hexenyl, etc.

[0241] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group having at least one triple bond, consisting only of carbon and hydrogen atoms, and having a specified carbon atom (e.g., C). 2-10 C is preferred 2-6 C is preferred 2-4 It is connected to the rest of the molecule through a single bond. For example, alkynyl groups include, but are not limited to, ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2,2-dimethylpropynyl, or n-hexynyl.

[0242] Term "C" 1-6 In alkyl-O-", C 1-6 The definition of alkyl groups is as described above.

[0243] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bridged rings, fused rings, or spirocyclic systems of bicyclic, tricyclic, or more rings) carbocyclic substituent, which may be connected to the rest of the molecule via a single bond through 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; the cycloalkyl group may be further substituted with oxo-substituents; for example, C 3-7 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or... wait.

[0244] The term "cycloalkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more cyclic bridged rings, fused rings, or spirocyclic systems) cyclic hydrocarbon group having at least one double bond (such as a carbon-carbon double bond), and which can be connected to the rest of the molecule via a single bond through 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; the cycloalkenyl group may be further substituted with oxo substituents; for example, C 3-7 Cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0245] The term "heterocyclic group" refers to a stable 3- to 20-membered (preferably 3-10-membered, more preferably 3-7-membered, most preferably 5-7-membered, and even more preferably 6-membered) saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring-bridged, fused-ring, or spirocyclic systems) heterocyclic hydrocarbon group composed of 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 heteroatoms or heteroatom groups selected from N, O, S, S(=O), and S(=O)2, wherein the heterocyclic group may be further substituted with oxo-substituents; preferably, it is a 3- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, such as azirropropyl, ethylene oxide, propylene oxide, thiocyclobutane, or tetrahydrothiophene. Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, piperidinyl, tetrahydropyranyl, piperazinyl, tetrahydropyridinyl, aziridine, pyrrolidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2H-pyranyl, oxazonyl, diazaonyl, thiazopyranyl, aziridine, heptyl, thiazolyl, dihydrofuranyl, imidazolinyl, imidazolinyl, thiazohexyl, triazinyl, dithiazohexyl, dithiazopentyl, dioxazohexyl, 2,6-diazaspiro[3.3]heptyl, 1,2-dihydropyridinyl, homopiperazinyl, thiomorpholinyl, thiaranyl, tetrahydrofuranyl, 4H-pyranyl or dihydropyrrolidinyl, for example,

[0246] The term "aryl" refers to an aromatic group consisting of a conjugated hydrocarbon ring system composed of carbon atoms that follows the 4n+2 rule, where each ring is 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 or naphthyl groups.

[0247] The term "heteroaryl" refers to a 5- to 20-membered (preferably 5- to 12-membered, more preferably 5- to 10-membered) conjugated cyclic group having 2 to 15 carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, heteroaryl groups can be monocyclic, bicyclic, tricyclic, or more cyclic systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the heteroaryl group is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. In one embodiment, the term "heteroaryl" refers to an aromatic group containing heteroatoms, each ring being aromatic; preferably, the heteroatoms are independently selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3, constituting a 5- to 10-membered or 5- to 6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, diazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzimidazolyl (e.g., ...). ), benzopyrazolyl, indolyl, furanyl, pyrroleyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isozolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purineyl, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazoyl, carbazoyl, phenanthridine, phenanthrolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazoyl, benzoisothiazoyl, benzothiophene, oxatriazolyl, cinolinyl, quinazolinyl, indoleyl, o-diaphenanthreneyl, isoxazolyl, phenoxazinyl, phenthiazinyl, benzoxazolyl or benzoisozolyl.

[0248] In the term “cycloalkyl-O-”, cycloalkyl is defined as described above.

[0249] In the term “cycloalkenyl-O-”, the definition of cycloalkenyl is as described above.

[0250] In the term "heterocyclic group -O-", the definition of heterocyclic group is as described above.

[0251] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site.

[0252] It should be understood that the singular form used in this invention, such as "a," includes plural references unless otherwise specified.

[0253] The term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0254] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0255] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used in chemical synthesis and chemical analysis.

[0256] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0257] Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this application is appropriate. "" means that the corresponding group R is connected to other fragments or groups in the compound through this site.

[0258] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0259] As used herein, the fused-ring compound of Formula I 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. This 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 of Formula I contains more than one chiral center, diastereomers may exist. This 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 primarily include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and trans-isomers. The compounds can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic mixtures, and equal mixtures of trans-isomers. Examples include a single enantiomer, a single diastereomer or a mixture of several diastereomers, or a single trans-isomer or a mixture thereof. When the compounds of this invention contain an olefinic double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The trans-isomers of this invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation.

[0260] As previously stated, the present invention provides compounds with the structures shown above, or in the form of cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, tautomers, tautomers, or mixtures thereof, wherein “mixtures thereof” includes any form of mixing between any of the aforementioned stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, tautomers), tautomers, and / or mixtures (meso compounds, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of tautomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereomers, mixtures of cis-trans isomers and tautomers, mixtures of tautomers and diastereomers, etc.

[0261] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in two positions within a molecule.

[0262] The fused-ring compound of Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts are intended to cover any isotopically labeled (or “radiolabeled”) variant of the fused-ring compound of Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts. Such a variant may be obtained by replacing one or more atoms of the fused-ring compound of Formula I, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts with atoms whose atomic mass or mass number differs from that commonly found in nature. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competitive assays, 3 H or 14 C is often useful. For radiographic imaging applications, 11 C or 18 F is often useful.

[0263] Specific isotopic variants of the compounds of the present invention, particularly isotopic variants in which one or more radioactive isotopes have been incorporated, can be beneficial, for example, in investigating the mechanism of action or the distribution of the active component in vivo; due to their relatively easy preparability and detectability, they are labeled with 3 H or 14 Compounds containing carbon isotopes are particularly suitable for this purpose. Furthermore, the inclusion of isotopes such as deuterium can produce particular therapeutic benefits due to the improved metabolic stability of the compounds, for example, by extending the half-life in vivo or reducing the required effective dose; therefore, such modifications to the compounds of the present invention may also constitute preferred embodiments of the 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 operational examples, by using specific reagents and / or starting compounds modified with the corresponding isotopes.

[0264] In this application, "pharmaceutical composition" refers to a formulation comprising the compounds of the present invention and a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0265] In this application, "pharmaceutical acceptable" means a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing an adverse biological reaction or interacting with any component contained in the composition in an undesirable manner.

[0266] The term "pharmaceutical excipient" or "pharmaceuticalally acceptable carrier" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances contained in a pharmaceutical preparation, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition). Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition. They may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting the effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient may be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0267] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0268] When used as a pharmaceutical, the fused-ring compounds of Formula I, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts may be administered in any form of pharmaceutical composition. These compositions may be prepared according to methods well known in the pharmaceutical field and may be administered via various routes, depending on the need for local or systemic treatment and the area to be treated. Administration may be in the form of topical (including epidermal and transdermal, ocular and mucous membrane, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., inhalation or blowing in via powder or aerosol, including via nebulizer; intratracheal or intranasal), oral (solid and liquid formulations), or parenteral administration. Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral administration formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Topical pharmaceutical compositions and formulations may include transdermal patches, ointments, emulsions, creams, gels, drops, suppositories, sprays, liquids, and powders. 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) dosing. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, 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 via a continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc., may be necessary or required. Pharmaceutical compositions including those of the present invention may also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0269] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving 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 disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0270] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0271] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0272] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. 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.

[0273] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0274] 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 patient use) acid or base. When a 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, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a 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 acids include inorganic 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).

[0275] The term "solvate" refers to a substance formed by the crystallization of a compound with a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0276] The term "pharmaceuticalally acceptable salt solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol, etc.). The pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" mentioned above.

[0277] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0278] The reagents and raw materials used in this invention are all commercially available.

[0279] The positive and progressive effects of this invention are that the fused-ring compound of this invention, as shown in Formula I, has good inhibitory activity against SOS1; it is expected to treat and / or prevent diseases related to SOS1 activity or expression level. Detailed Implementation

[0280] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Reaction steps in the following embodiments that do not specify specific conditions can be performed according to conventional methods and conditions in the art, or according to the product specification.

[0281] The following embodiments illustrate the present invention in more detail, but are not intended to limit the scope of the invention.

[0282] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR 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 spectrometry (LC-MS) system with an electrospray ionization (ESI) source.

[0283] For silica column chromatography, the Biotage Selekt rapid preparative chromatograph and appropriate Biotage BK-SIL silica pre-packed columns or Agela Claricep Flash silica pre-packed columns were used.

[0284] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254, with a size of 0.15mm to 0.20mm. The size used for preparative thin-layer chromatography is 0.4mm to 0.5mm.

[0285] Preparative high-performance liquid chromatography (preparative HPLC) was performed using a Waters AutoPurification LC preparative system equipped with an ACQUITyQDa mass spectrometer detector. A SunFire C18 5μm 19x250mm OBD preparative column was used. Different gradients of water (containing 0.1% formic acid)-acetonitrile were used as the mobile phase to elute the compounds.

[0286] I. Examples of Compound Preparation of the Invention

[0287] Example 1 (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 1)

[0288]

[0289] Step 1: 4-Bromo-6-chloro-2-fluoropyridine-3-ol

[0290]

[0291] 6-Chloro-2-fluoropyridin-3-ol (80.0 g, 542 mmol) was dissolved in acetonitrile (800 mL), and N-bromosuccinimide (106.4 g, 596 mmol) was added. The mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated, diluted with water (600 mL), and extracted with ethyl acetate (2 L). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, a yellow oil (128 g, crude). ESI-MS m / z: 225.9, 227.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.34 (s, 1H), 7.73 (s, 1H).

[0292] Step 2: 4-Bromo-6-chloro-2-fluoro-3-((4-methoxybenzyl)oxy)pyridine

[0293]

[0294] 4-Bromo-6-chloro-2-fluoropyridin-3-ol (20 g, 88.3 mmol) was dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (36.6 g, 265 mmol) and 4-methoxybenzyl chloride (18.0 g, 115 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was slowly poured into water (400 mL) and filtered. The filter cake was slurried with anhydrous ethanol (100 mL) to give the product, a pale yellow solid (25.0 g, 83% yield). ESI-MS m / z: 346.0, 348.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.39 (d, J=8.6Hz, 2H), 6.94 (d, J=8.7Hz, 2H), 5.16-5.07 (m, 2H), 3.76 (s, 3H).

[0295] Step 3: 4-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-3-((4-methoxybenzyl)oxy)pyridine

[0296]

[0297] 4-Bromo-6-chloro-2-fluoro-3-((4-methoxybenzyl)oxy)pyridine (3.48 g, 10 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium hydride (600 mg, 13 mmol) was added at 0 °C, and the mixture was stirred for 10 minutes. Then, 2-((tert-butyldimethylsilyl)oxy)ethanol (3.52 g, 20 mmol) was added, and the mixture was reacted at 0 °C for 0.5 hours, followed by stirring at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction. ESI-MS m / z: 502.1, 504.1 [M+H] + .

[0298] Step 4: 4-Bromo-6-chloro-2-(2-hydroxyethoxy)pyridine-3-ol

[0299]

[0300] The crude 4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-3-((4-methoxybenzyl)oxy)pyridine obtained in step 3 was dissolved in 4.0 M hydrochloric acid-methanol solution (45 mL), and the mixture was stirred at room temperature for 30 minutes. The solution was then concentrated under reduced pressure. The residue was neutralized to neutral by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product, a white solid (5.1 g, crude). ESI-MS m / z: 268.0, 270.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ=10.07 (s, 1H), 7.27 (s, 1H), 4.29 (t, J=4.0Hz, 2H), 3.74 (t, J=4.0Hz, 2H).

[0301] Step 5: 8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine

[0302]

[0303] 4-Bromo-6-chloro-2-(2-hydroxyethoxy)pyridin-3-ol (5.1 g, 19 mmol) was dissolved in tetrahydrofuran (60 mL), and triphenylphosphine (6.0 g, 28 mmol) was added. Diisopropyl azodicarbonate (5.68 g, 28 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give the product as a white solid (3.68 g). ESI-MS m / z: 249.9, 251.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.14 (s, 1H), 4.47-4.45 (m, 2H), 4.36-4.34 (m, 2H).

[0304] Step 6: 6-Chloro-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine

[0305]

[0306] 1.75 g (7 mmol) of 8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine was dissolved in ethylene glycol dimethyl ether (20 mL), and 25 mL of aqueous methylamine solution was added. The mixture was heated to 100 °C and stirred for 4 hours. After cooling to room temperature, ethyl acetate was added, followed by washing with water and saturated sodium chloride, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product, which was directly used in the next reaction. ESI-MS m / z: 201.0 [M+H] + .

[0307] Step 7: 6-Chloro-7-iodo-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine

[0308]

[0309] The crude product of 6-chloro-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine obtained in step 6 (1.1 g) was dissolved in N,N-dimethylformamide (15 mL), and N-iodosuccinimide (1.48 g, 6.6 mmol) was added. The mixture was heated to 85 °C for 2 hours under argon protection. After cooling to room temperature, the reactants were diluted with ethyl acetate, washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a white solid (819 mg). ESI-MS m / z: 326.9, 328.9 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ4.36-4.34(m, 2H), 4.19-4.17(m, 2H), 3.30(s, 1H), 3.11(s, 3H).

[0310] Step 8: Ethyl 3-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-7-yl)acrylate

[0311]

[0312] 6-Chloro-7-iodo-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine (819 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (15 mL), and ethyl acrylate (376 mg, 3.76 mmol), triethylamine (380 mg, 3.76 mmol), palladium acetate (56 mg, 0.25 mmol), and tris(o-methylphenyl)phosphine (152 mg, 0.5 mmol) were added. The reaction mixture was heated to 100 °C for 2 hours under argon protection. After cooling to room temperature, the reactants were diluted with ethyl acetate, washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a white solid (406 mg). ESI-MS m / z: 299.1 [M+H] + .

[0313] Step 9: 6-Chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0314]

[0315] Ethyl 3-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-7-yl)acrylate (406 mg, 1.36 mmol) was dissolved in ethanol (8 mL), and sodium methanethiol (105 mg, 1.5 mmol) was added. The mixture was reacted at room temperature for 15 minutes. The solution was concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a white solid (200 mg). ESI-MS m / z: 253.0 [M+H] + .

[0316] Step 10: 8-Bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0317]

[0318] 6-Chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (1.29 g, 5.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N-bromosuccinimide (2.27 g, 12.7 mmol) was added. The mixture was heated to 70 °C and reacted for 2 hours. The solution was diluted with saturated sodium sulfite aqueous solution (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a white solid (2.03 g). ESI-MS m / z: 330.9, 332.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ=8.33 (s, 1H), 4.53-4.51 (m, 2H), 4.37-4.35 (m, 2H), 3.86 (s, 3H).

[0319] Step 11: 8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one

[0320]

[0321] 8-Bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one (390 mg, 1.18 mmol) was dissolved in tetrahydrofuran (20 mL), and 1-acetylpiperidin-4-one (664 mg, 4.71 mmol) was added. The reaction mixture was cooled to -40 °C, and samarium iodide (82 mL, 8.2 mmol, 0.1 M in THF) was slowly added. The reaction mixture was stirred at -40 °C for 2 hours. The mixture was diluted with saturated ammonium chloride aqueous solution (60 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give the product as a brown solid (239 mg). ESI-MS m / z: 394.1 [M+H] + .

[0322] Step 12: (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 1)

[0323]

[0324] 8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one (239 mg, 0.61 mmol) dissolved in toluene (8 mL), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (270 mg, 1.21 mmol, prepared according to the method described in patent WO2019122129A1), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Brettphos Pd G3 (55 mg, 0.06 mmol) and sodium tert-butoxide (175 mg, 1.82 mmol). The reaction was carried out under nitrogen protection and stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give compound 1, a white solid (209 mg). ESI-MS m / z: 547.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 7.64-7.61 (m, 1H), 7.47 (t, J=4.0Hz, 1H), 7.26 (t, J=4.0Hz , 1H), 7.23 (s, 1H), 5.48-5.44 (m, 1H), 4.32-4.30 (m, 2H), 4.12-4.11 (m, 2H), 3.75 (s, 3H), 3.72-3 .69(m, 1H), 3.51-3.43(m, 1H), 2.95-2.91(m, 1H), 2.45-2.36(m, 2H), 2.03(s, 3H), 1.64-1.61(m, 1H), 1.56-1.52 (m, 1H), 1.50 (d, J=4.8Hz, 3H), 1.40-1.37 (m, 1H), 1.34 (s, 1H), 1.30-1.25 (m, 1H). 13 C NMR (400MHz, DMSO-d6) δ168.30, 162.83, 150.47, 148.30, 148.24, 137.76, 129.82, 124.9 7, 118.35, 99.14, 65.41, 63.74, 42.40, 37.36, 35.41, 34.64, 32.01, 31.75, 22.12, 21.78.

[0325] Example 2 (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 2)

[0326]

[0327] Step 1: (S)-4-bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-((4-methoxybenzyl)oxy)pyridine

[0328]

[0329] Add sodium hydride (2.3 g, 57.8 mmol) and anhydrous N,N-dimethylformamide (100 mL) to a 500 mL three-necked flask. Cool to 0 °C, and slowly add (S)-glycerol acetal (5.7 g, 43.4 mmol) dissolved in 50 mL of anhydrous N,N-dimethylformamide solution. After the addition is complete, continue stirring at 0 °C for 1 hour. Then slowly add 4-bromo-6-chloro-2-fluoro-3-((4-methoxybenzyl)oxy)pyridine (10.0 g, 28.9 mmol) dissolved in 50 mL of anhydrous N,N-dimethylformamide solution. After the addition is complete, continue stirring the reaction mixture at 0 °C for 1 hour. Quench the reaction by adding 50 mL of saturated ammonium chloride aqueous solution. The reaction mixture was added to ethyl acetate (300 mL) and water (100 mL), extracted, and separated into layers. The organic phase was washed with water (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give the product as a white solid (12.8 g, 97% yield). ESI-MS m / z: 458.0, 460.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.39 (d, J=8.4Hz, 2H), 7.39 (s, 1H), 6.91 (d, J=8.4Hz, 2H), 5.03 (s, 2H), 4.46-4.52 (m, 1H), 4.39 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.33 (dd, J=5.6Hz, J=11.2Hz, 1H), 4.10 (dd, J=6.8Hz, J=8.4Hz, 1H), 3.85 (dd, J=6.0Hz, J=8.4Hz, 1H), 3.75 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H).

[0330] Step 2: (R)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol

[0331]

[0332] (S)-4-bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-((4-methoxybenzyl)oxy)pyridine (12.8 g, 27.9 mmol) was dissolved in methanol (30 mL). A 4.0 M hydrochloric acid-methanol solution (30 mL) was added at 0 °C, and the reaction was stirred at room temperature for 1 hour. Triethylamine was added at 0 °C to adjust the pH to neutral. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow solid (10.5 g, 90% yield). ESI-MS m / z: 418.0, 420.0 [M+1] + .

[0333] Step 3: (S)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol dimethylsulfonate

[0334]

[0335] (R)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol (10.5 g, 25.1 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (6.3 g, 62.6 mmol) and methanesulfonyl chloride (7.2 g, 62.6 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (14.4 g). The crude product was used directly in the next reaction. ESI-MS m / z: 574.0, 576.0 [M+1] + .

[0336] Step 4: (S)-3-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimethylsulfonate

[0337]

[0338] The crude product obtained in step 3 (14.4 g) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was evaporated to dryness under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (300 mL), and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / ethyl acetate = 8:1, v / v) to give the product, a yellow oil (8.2 g, 72% yield in two steps). ESI-MS m / z: 453.9, 455.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 7.36 (s, 1H), 5.21 (dd, J=6.4, 3.6Hz, 1H ), 4.71 (dd, J=11.5, 6.3Hz, 1H), 4.65-4.46 (m, 3H), 3.30 (s, 3H), 3.26 (s, 3H).

[0339] Step 5: (R)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl methanesulfonate

[0340]

[0341] (S)-3-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimethanesulfonate (8.2 g, 18.0 mmol) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (7.5 g, 54.1 mmol) was added. The mixture was stirred at 60 °C for 1 hour. The solution was diluted with water (300 mL) and extracted with ethyl acetate (600 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give the product as a yellow oil (6.4 g, 98% yield). ESI-MS m / z: 357.9, 359.9 [M+1] + .

[0342] Step 6: (S)-6-chloro-N-methyl-2-((methylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine

[0343]

[0344] (R)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl methanesulfonate (6.4 g, 17.8 mmol) was dissolved in 1,4-dioxane (50 mL), and methylamine aqueous solution (40 mL) was added. The mixture was then stirred in a sealed tube at 100 °C for 16 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction. ESI-MS m / z: 244.1 [M+1] + .

[0345] Step 7: tert-butyl(S)-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl)(methyl)carbamate

[0346]

[0347] The crude product obtained in step 6 was dissolved in tetrahydrofuran (60 mL), and triethylamine (1.8 g, 17.8 mmol) and di-tert-butyl dicarbonate (5.8 g, 26.7 mmol) were added. The mixture was stirred at room temperature for 6 hours. The solution was diluted with water (150 mL) and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow oil (3.0 g, 49% yield in two steps). ESI-MS m / z: 344.2 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ6.23 (s, 1H), 6.16 (d, J = 20.9Hz, 1H), 4.40 (d, J = 39.2Hz, 1H), 4.27 (d, J = 11.2Hz, 1H), 4.21-4. 03 (m, 1H), 3.59 (dd, J=14.8, 8.0Hz, 1H), 3.44 (s, 1H), 2.91-2.85 (m, 3H), 2.72 (d, J=4.8Hz, 3H), 1.35 (d, J=43.9Hz, 9H).

[0348] Step 8: tert-butyl(S)-(6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl)(methyl)carbamate

[0349]

[0350] tert-Butyl(S)-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl)(methyl)carbamate (3.0 g, 8.73 mmol) was dissolved in acetic acid (30 mL), and N-iodosuccinimide (2.1 g, 9.60 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was diluted with saturated sodium sulfite aqueous solution (100 mL), neutralized with saturated sodium bicarbonate aqueous solution (150 mL), and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow oil (3.1 g, 76% yield). ESI-MS m / z: 470.1 [M+1] + .

[0351] Step 9: (S)-3-(2-(tert-butoxycarbonyl)(methyl)amino)methyl)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-7-yl)ethyl acrylate

[0352]

[0353] tert-Butyl(S)-(6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl)(methyl)carbamate (3.1 g, 6.60 mmol), palladium acetate (148 mg, 0.660 mmol), tris(o-methylphenyl)phosphine (400 mg, 1.32 mmol), triethylamine (1.4 g, 13.2 mmol), and ethyl acrylate (2.0 g, 19.9 mmol) were dissolved in N,N-dimethylformamide (40 mL). The reaction was carried out under nitrogen protection with stirring at 100 °C for 3 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a yellow oil (2.3 g, 79% yield). ESI-MS m / z: 442.2 [M+1] + .

[0354] Step 10: tert-butyl(S)-((6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate

[0355]

[0356] Ethyl (S)-3-(2-(tert-butoxycarbonyl)(methyl)amino)methyl)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-7-yl)acrylate (2.3 g, 5.20 mmol) was dissolved in ethanol (20 mL), and sodium methanethiol (400 mg, 5.72 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The solution 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 give the product as a yellow solid (1.9 g, 93% yield). ESI-MS m / z: 396.2 [M+1] + .

[0357] Step 11: tert-butyl(S)-((8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate

[0358]

[0359] tert-Butyl(S)-((6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate (1.9 g, 4.80 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N-bromosuccinimide (2.5 g, 14.4 mmol) was added. The reaction mixture was stirred at 70 °C for 2 h. The mixture was diluted with saturated sodium sulfite aqueous solution (100 mL) and extracted with ethyl acetate (250 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a yellow solid (1.2 g, 53% yield). ESI-MS m / z: 474.1, 476.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.52-8.25 (m, 1H), 4.76-4.51 (m, 2H), 4.43-4.22 (m, 1H), 3 .85(s, 3H), 3.84-3.74(m, 1H), 3.40-3.25(m, 1H), 2.96-2.80(m, 3H), 1.29(m, 9H).

[0360] Step 12: tert-butyl(S)-((8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate

[0361]

[0362] tert-butyl(S)-((8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate (400 mg, 0.842 mmol) and 1-acetylpiperidin-4-one (475 mg, 3.37 mmol) were dissolved in tetrahydrofuran (20 mL) under nitrogen protection, and samarium iodide (33.7 mL, 3.37 mmol, 0.1 M in THF) was added dropwise at -30 °C. The reaction was stirred at -30 °C for 0.5 h. The mixture was then diluted with saturated ammonium chloride aqueous solution (100 mL) at -30 °C and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give the product as a white solid (230 mg, 51% yield). ESI-MS m / z: 481.2 [Mt-Bu] + .

[0363] Step 13: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((methylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0364]

[0365] tert-butyl(S)-((8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate (230 mg, 0.428 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction. ESI-MS m / z: 437.2 [M+1] + .

[0366] Step 14: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0367]

[0368] The crude product obtained in step 13 was dissolved in tetrahydrofuran (15 mL), and 30% formaldehyde aqueous solution (3 mL) was added. Sodium triacetoxyborohydride (227 mg, 1.07 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 12:1, v / v) to give the product as a white solid (130 mg, 67% yield in two steps). ESI-MS m / z: 451.2 [M+1] + .

[0369] Step 15: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 2)

[0370]

[0371] (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one (130 mg, 0.288 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Brettphos Pd G3 (39 mg, 0.029 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (196 mg, 0.865 mmol, prepared according to the method described in patent WO2019122129A1) and sodium tert-butoxide (166 mg, 1.73 mmol) were dissolved in toluene (6 mL). The reaction was carried out under nitrogen protection and stirred at 100 °C for 16 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 = 20:1, v / v) to give compound 2, a yellow solid (120 mg, 69% yield). ESI-MS m / z: 604.3 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.76 (d, J=1.6Hz, 1H), 7.50 (dq, J=22.0, 7.2Hz, 2H), 7.17 (td, J=7.6, 2.4Hz, 1H), 6.92 (t, J=55.1Hz, 1H), 5.97 (brs, 1H), 5.89 (dd, J=10.8, 7.2Hz, 1H), 5.64-5.65 (m, 1H), 4.54 (d, J=12.6Hz, 1H), 4.49 (dt, J=11.2, 2.0Hz, 1H), 4.25-4.1 8 (m, 1H), 4.14 (dd, J=11.2, 7.6Hz, 1H), 3.92 (s, 3H), 3.66 (d, J=9.6, 2H), 3.12 (td, J=12.8, 2.8Hz, 1H), 2.68-2.57 (m, 2H), 2.33 ( s, 6H), 2.18 (td, J=13.6, 2.8Hz, 1H), 2.07 (d, J=12.8Hz, 3H), 2.03-1.96 (m, 1H), 1.93-1.77 (m, 2H), 1.58 (dd, J=7.2, 3.2Hz, 3H).

[0372] Example 3 (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 3)

[0373]

[0374] Compound 3 was synthesized following steps 1 to 15 of Example 2, except that the starting material (S)-glycerol acetal condensate in step 1 was replaced with (R)-glycerol acetal condensate. ESI-MS m / z: 604.3 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.65 (s, 1H), 7.42 (dt, J=13.0, 7.0Hz, 2H), 7.09 (t, J=7.1Hz, 1H), 6.86 (dd, J=74. 1, 36.0Hz, 1H), 5.70 (s, 1H), 5.52 (d, J=4.3Hz, 1H), 4.44 (dd, J=33.3, 11.4Hz, 2H), 4.26 (s, 1H), 4.17-4. 06 (m, 1H), 3.84 (s, 3H), 3.60 (s, 2H), 3.06 (t, J = 12.7Hz, 1H), 2.66 (s, 2H), 2.34 (d, J = 2.6Hz, 6H), 2.11 ( d, J=12.2Hz, 1H), 2.00 (t, J=11.6Hz, 3H), 1.94 (d, J=15.1Hz, 1H), 1.89-1.71 (m, 2H), 1.58-1.45 (m, 3H). 13 C NMR (101MHz, CDCl3) δ167.83(s), 163.15(s), 149.25(s), 147.22(s), 136.70(s), 131.40(d, J =12.6Hz), 129.52(s), 126.45(s), 124.28(s), 123.30(s), 116.52(s), 109.70(s), 98.69(s), 69.73(d, J=14.5Hz), 66.68(s), 58.12(s), 45.02(s), 44.76(s), 41.47(s), 36.49(s), 35.67( d, J=14.5Hz), 34.31 (d, J=7.4Hz), 33.83 (s), 28.68 (s), 25.92 (s), 20.57 (dd, J=21.5, 6.8Hz).

[0375] Example 4 (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 4)

[0376]

[0377] Step 1: (S)-2-((1-azido-3-((4-methoxybenzyl)oxy)propane-2-yl)oxy)-4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridine

[0378]

[0379] Prepared according to step 1 of Example 2, except that (S)-glycerol acetal was replaced with (S)-1-azido-3-((4-methoxybenzyl)oxy)propyl-2-ol. ESI-MS m / z: 563.1, 565.1 [M+1] + .

[0380] Step 2: (S)-2-((1-azido-3-hydroxypropane-2-yl)oxy)-4-bromo-6-chloropyridin-3-ol

[0381]

[0382] (S)-2-((1-azido-3-((4-methoxybenzyl)oxy)propane-2-yl)oxy)-4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridine (24.4 g, 43.4 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (50 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (600 mL). The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with water (400 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a white solid (12 g, 85.7% yield). ESI-MS m / z: 323.0, 325.0 [M+1] + .

[0383] Step 3: (S)-N-((8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-3-yl)methyl)-1,1,1-triphenylphosphine

[0384]

[0385] (S)-2-((1-azido-3-hydroxypropane-2-yl)oxy)-4-bromo-6-chloropyridin-3-ol (960 mg, 3 mmol) was dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (1.57 g, 6 mmol) and diisopropyl azodicarbonate (667 mg, 3.3 mmol) were added under nitrogen protection at 0 °C. The reaction was brought to room temperature and stirred for 1 hour. The product was concentrated under reduced pressure to obtain crude product, which was used directly in the next reaction. ESI-MS m / z: 539.0, 541.0 [M+1] + .

[0386] Step 4: (S)-3-(aminomethyl)-6-chloro-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine

[0387]

[0388] The crude (S)-N-((8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-3-yl)methyl)-1,1,1-triphenylphosphine imine (3.5 g) obtained in step 3 was dissolved in methylamine aqueous solution (40 mL), and stirred in a sealed tube at 100 °C for 24 hours. The solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). 4M hydrochloric acid-methanol solution (10 mL) was added, and the mixture was stirred at room temperature for 5 minutes. Water (100 mL) was added for extraction. The aqueous phase was then alkalized to pH 10 with concentrated ammonia. Ethyl acetate (50 mL, 3 times) was added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, a yellow oil (960 mg), which was used directly in the next reaction. ESI-MS m / z: 230.1 [M+1] + .

[0389] Step 5: tert-butyl(S)-((6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-3-yl)methyl)carbamate

[0390]

[0391] The crude (S)-3-(aminomethyl)-6-chloro-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8-amine obtained in step 4 was dissolved in tetrahydrofuran (30 mL), triethylamine (1 mL) was added, followed by di-tert-butyl dicarbonate (972 mg, 1.5 mmol), and the mixture was stirred at room temperature for 1 hour. The solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give the product as a white solid (960 mg, 46% overall yield of the three steps). ESI-MS m / z: 330.1 [M+1] + .

[0392] Step 6: tert-butyl(S)-((6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-3-yl)methyl)carbamate

[0393]

[0394] Prepared according to step 8 of Example 2. ESI-MS m / z: 456.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ5.09 (s, 1H), 4.39 (dd, J=7.0, 4.9Hz, 1H), 4.30 (dd, J=11.5, 2.1Hz, 1H), 3.83 (dd, J=11.2, 8.3Hz, 1H), 3.55 (d, J=14.3Hz, 1H), 3.41 (d, J=15.2Hz, 1H), 3.22 (s, 3H), 1.44 (s, 9H).

[0395] Step 7: (S)-3-(3-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-7-yl)ethyl acrylate

[0396]

[0397] Prepared according to step 9 of Example 2. ESI-MS m / z: 428.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.71 (d, J=16.3Hz, 1H), 6.20 (t, J=9.9Hz, 1H), 4.37 (ddd, J=13.7, 7.9, 2.2Hz, 2H), 4.27 (q, J=7.1Hz, 2H), 3.9 6-3.83 (m, 1H), 3.54 (t, J=14.9Hz, 1H), 3.43 (dd, J=13.0, 6.9Hz, 1H), 2.95 (d, J=11.4Hz, 3H), 1.44 (s, 11H), 1.34 (t, J=7.1Hz, 3H).

[0398] Step 8: tert-butyl(S)-((6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-3-yl)methyl)carbamate

[0399]

[0400] Prepared according to step 10 of Example 2. ESI-MS m / z: 382.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.92 (t, J=9.4Hz, 1H), 6.62 (d, J=9.8Hz, 1H), 5.16 (s, 1H), 4.58-4.39 (m, 2H), 4.00-3.86 (m, 4H), 3.66-3.44 (m, 2H), 1.47 (d, J=21.6Hz, 9H).

[0401] Step 9: tert-butyl(S)-((8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-3-yl)methyl)carbamate

[0402]

[0403] Prepared according to step 11 of Example 2. ESI-MS m / z: 460.0, 462.0 [M+1] + .

[0404] Step 10: tert-butyl(S)-((8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthidin-3-yl)methyl)carbamate

[0405]

[0406] Prepared according to step 12 of Example 2. ESI-MS m / z: 523.2 [M+1] + .

[0407] Step 11: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-3-(aminomethyl)-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0408]

[0409] Prepared according to step 13 of Example 2. ESI-MS m / z: 423.1 [M+1] + .

[0410] Step 12: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-3-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0411]

[0412] Prepared according to step 14 of Example 2. ESI-MS m / z: 451.2 [M+1] + .

[0413] Step 13: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 4)

[0414]

[0415] Compound 4 was prepared according to step 15 of Example 2. ESI-MS m / z: 604.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ8.19 (s, 1H), 7.60-7.50 (m, 1H), 7.45 (t, J=7.0Hz, 1H), 7.20 (t, J=7.7Hz, 1H), 7.00 (t , J=54.9Hz, 1H), 5.62-5.47 (m, 1H), 4.62 (s, 1H), 4.50 (d, J=12.9Hz, 1H), 4.22 (dt, J=15.9, 8.0Hz, 1H), 3. 95-3.78 (m, 5H), 3.65 (td, J=13.1, 2.5Hz, 1H), 3.10 (ddd, J=21.0, 13.5, 9.1Hz, 2H), 2.80 (dd, J=13.4, 3.5 Hz, 1H), 2.55 (d, J=7.6Hz, 6H), 2.37-2.22 (m, 2H), 2.17 (s, 3H), 2.00-1.75 (m, 2H), 1.60 (d, J=7.0Hz, 3H). 13 C NMR (101MHz, MeOD) δ171.42(s), 164.98(s), 151.29(s), 150.11(s), 138.92(s), 134 .91(d, J=13.6Hz), 132.00(s), 130.98(s), 130.30(s), 126.14(s), 125.44(s), 119. 29(s), 100.98(s), 73.04(s), 72.53(s), 66.47(s), 59.94(s), 46.27(s), 45.74(s), 43.76(s), 38.87(s), 36.68(s), 35.85(d, J=6.8Hz), 35.20(s), 21.85(s), 21.22(s).

[0416] Example 5 (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((R)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 5)

[0417]

[0418] Step 1: tert-butyl(R)-2-((S)-2-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester

[0419]

[0420] (R)-2-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30.0 g, 130 mmol), 4-bromo-6-chloro-2-fluoro-3-((4-methoxybenzyl)oxy)pyridine (36.0 g, 104 mmol), and cesium carbonate (50.7 g, 156 mmol) were dissolved in dimethyl sulfoxide (300 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with water (1.5 L) and extracted with ethyl acetate (1 L). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 12:1, v / v) to give the product as a yellow oil (11.5 g, 24% yield). ESI-MS m / z: 579.1, 581.1 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ7.47 (s, 2H), 7.10-7.03 (m, 1H), 6.94-6.82 (m, 2H), 5 .20-5.09 (m, 1H), 5.05 (d, J=10.0Hz, 1H), 4.49 (dd, J=11.4, 2.9Hz, 1H), 4.3 6(dd, J=11.4, 4.7Hz, 1H), 4.13(brs, 1H), 3.89(brs, 1H), 3.84-3.77(m, 3H) , 3.51 (s, 1H), 3.42-3.25 (m, 1H), 2.03-1.59 (m, 4H), 1.49 (d, J=3.7Hz, 9H).

[0421] Step 2: 4-Bromo-6-chloro-2-((S)-2-hydroxy-2-((R)-pyrrolidine-2-yl)ethoxy)pyridine-3-ol

[0422]

[0423] 11.5 g (20.6 mmol) of tert-butyl(R)-2-((S)-2-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain the crude product, which was used directly in the next reaction. ESI-MS m / z: 337.0, 339.0 [M+1] + .

[0424] Step 3: tert-butyl(R)-2-((S)-2-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester

[0425]

[0426] The crude product obtained in step 2 was dissolved in tetrahydrofuran (60 mL) and water (20 mL). Triethylamine was added to adjust the pH to 8-9, followed by the addition of di-tert-butyl dicarbonate (8.9 g, 41.2 mmol). The mixture was stirred at room temperature for 16 hours. The solution was diluted with water (300 mL) and extracted with ethyl acetate (600 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 9:1, v / v) to give the product as a white solid (5.3 g, 59% yield). ESI-MS m / z: 459.0, 461.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 7.27 (s, 1H), 5.03-4.97 (m, 1H), 4.30 (d, J=8.0Hz, 1H), 4.04 (brs, 1H) , 3.95(brs, 1H), 3.72-3.60(m, 1H), 3.40(brs, 1H), 3.20(brs, 1H), 1.93(s, 3H), 1.73(s, 1H), 1.42(s, 9H).

[0427] Step 4: tert-butyl(R)-2-((R)-8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester

[0428]

[0429] tert-Butyl(R)-2-((S)-2-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester (5.3 g, 12.1 mmol) was dissolved in tetrahydrofuran (50 mL) under nitrogen protection. Triphenylphosphine (3.8 g, 14.6 mmol) and diisopropyl azodicarbonate (2.9 g, 14.6 mmol) were added at 0 °C. The reaction was stirred at room temperature for 1 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (400 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12:1, v / v) to give the product as a white solid (4.0 g, 79% yield). ESI-MS m / z: 363.0 [Mt-Bu] + . 1 H NMR (400MHz, CDCl3) δ7.13 (s, 1H), 4.54 (d, J=10.8Hz, 1H), 4.27-4.09 (m, 2H), 4.02 (s, 1 H), 3.61-3.30(m, 2H), 2.21(s, 1H), 2.08-2.03(m, 1H), 2.00-1.90(m, 2H), 1.48(s, 9H).

[0430] Step 5: tert-butyl(R)-2-((R)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester

[0431]

[0432] 4.0 g (9.55 mmol) of tert-butyl(R)-2-((R)-8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester was dissolved in dimethyl sulfoxide (40 mL), and 30 mL of aqueous methylamine solution was added. The mixture was stirred in a sealed tube at 100 °C for 24 hours. After cooling to room temperature, the solution was 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 give the product as a yellow oil (3.5 g, 100% crude yield). ESI-MS m / z: 370.2 [M+1] + .

[0433] Step 6: tert-butyl(R)-2-((R)-6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester

[0434]

[0435] tert-Butyl(R)-2-((R)-6-chloro-8-(methylamino)-23-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester (3.5 g, 9.55 mmol) was dissolved in acetic acid (20 mL), and N-iodosuccinimide (2.3 g, 10.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was diluted with saturated sodium sulfite aqueous solution (100 mL), neutralized with saturated sodium bicarbonate aqueous solution (150 mL), and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to give the product as a white solid (3.5 g, 74% yield). ESI-MS m / z: 496.1 [M+1] + .

[0436] Step 7: tert-Butyl(R)-2-((R)-6-chloro-7-(3-ethoxy-3-oxopropane-1-en-1-yl)-8-(methylamino)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester

[0437]

[0438] tert-Butyl(R)-2-((R)-6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester (3.5 g, 7.06 mmol), palladium acetate (159 mg, 0.706 mmol), tris(o-methylphenyl)phosphine (430 mg, 1.41 mmol), triethylamine (1.4 g, 14.1 mmol), and ethyl acrylate (1.8 g, 1.16 mmol) were dissolved in N,N-dimethylformamide (40 mL). The reaction was carried out under nitrogen protection and stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to give the product as a yellow oil (2.3 g, 70% yield). ESI-MS m / z: 468.2 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.71 (d, J=16.4Hz, 1H), 6.20 (d, J=16.4Hz, 1H), 4.46 (d, J=10.4Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 4.17-4.07 ( m, 2H), 4.00 (brs, 1H), 3.57-3.43 (m, 1H), 3.40-3.28 (m, 1H), 3.00 (s, 3H), 2.12-1.93 (m, 4H), 1.48 (s, 9H), 1.34 (t, J=7.2Hz, 3H).

[0439] Step 8: tert-butyl(R)-2-((R)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)pyrrolidine-1-carboxylic acid ester

[0440]

[0441] tert-Butyl(R)-2-((R)-6-chloro-7-(3-ethoxy-3-oxopropane-1-en-1-yl)-8-(methylamino)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ester (2.3 g, 4.91 mmol) was dissolved in ethanol (30 mL), and sodium methanethiol (378 mg, 5.41 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The solvent was evaporated under reduced pressure, 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 give the product as a yellow solid (2.2 g, 100% yield). ESI-MS m / z: 422.2 [[M+1]] + .

[0442] Step 9: tert-butyl(R)-2-((R)-8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)pyrrolidine-1-carboxylic acid ester

[0443]

[0444] tert-Butyl(R)-2-((R)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)pyrrolidine-1-carboxylic acid ester (2.2 g, 4.91 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N-bromosuccinimide (2.6 g, 14.7 mmol) was added. The mixture was stirred at 70 °C for 2 h. The solution was diluted with saturated sodium sulfite aqueous solution (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a white solid (535 mg, 90% yield). ESI-MS m / z: 500.1, 502.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 4.56 (d, J=11.6Hz, 1H), 4.37-4.26 (m, 1H), 4.24 (dd, J=11.6, 8.8Hz, 1H ), 4.00(s, 1H), 3.86(s, 3H), 3.40(s, 1H), 3.23(brs, 1H), 2.03-1.90(m, 3H), 1.85-1.78(m, 1H), 1.41(s, 9H).

[0445] Step 10: tert-butyl(R)-2-((R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxy[2,3-h][1,6]naphthidin-2-yl)pyrrolidine-1-carboxylic acid ester

[0446]

[0447] tert-Butyl(R)-2-((R)-8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthid-2-yl)pyrrolidine-1-carboxylic acid ester (500 mg, 1.00 mmol) and 1-acetylpiperidin-4-one (564 mg, 4.00 mmol) were dissolved in tetrahydrofuran (25 mL) under nitrogen protection, and samarium iodide (40.0 mL, 4.00 mmol, 0.1 M in THF) was added dropwise at -30 °C. The reaction was stirred at -30 °C for 0.5 h. The mixture was then diluted with saturated ammonium chloride aqueous solution (100 mL) at -30 °C and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 30:1, v / v) to give the product as a yellow solid (380 mg, 68% yield). ESI-MS m / z: 507.2 [Mt-Bu] + .

[0448] Step 11: (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((R)-pyrrolidine-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0449]

[0450] tert-Butyl(R)-2-((R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxy[2,3-h][1,6]naphthidin-2-yl)pyrrolidine-1-carboxylic acid ester (380 mg, 0.676 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain the crude product, which was used directly in the next reaction. ESI-MS m / z: 463.2 [[M+1] + .

[0451] Step 12: (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((R)-1-methylpyrrolidine-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0452]

[0453] The crude product obtained in step 11 was dissolved in tetrahydrofuran (20 mL), and formaldehyde aqueous solution (3 mL) and sodium triacetoxyborohydride (358 mg, 1.69 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 8:1, v / v) to give the product as a white solid (280 mg, 88% yield). ESI-MS m / z: 477.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 4.77 (s, 1H), 4.68 (d, J=11.3Hz, 1H), 4.35-4 .22(m, 2H), 3.83-3.80(m, 1H), 3.81(s, 3H), 3.70(d, J=12.0Hz, 1H), 3.59(brs, 2H ), 3.22-3.14(m, 1H), 2.95(s, 3H), 2.91-2.85(m, 2H), 2.64-2.54(m, 1H), 2.46-2. 40 (m, 1H), 2.26-2.05 (m, 3H), 2.03 (s, 3H), 2.00-1.86 (m, 2H), 1.42-1.22 (m, 2H).

[0454] Step 13: (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((R)-1-methylpyrrolidone-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 5)

[0455]

[0456] (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((R)-1-methylpyrrolidine-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (200 mg, 0.42 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Brettphos Pd G3 (39 mg, 0.042 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (285 mg, 1.26 mmol, prepared according to the method described in patent WO2019122129A1), and sodium tert-butoxide (242 mg, 2.56 mmol) were dissolved in 1,4-dioxane (15 mL), and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give a crude product. This crude product was then purified by preparative HPLC to give compound 5 as a yellow solid (43 mg, yield 16.3%). ESI-MS m / z: 630.3 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.49 (d, J = 9.2Hz, 3H), 7.18 (t, J = 7.6Hz, 1H), 6.91 (m, 1H), 5.75 (brs, 1H), 5.57 (s , 1H), 5.26 (s, 1H), 4.60 (d, J=13.2Hz, 1H), 4.50 (d, J=11.8Hz, 1H), 4.36 (t, J=9.3Hz, 1H), 4.19 (s, 1H), 3.92 (s, 3H), 3.76-3.63 (m, 2H), 3.29 (s, 1H), 3.16 (t, J=12.8Hz, 1H), 2.89 (s, 1H), 2.57 (d, J=5.2Hz, 2H), 2.51 (s, 1H), 2.21 (d, J= 10.8Hz, 2H), 2.12 (d, J=6.1Hz, 3H), 2.05-2.00 (m, 2H), 1.97-1.84 (m, 4H), 1.83-1.69 (m, 2H), 1.62 (d, J=7.2Hz, 3H).

[0457] Example 6 (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((R)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 6)

[0458]

[0459] Compound 6 was synthesized following steps 1 to 13 of Example 5, except that the starting material (R)-2-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (R)-2-((R)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in step 1. ESI-MS m / z: 630.3 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.55-7.47 (m, 3H), 7.20 (td, J=7.6, 2.0Hz, 1H), 6.92 (t, J=55.0Hz, 1H), 5.75 (s, 1H), 5.58 ( p, J=6.8Hz, 1H), 5.45-5.27 (m, 1H), 4.58 (d, J=13.6Hz, 1H), 4.50-4.37 (m, 2H), 4.21 (dd, J=11.6, 6.8Hz, 1H), 3.9 3(s, 3H), 3.73-3.63(m, 2H), 3.34(s, 1H), 3.15(td, J=12.8, 3.2Hz, 1H), 2.90(s, 1H), 2.64-2.42(m, 3H), 2.28-2. 16 (m, 2H), 2.11 (d, J=4.4Hz, 3H), 2.07-1.97 (m, 2H), 1.96-1.85 (m, 4H), 1.83-1.72 (m, 2H), 1.61 (d, J=6.8Hz, 3H).

[0460] Example 7 (R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((S)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 7)

[0461]

[0462] Compound 7 was synthesized following steps 1 to 13 of Example 5, except that the starting material (R)-2-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S)-2-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in step 1. ESI-MS m / z: 630.3 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.49 (dt, J=15.2, 7.3Hz, 2H), 7.16 (td, J=7.6, 2.1Hz, 1H), 7.07-6.74 (m, 1H), 5.95 (dd, J=18.8, 10.0Hz, 1H), 5.61 (dd, J=12.0, 6.9Hz, 1H), 4.62-4.51 (m, 1H), 4.47 (d, J=9.7H z, 1H), 4.23-4.09 (m, 2H), 3.93 (s, 3H), 3.67 (t, J=6.5Hz, 2H), 3.22-3.06 (m, 2H), 2.78 (s, 1H), 2.41 (t, J =10.6Hz, 3H), 2.38-2.13 (m, 3H), 2.07 (d, J = 18.4Hz, 3H), 2.02-1.88 (m, 3H), 1.58 (dd, J = 6.8, 3.0Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 168.77 (d, J = 4.1Hz), 164.25 (s), 157.11 (s), 150.60 (s), 148.17 (s), 137.58 (s), 132.51 (d, J = 12. 8Hz), 130.43(s), 130.18(s), 127.78(d, J=4.5Hz), 125.20(s), 124.22(s), 118.14(s), 110.77(s), 99.62(d, J=6.0Hz), 74.71 (s), 70.81 (d, J = 3.2Hz), 66.23 (s), 65.07 (d, J = 6.5Hz), 57.64 (s), 45.78 (s), 42.42 (d, J = 10.7Hz), 37.51 (s), 36. 79 (s), 36.56 (s), 35.37 (d, J = 16.2Hz), 34.92 (d, J = 5.4Hz), 29.69 (s), 27.00 (s), 23.38 (s), 21.57 (dd, J = 14.1, 8.4Hz).

[0463] Example 8 (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((S)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 8)

[0464]

[0465] Compound 8 was synthesized following steps 1 to 13 of Example 5, except that the starting material (R)-2-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S)-2-((R)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in step 1. ESI-MS m / z: 630.3 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.71 (d, J=2.5Hz, 1H), 7.57-7.42 (m, 2H), 7.16 (t, J=7.3Hz, 1H), 6.90 (t, J=55.1Hz, 1H), 5.77 (d d, J=13.7, 6.5Hz, 1H), 5.58 (d, J=2.9Hz, 1H), 4.54 (d, J=12.5Hz, 1H), 4.47 (d, J=11.4Hz, 1H), 4.30-4.20 (m, 1H), 3.98 (s, 1H), 3.91 (s, 3H), 3.66 (d, J=8.4Hz, 2H), 3.13 (dd, J=20.6, 9.4Hz, 2H), 2.68 (s, 1H), 2.43 (s, 3H), 2.35 (d, J=5.8Hz , 1H), 2.24-2.12 (m, 2H), 2.07 (d, J=10.7Hz, 3H), 1.99 (d, J=9.3Hz, 2H), 1.82 (d, J=18.4Hz, 4H), 1.57 (d, J=5.2Hz, 3H).

[0466] Example 9 (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-(pyrrolidone-1-ylmethyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 9)

[0467]

[0468] Compound 9 was synthesized according to Example 2. ESI-MS m / z: 630.3 [M+1] + .

[0469] Example 10(R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4,10-dimethyl-3,4-dihydro-[1,4]oxazine[3,2-h][1,6]naphthidium-9(10H)-one (Compound 10)

[0470]

[0471] Compound 10 was synthesized according to Example 1, except that the starting material 2-((tert-butyldimethylsilyl)oxy)ethanol in step 3 was replaced with N-[2-(tert-butyldimethylsilyl)ethyl]methylamine. ESI-MS m / z: 560.2 [M+1] + .

[0472] Example 11 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 11)

[0473]

[0474] Step 1:

[0475]

[0476] (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (compound 2, 80 mg, 0.132 mmol) was dissolved in dichloromethane (3 mL), and under nitrogen protection, diethylaminosulfur trifluoride (DAST, 42 mg, 0.265 mmol) was added at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 606.3 [M+1] + .

[0477] Step 2:

[0478]

[0479] The crude product obtained in step 1 was dissolved in anhydrous methanol (10 mL), and then a methanol solution of sodium methoxide (238 mg, 1.32 mmol, 30% wt. MeOH) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, cooled to room temperature, and concentrated again under reduced pressure. The residue was purified by HPLC to give compound 11 as a yellow solid (6 mg, 15% yield). ESI-MS m / z: 618.4 [M+1] + .1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.60-7.39 (m, 3H), 7.19 (t, J=7.6Hz, 1H), 6.90 (t, J=55.2Hz , 1H), 5.58 (s, 1H), 5.30 (s, 1H), 4.52 (dd, J=23.6, 12.0Hz, 2H), 4.34-4.11 (m, 3H), 3.99-3.75 ( m, 5H), 3.69-3.62 (m, 1H), 3.56-3.39 (m, 1H), 3.24 (s, 3H), 3.00-2.85 (m, 1H), 2.82-2.59 (m, 3H ), 2.57-2.42(m, 2H), 2.39(s, 6H), 2.21-1.98(m, 4H), 1.95-1.82(m, 1H), 1.62(d, J=6.8Hz, 3H).

[0480] Example 12 (R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 12)

[0481]

[0482] Compound 12 was prepared from compound 1 according to Example 11. ESI-MS m / z: 561.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 7.64-7.61 (m, 1H), 7.42-7.34 (m, 2H), 7.24 (t, J = 4.0Hz, 1H), 6 .90(t, J=4.0Hz, 1H), 5.26-5.34(m, 1H), 4.32-4.23(m, 2H), 3.55(s, 2H), 3.51-3.43(m, 2 H), 3.35(s, 3H), 3.17-3.15(m, 1H), 3.09-3.08(m, 2H), 2.20-2.09(m, 1H), 2.03-2.01(m, 1H), 1.99(s, 3H), 1.55-1.46(m, 1H), 1.42-1.34(m, 2H), 1.30-1.26(m, 2H), 1.24(s, 3H).

[0483] Example 13 (R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 13)

[0484]

[0485] Compound 13 was prepared from compound 3 according to Example 11. ESI-MS m / z: 618.3 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.58 (s, 1H), 7.41 (dd, J=17.2, 9.8Hz, 2H), 7.11 (t, J=7.5Hz, 1H), 6.99-6.66 (m, 1H), 5.49 (dd, J=14. 1, 7.0Hz, 1H), 5.12 (d, J = 7.6Hz, 1H), 4.49 (d, J = 12.7Hz, 1H), 4.41 (d, J = 10.7Hz, 1H), 4.20-4.01 (m, 2H), 3.92-3.72 (m, 3H), 3.66-3.55 (m, 1H), 3.40 (dd, J=25.6, 13.1Hz, 1H), 3.14 (d, J=26.1Hz, 3H), 3.06 (s, 1H), 2.85 (dd, J=25.4, 12.8Hz, 1H), 2.70 (s, 1H), 2.38 (t, J = 8.0Hz, 3H), 2.27-2.14 (m, 2H), 2.05 (s, 3H), 1.81 (t, J = 12.1Hz, 2H), 1.70 (s, 3H), 1.55 (d, J = 6.9Hz, 3H).

[0486] Example 14 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 14)

[0487]

[0488] Compound 14 was prepared from compound 4 according to Example 11. ESI-MS m / z: 618.4 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.56 (s, 1H), 7.42 (dt, J=14.1, 6.7Hz, 2H), 7.11 (t, J=7.6Hz, 1H), 6.99-6.66 (m, 1H), 5.50 (dd, J=14.2, 7.0Hz, 1 H), 5.10 (d, J=7.7Hz, 1H), 4.48 (d, J=11.1Hz, 1H), 4.39 (d, J=5.9Hz, 1H), 4.26-4.13 (m, 1H), 3.83 (t, J=5.3Hz, 1H), 3.79 (d, J=8.7Hz, 3 H), 3.66-3.58 (m, 1H), 3.39 (dd, J=23.3, 10.5Hz, 1H), 3.17 (d, J=1.8Hz, 3H), 2.85 (dd, J=22.7, 10.2Hz, 1H), 2.61 (ddd, J=20.0, 13.0, 6.5Hz, 2H), 2.51-2.38 (m, 2H), 2.29 (s, 6H), 2.03 (d, J=14.5Hz, 3H), 2.01-1.91 (m, 1H), 1.81 (t, J=12.9Hz, 1H), 1.54 (d, J=6.9Hz, 3H). 13 C NMR (101MHz, CDCl3) δ167.92(s), 161.12(s), 149.19(s), 146.86(s), 137.23(s), 131.28(d, J=11.9Hz), 129.87(s), 128.15(s), 126.61(s), 124.41(s), 123.42(s), 117.38(s), 109.70(s) ), 98.09(s), 71.60(s), 64.84(s), 58.24(s), 49.23(s), 45.85(s), 45.08(s), 41.34(s), 36. 33(s), 33.52(s), 31.90(s), 31.14(s), 30.78(s), 29.94(s), 28.67(s), 20.92(s), 20.42(s).

[0489] Example 15 (R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((R)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 15)

[0490]

[0491] Compound 15 was prepared from compound 5 according to Example 11. ESI-MS m / z: 644.4 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.14 (brs, 1H), 7.63 (s, 1H), 7.55-7.43 (m, 2H), 7.19 (t, J=7.6Hz, 1H), 6.89 (t, J=55.2Hz, 1 H), 5.56 (s, 1H), 5.15 (s, 1H), 4.57 (d, J = 13.6Hz, 1H), 4.50 (d, J = 11.6Hz, 1H), 4.36-4.30 (m, 1H), 4.16 (s, 1H), 3. 86 (s, 3H), 3.69 (d, J=12.4Hz, 1H), 3.47 (dt, J=13.6, 3.0Hz, 1H), 3.29 (s, 1H), 3.25 (s, 2H), 3.00-2.84 (m, 2H), 2. 58 (d, J=6.4Hz, 3H), 2.53-2.43 (m, 3H), 2.13 (s, 3H), 2.07-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.63 (d, J=7.2Hz, 3H).

[0492] Example 16 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((R)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 16)

[0493]

[0494] Compound 16 was prepared from compound 6 according to Example 11. ESI-MS m / z: 644.4 [M+1] + .

[0495] Example 17 (R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((S)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 17)

[0496]

[0497] Compound 17 was prepared from compound 7 according to Example 11. ESI-MS m / z: 644.4 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.56 (s, 1H), 7.41 (dd, J=14.0, 6.6Hz, 2H), 7.11 (t, J=7.6Hz, 1H), 6.85 (dd, J=76.5, 3 3.6Hz, 1H), 5.59-5.38 (m, 1H), 5.07 (d, J=7.7Hz, 1H), 4.44 (dt, J=14.9, 8.6Hz, 2H), 4.09 (dd, J=6.6, 3.3Hz, 2H), 3.79 (s, 3H), 3.62 (d, J=12.7Hz, 1H), 3.40 (dd, J=26.7, 13.4Hz, 1H), 3.18 (d, J=1.7Hz, 3H), 2.85 (dd, J =26.6, 13.1Hz, 1H), 2.66-2.33 (m, 4H), 2.25 (s, 3H), 2.05 (s, 3H), 2.00-1.78 (m, 6H), 1.55 (d, J = 6.9Hz, 3H). 13 C NMR (101MHz, CDCl3) δ167.94(s), 161.16(s), 149.30(s), 146.65(s), 137.43( s), 128.14(s), 126.68(s), 124.47(s), 123.44(s), 116.93(s), 98.20(s), 70.0 7(s), 66.92(s), 58.41(s), 49.24(s), 45.98(s), 45.14(s), 41.35(s), 36.36( s), 33.63(s), 32.09(s), 30.93(s), 29.79(s), 28.68(s), 20.95(s), 20.41(s).

[0498] Example 18 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((S)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 18)

[0499]

[0500] Compound 18 was prepared from compound 8 according to Example 11. ESI-MS m / z: 644.4 [M+1] + .

[0501] Example 19 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-(pyrrolidone-1-ylmethyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 19)

[0502]

[0503] Compound 19 was prepared from compound 9 according to Example 11. ESI-MS m / z: 644.3 [M+1] + .

[0504] Example 20(R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4,10-dimethyl-3,4-dihydro-[1,4]oxazine[3,2-h][1,6]naphthidium-9(10H)-one (Compound 20)

[0505]

[0506] Compound 20 was prepared from compound 10 according to Example 11. ESI-MS m / z: 574.3 [M+1] + .

[0507] Example 21 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 21)

[0508]

[0509] Step 1:

[0510]

[0511] Following the method in step 15 of Example 2, the mixture was prepared by reacting the intermediate (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one with the starting material (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-amine hydrochloride (prepared according to the method described in patent WO2019122129A1). ESI-MS m / z: 600.3 [M+1] + .

[0512] Step 2:

[0513]

[0514] Prepared according to the method in step 1 of Example 11. ESI-MS m / z: 602.3 [M+1] + .

[0515] Step 3:

[0516]

[0517] Compound 21 was prepared according to the method in step 2 of Example 11. ESI-MS m / z: 614.3 [M+1] + .

[0518] Referring to the preparation method of Example 21, and using appropriate intermediates and amine derivatives as raw materials, Examples 22 to 36 in Table 1, namely compounds 22 to 36, were prepared.

[0519] Table 1 Examples 22-36

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] Example 37(R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-8-(1-methylcyclopropyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one (Compound 37)

[0526]

[0527] Step 1:

[0528]

[0529] 8-Bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one (100 mg, 0.3 mmol), 4,4,5,5-tetramethyl-2-(1-methylcyclopropyl)-1,3-dioxolane (109 mg, 0.6 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (24 mg, 0.03 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and the mixture was stirred at 90 °C for 16 hours under nitrogen protection. After cooling to room temperature, the solvent was evaporated, the residue was diluted with water, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to thin-layer chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give the product 6-chloro-10-methyl-8-(1-methylcyclopropyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one, a yellow solid (25 mg, 27%). ESI-MS m / z: 307.2 [M+1] + .

[0530] Step 2: (R)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-8-(1-methylcyclopropyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidium-9(10H)-one

[0531]

[0532] 6-Chloro-10-methyl-8-(1-methylcyclopropyl)-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidin-9(10H)-one (25 mg, 0.0847 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Brettphos Pd G3 (7.7 mg, 0.00847 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (38 mg, 0.17 mmol, prepared according to the method described in patent WO2019122129A1), and sodium tert-butoxide (25 mg, 0.254 mmol) were dissolved in toluene (3 mL), and the mixture was stirred at 100 °C for 14 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure, and prepared by thin-layer chromatography (dichloromethane / methanol = 20:1, v / v) to give compound 37 (5 mg, yield 12.8%). ESI-MS m / z: 460.1 [M+1] + .

[0533] Referring to the preparation method of Example 37, using the intermediate 8-bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthidine-9(10H)-one and appropriate borate esters or amine derivatives as raw materials, Examples 38 to 43 in Table 2, namely compounds 38 to 43, were prepared.

[0534] Table 2 Examples 38-43

[0535]

[0536]

[0537] Example 44 (R)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-(difluoromethyl)cyclopropyl)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-c][2,7]naphthidium-9(8H)-one (Compound 44)

[0538]

[0539] Step 1: (R)-4-bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-((4-methoxybenzyl)oxy)pyridine

[0540]

[0541] A 1L three-necked flask was equipped with a low-temperature thermometer, mechanical stirrer, and constant-pressure dropping funnel. Sodium hydride (60%, 53g, 0.1328mol) and 200mL of anhydrous N,N-dimethylformamide were added. The reaction mixture was cooled to 0°C, and under argon protection, (R)-glycerol acetal (13.2g, 0.0996mol) dissolved in 50mL of anhydrous N,N-dimethylformamide was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. Then, 4-bromo-6-chloro-2-fluoro-3-((4-methoxybenzyl)oxy)pyridine (23g, 0.0664mol) dissolved in 100mL of anhydrous N,N-dimethylformamide was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched at 0°C with 100mL of saturated ammonium chloride aqueous solution. The reaction mixture was added to ethyl acetate (500 mL) and water (300 mL), and the layers were extracted and separated. The organic layer was washed with water (200 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give the product as a white solid (27.8 g, 91% yield). ESI-MS m / z: 458.0, 460.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.39 (d, J=8.4Hz, 2H), 7.39 (s, 1H), 6.91 (d, J=8.4Hz, 2H), 5.03 (s, 2H), 4.46-4.52 (m, 1H), 4.39 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.33 (dd, J=5.6Hz, J=11.2Hz, 1H), 4.10 (dd, J=6.8Hz, J=8.4Hz, 1H), 3.85 (dd, J=6.0Hz, J=8.4Hz, 1H), 3.75 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H).

[0542] Step 2: (S)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol

[0543]

[0544] (R)-4-bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-((4-methoxybenzyl)oxy)pyridine (27.8 g, 0.0606 mol) was dissolved in tetrahydrofuran (100 mL), followed by the addition of water (20 mL). A dioxane hydrochloride solution (4 M, 20 mL, 0.080 mol) was then added. The reaction mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and solid potassium carbonate was added to adjust the pH to approximately 8. The organic solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain a white solid (22.4 g, 88% yield). ESI-MS m / z: 418.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.40 (d, J=8.8Hz, 2H), 7.39 (s, 1H), 6.92 (d, J=8.8Hz, 2H), 5.05 (s, 2H), 4.37 (dd, J=4.0Hz, J=11. 2Hz, 1H), 4.25 (dd, J=6.0Hz, J=10.8Hz, 1H), 3.88-3.93 (m, 1H), 3.75 (s, 3H), 3.73 (t, J=4.4Hz, 1H), 3.51 (d, J=5.6Hz, 2H).

[0545] Step 3: (R)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol dimethylsulfonate

[0546]

[0547] (S)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol (22.4 g, 0.0535 mol) and triethylamine (32.5 g, 0.321 mol) were added to dichloromethane (150 mL), and the mixture was cooled to 0 °C. Methanesulfonyl chloride (18.4 g, 0.1605 mol) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, a brown liquid (27.9 g, 90% yield). ESI-MS m / z: 574.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.48 (s, 1H), 7.41 (d, J=8.4Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 5.33-5.37 (m, 1H), 5.03 (s, 2H), 4.63 (dd, J=3. 2Hz, J=11.6Hz, 2H), 4.57 (dd, J=6.0Hz, J=15.2Hz, 1H), 4.54 (dd, J=6.0Hz, J=14.8Hz, 1H), 3.76 (s, 3H), 3.28 (s, 3H), 3.28 (s, 3H).

[0548] Step 4: (R)-3-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimethylsulfonate

[0549]

[0550] (R)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-diol disulfonate (27.9 g, 0.0485 mol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (44.7 g, 0.392 mol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, adjusted to neutral with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (150 mL), dried over anhydrous sodium sulfate, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give the product, a white solid (11.5 g, 52% yield). ESI-MS m / z: 453.9 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 7.36 (s, 1H), 5.18-5.23 (m, 1H), 6.70 (dd, J=6.4Hz, J=11.6Hz, 1H), 4.61 (dd, J= 3.2Hz, J=11.6Hz, 1H), 4.57 (dd, J=4.4Hz, J=12.4Hz, 1H), 4.51 (dd, J=4.8Hz, J=12.0Hz, 1H), 3.30 (s, 3H), 3.26 (s, 3H).

[0551] Step 5: (S)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl methanesulfonate

[0552]

[0553] (R)-3-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimethanesulfonate (11.5 g, 0.0253 mol) was dissolved in N,N-dimethylformamide (150 mL), and potassium carbonate (7.0 g, 0.0506 mol) was added. The mixture was heated to 60 °C and stirred for 2 hours. The reaction solution was poured into water (300 mL), extracted with ethyl acetate (300 mL), and the organic phase was washed with 100 mL of water three times. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give the product as a white solid (7.5 g, 83% yield). ESI-MS m / z: 357.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.48 (s, 1H), 4.72-4.76 (m, 1H), 4.61 (dd, J=2.8Hz, J=12.0Hz, 1H), 4.58 (dd, J=2 .0Hz, J=10.4Hz, 1H), 4.48 (dd, J=6.0Hz, J=11.6Hz, 1H), 4.34 (dd, J=6.8Hz, J=11.6Hz, 1H), 3.26 (s, 3H).

[0554] Step 6: (R)-1-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)-N-(2,4-dimethoxybenzyl)methylamine

[0555]

[0556] (S)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methyl methanesulfonate (8.9 g, 0.0248 mol), 2,4-dimethylbenzylamine (10 g, 0.0744 mol), and triethylamine (19.4 g, 0.192 mol) were dissolved in N,N-dimethylacetamide (150 mL) and heated to 100 °C with stirring overnight. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (300 mL), the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give the product, a colorless liquid (7.4 g, yield 69.4%). ESI-MS m / z: 451.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ7.42 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 6.53 (d, J = 2.4Hz, 1H), 6.47 (dd, J = 2.4Hz, J = 8.0Hz, 1H), 4.55 (dd, J = 2.4Hz, J = 11.6Hz, 1H) , 4.28-4.43(m, 1H), 4.27(dd, J=7.2Hz, J=11.6Hz, 1H), 3.77(s, 3H), 3.74( s, 3H), 3.64 (dd, J=13.6Hz, J=20.8Hz, 2H), 2.72-2.80 (m, 2H), 2.14 (s, 1H).

[0557] Step 7: (R)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methylamine

[0558]

[0559] (R)-1-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)-N-(2,4-dimethoxybenzyl)methylamine (7.4 g, 0.0172 mol) was mixed with trifluoroacetic acid (148.9 g, 1.306 mol) and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure to give the product, a blue-violet liquid (6.8 g, 100% yield), which was used directly in the next reaction. ESI-MS m / z: 278.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.16 (s, 3H), 7.51 (s, 1H), 4.64-4.69 (m, 1H), 4.57 (dd, J=2.8Hz, J=12.0Hz, 1H), 4.35 (dd, J=6.0Hz, J=12.0Hz, 1H), 3.25-3.31 (m, 1H), 3.13-3.19 (m, 1H).

[0560] Step 8: (R)-1-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)-N,N-dimethylmethylamine

[0561]

[0562] The crude (R)-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)methylamine obtained in step 7 (6.8 g, 0.0172 mol) was dissolved in methanol (80 mL), and formaldehyde (40% aqueous solution, 12.8 g, 0.170 mol) and acetic acid (0.1 g, 0.0017 mol) were added. The mixture was stirred at room temperature for 10 minutes, and then sodium triacetylborohydride (36.0 g, 0.17 mol) was slowly added. The reaction mixture was stirred at room temperature for another hour. The reaction mixture was concentrated under reduced pressure, and water (80 mL) was added. The pH was adjusted to approximately 1 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was discarded, and the aqueous phase was adjusted to approximately 8 with solid potassium carbonate. The mixture was extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, a colorless liquid (4.3 g, yield 81%). ESI-MS m / z: 307.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.43 (s, 1H), 4.64-4.69 (m, 1H), 4.50 (dd, J=4.8Hz, J=10.4Hz, 1H), 4.23 (dd, J=7 .6Hz, J=12.0Hz, 1H), 2.63 (dd, J=5.2Hz, J=13.2Hz, 1H), 2.56 (dd, J=7.2Hz, J=13.2Hz, 1H), 2.27 (s, 6H).

[0563] Step 9: (R)-8-bromo-6-chloro-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-7-carboxaldehyde

[0564]

[0565] (R)-1-(8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-2-yl)-N,N-dimethylmethylamine (4.5 g, 0.0146 mol) was dissolved in anhydrous tetrahydrofuran (63 mL) under argon protection, and the internal temperature was lowered to -40 °C. Diisopropylaminolithium (2 M tetrahydrofuran solution, 23 mL, 0.046 mol) was slowly added dropwise. After the addition was complete, the reaction solution was maintained at an internal temperature of -40 °C to -50 °C and stirred for 2 hours. The internal temperature of the reaction solution was lowered to -70 °C, and then anhydrous N,N-dimethylformamide (8.8 g, 0.120 mol) was slowly added dropwise. After the addition was complete, the internal temperature was maintained at -70 °C and stirred for 2 hours. The reaction solution was maintained at an internal temperature of -70 °C, and the reaction was quenched with acetic acid (6 mL), followed by the addition of water (5 mL). The reaction mixture was brought to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 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 = 1:8, v / v) to give the product as a pale yellow solid (1.51 g, 31% yield). ESI-MS m / z: 335.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 4.61 (dd, J=2.8Hz, J=12.0Hz, 1H), 4.55-4.60 (m, 1H), 4.34 (dd, J= 7.2Hz, J=11.6Hz, 1H), 2.64 (dd, J=5.2Hz, J=13.6Hz, 1H), 2.56 (dd, J=7.2Hz, J=13.2Hz, 1H), 2.27 (s, 6H).

[0566] Step 10: Ethyl(R)-2-(6-chloro-2-((dimethylamino)methyl)-7-formyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-8-yl)ethyl acetate

[0567]

[0568] (R)-8-bromo-6-chloro-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-7-carboxaldehyde (330 mg, 0.98 mmol), dimethyl malonate (259 mg, 1.96 mmol), 2-pyridinecarboxylic acid (24 mg, 0.196 mmol), cuprous iodide (19 mg, 0.098 mmol), and potassium carbonate (406 mg, 2.94 mmol) were added to anhydrous DMSO (15 mL). Under argon protection, the reaction mixture was heated at 90 °C for 1 hour. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL), the organic layer was discarded, and the aqueous phase was adjusted to pH 1 with dilute hydrochloric acid and concentrated under reduced pressure. Ethanol (50 mL) was added to the residue, followed by the slow addition of concentrated sulfuric acid (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove ethanol, and water (50 mL) was added. The pH was adjusted to 8 with solid potassium carbonate, and the mixture was extracted with ethyl acetate (50 mL). After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure to give the product, a colorless liquid (85 mg, yield 25%). ESI-MS m / z: 343.1 [M+1] + .

[0569] Step 11: (R)-6-chloro-8-(1-(difluoromethyl)cyclopropane)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-c][2,7]naphthidium-9(8H)-one

[0570]

[0571] Ethyl (R)-2-(6-chloro-2-((dimethylamino)methyl)-7-formyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-8-yl)acetate (85 mg, 0.25 mmol), 1-(difluoromethyl)cyclopropyl-1-amine hydrochloride (72 mg, 0.50 mmol), potassium phosphate (53 mg, 0.25 mmol), and 2,2,2-trifluoroethanol (50 mg, 0.50 mmol) were added to anhydrous tetrahydrofuran (10 mL). The reaction mixture was heated at 100 °C for 2 hours in a sealed tube. The reaction mixture was cooled to room temperature, filtered to remove the solid, and the filtrate was concentrated under reduced pressure and added to anhydrous dioxane (10 mL). Zirconium tetrachloride (58 mg, 0.25 mmol) was added, and the mixture was heated at 100 °C overnight in a sealed tube. The reaction solution was cooled to room temperature, and saturated potassium carbonate aqueous solution (10 mL) was added. Extraction was performed with ethyl acetate (50 mL), and the mixture was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography to obtain the product, an orange-yellow solid (22 mg, 23%). ESI-MS m / z: 386.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 6.50 (s, 1H), 6.29 (t, J=56.4Hz, 1H), 4.53-4.70 (m, 1H), 4.52 (dd, J=4.0Hz, J=11.6Hz, 1H), 4 .22 (dd, J=6.4Hz, J=11.6Hz, 1H), 3.08 (dd, J=8.0Hz, J=16.0Hz, 1H), 2.74 (dd, J=4.0Hz, J=12.0Hz, 1H), 2.50 (s, 6H), 1.24 (m, 4H).

[0572] Step 12: (R)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-(difluoromethyl)cyclopropyl)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-c][2,7]naphthidium-9(8H)-one (Compound 44)

[0573]

[0574] (R)-6-chloro-8-(1-(difluoromethyl)cyclopropane)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-c][2,7]naphthidium-9(8H)-one (13 mg, 0.0337 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (13 mg, 0.0674 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Brettphos Pd G3 (3 mg, 0.00337 mmol) and sodium tert-butoxide (13 mg, 0.135 mmol) were added to anhydrous dioxane (3 mL), and the mixture was heated at 90 °C for 2 hours under argon protection. The reaction solution was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product, a yellow solid (3 mg). ESI-MS m / z: 539.2 [M+1] + .

[0575] Referring to the preparation method of Example 44, and using appropriate raw materials, Examples 45 to 70 in Table 3, namely compounds 45 to 70, were prepared.

[0576] Table 3 Examples 45-70

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] Example 71 (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 71)

[0587]

[0588] Step 1: (R)-4-(6-chloro-3-methoxypyridin-2-yl)-1-((4-methoxybenzyl)oxy)butanol

[0589]

[0590] Lithium diisopropylamino (106.5 mL, 213 mmol, 2.0 M in THF) was added to a tetrahydrofuran solution (150 mL) at -70 °C. Under nitrogen protection, a tetrahydrofuran solution (50 mL) of 6-chloro-3-methoxy-2-methylpyridine (21 g, 133 mmol) was added dropwise at -70 °C. The reaction was stirred at -70 °C for 1 hour, followed by a tetrahydrofuran solution (50 mL) of (R)-2-((4-methoxybenzyl)oxy)methyl)epoxide (26 g, 133 mmol) at -70 °C. The reaction was then stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated ammonium chloride (600 mL) and water (600 mL), and extracted with ethyl acetate (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a yellow liquid (34.5 g, 74% yield). ESI-MS m / z: 352.1 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ7.31-7.22 (m, 2H), 7.12 (d, J=8.6Hz, 1H), 7.08 (d, J=8.6Hz, 1H), 4.48 (s, 2H), 3.82 (s, 3H), 3 .81 (s, 3H), 3.49 (dd, J=9.5, 3.7Hz, 1H), 3.39 (dd, J=9.5, 7.3Hz, 1H), 3.07-2.81 (m, 2H), 2.53 (brs, 1H), 1.97-1.73 (m, 2H).

[0591] Step 2: (R)-6-chloro-2-(3-hydroxy-4-((4-methoxybenzyl)oxy)butyl)pyridine-3-ol

[0592]

[0593] (R)-4-(6-chloro-3-methoxypyridin-2-yl)-1-((4-methoxybenzyl)oxy)butanol (34.5 g, 98.0 mmol) was dissolved in N,N-dimethylformamide (350 mL), and sodium hydroxide (23.5 g, 588 mmol) and dodecyl mercaptan (59 g, 294 mmol) were added. The reaction mixture was stirred at 80 °C for 6 hours. The reaction solution was diluted with saturated ammonium chloride (600 mL) and water (600 mL), and extracted with ethyl acetate (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:2, v / v) to give the product as a colorless liquid (28 g, 85% yield). ESI-MS m / z: 352.1 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.25-7.19 (m, 2H), 7.17 (d, J=8.4Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 6.93-6.83 (m, 2H), 4.45 (d, J=1.7Hz, 2H), 3.81 (s, 3H), 3 .74-3.63 (m, 1H), 3.47 (dd, J=9.5, 3.0Hz, 1H), 3.30 (dd, J=9.5, 8.2Hz, 1H), 3.14-3.03(m, 1H), 2.90-2.81(m, 1H), 1.96-1.84(m, 1H), 1.84-1.74(m, 1H).

[0594] Step 3: (R)-4-bromo-6-chloro-2-(3-hydroxy-4-((4-methoxybenzyl)oxy)butyl)pyridine-3-ol

[0595]

[0596] (R)-6-chloro-2-(3-hydroxy-4-((4-methoxybenzyl)oxy)butyl)pyridine-3-ol (12.8 g, 27.9 mmol) was dissolved in dichloromethane (300 mL), and sodium acetate (15.2 g, 186 mmol) and pyridine tribromide (29.7 g, 92.7 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated sodium sulfite aqueous solution (600 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with dilute hydrochloric acid (300 mL, 1 M in H2O), washed with sodium bicarbonate aqueous solution (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow liquid (31 g, 89% yield). ESI-MS m / z: 337.1 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ7.36 (s, 1H), 7.25-7.19 (m, 2H), 6.98-6.84 (m, 2H), 4.54-4.40 (m, 2H), 3.81 (s, 3H), 3.76-3.68 (m, 1H), 3.48 (dd, J=9.5, 3.0Hz, 1H), 3.30 (dd, J=9.5, 8.1Hz, 1H), 3.15-3.03 (m, 1H), 2.96-2.85 (m, 1H), 1.98-1.85 (m, 1H), 1.85-1.74 (m, 1H).

[0597] Step 4: (S)-8-bromo-6-chloro-2-((4-methoxybenzyl)oxy)methyl)-3,4-dihydro-2H-pyran[3,2-b]pyridine

[0598]

[0599] (R)-4-bromo-6-chloro-2-(3-hydroxy-4-((4-methoxybenzyl)oxy)butyl)pyridin-3-ol (31 g, 74.3 mmol) was dissolved in tetrahydrofuran (300 mL), and triphenylphosphine (29 g, 111 mmol) and diisopropyl azodicarbonate (30 g, 149 mmol) were added under nitrogen protection at 0 °C. The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to give the product as a yellow liquid (25.5 g, 86% yield). ESI-MS m / z: 397.1 [M+1] + .

[0600] Step 5: (S)-(8-bromo-6-chloro-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methanol

[0601]

[0602] (S)-8-bromo-6-chloro-2-((4-methoxybenzyl)oxy)methyl)-3,4-dihydro-2H-pyran[3,2-b]pyridine (25.5 g, 63.9 mmol) was dissolved in dichloromethane (70 mL), and trifluoroacetic acid (70 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness, diluted with saturated sodium bicarbonate aqueous solution (300 mL), and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / ethyl acetate = 3:1, v / v) to give the product as a yellow liquid (14.5 g, 82% yield). ESI-MS m / z: 278.0 [M+1] + .

[0603] Step 6: (S)-(8-bromo-6-chloro-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl methanesulfonate

[0604]

[0605] (S)-(8-bromo-6-chloro-3,4-dihydro-2H-pyridin-2-yl)methanol (14.5 g, 52.0 mmol) was dissolved in dichloromethane (150 mL), and triethylamine (7.9 g, 78.0 mmol) and methanesulfonyl chloride (7.1 g, 62.4 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with water (200 mL) at 0 °C and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow solid (17 g, 92% yield, crude product). ESI-MS m / z: 356.0 [M+1] + .

[0606] Step 7: (S)-6-chloro-N-methyl-2-((methylamino)methyl)-3,4-dihydro-2H-pyran[3,2-b]pyridine-8-amine

[0607]

[0608] (S)-(8-bromo-6-chloro-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl methanesulfonate (17 g, 47.6 mmol) was dissolved in 1,4-dioxane (100 mL), and an aqueous solution of methylamine (200 mL, 23% in H2O) was added. The mixture was then sealed in a tube and stirred for 20 hours at 120 °C. After cooling to room temperature, the solution was concentrated under reduced pressure, and the residue was used directly for the next reaction. ESI-MS m / z: 242.2 [M+1] + .

[0609] Step 8: tert-butyl(S)-(6-chloro-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate

[0610]

[0611] The crude product obtained in step 7 was dissolved in tetrahydrofuran (300 mL), and triethylamine (9.6 g, 95.2 mmol) and di-tert-butyl dicarbonate (21 g, 95.2 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solution was diluted with water (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a colorless liquid (15 g, 92% yield). ESI-MS m / z: 342.2 [M+1] + .

[0612] Step 9: tert-butyl(S)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate

[0613]

[0614] tert-butyl(S)-(6-chloro-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate (15.0 g, 43.9 mmol) was dissolved in acetic acid (50 mL), and N-iodosuccinimide (10.8 g, 18.2 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solution was diluted with saturated sodium sulfite aqueous solution (200 mL), neutralized with saturated sodium bicarbonate aqueous solution (300 mL), and extracted with ethyl acetate (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to give the product as a colorless liquid (18 g, 88% yield). ESI-MS m / z: 468.1 [M+1] + . 1H NMR (400MHz, Chloroform-d) δ4.70 (brs, 1H), 4.26-4.14 (m, 1H), 3.76-3.58 (m, 1H), 3.38 (dd, J=14.6, 4.5Hz, 1H) , 3.22 (s, 3H), 2.96 (s, 3H), 2.93-2.85 (m, 2H), 2.06 (d, J = 10.6Hz, 1H), 1.88-1.75 (m, 1H), 1.45 (d, J = 8.3Hz, 9H).

[0615] Step 10: tert-butyl(S,E)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate

[0616]

[0617] Tert-butyl(S)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate (18 g, 38.5 mmol), palladium acetate (860 mg, 3.85 mmol), tris(o-methylphenyl)phosphine (2.3 mg, 7.69 mmol), triethylamine (7.7 g, 76.9 mmol), and ethyl acrylate (11.5 g, 115 mmol) were dissolved in N,N-dimethylformamide (150 mL). The reaction was carried out under nitrogen protection with stirring at 95 °C for 6 hours. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow liquid (15 g, 89% yield). ESI-MS m / z: 440.2 [M+1] + .

[0618] Step 11: tert-butyl(S)-(6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate

[0619]

[0620] 15 g (34.1 mmol) of tert-butyl(S,E)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyran[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate was dissolved in ethanol (25 mL), and sodium methanethiol (2.6 g, 37.5 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with water (300 mL) and extracted with ethyl acetate (400 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give the product as a yellow liquid (10 g, 75% yield). ESI-MS m / z: 394.2 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ8.01 (d, J=9.6Hz, 1H), 6.74 (d, J=9.6Hz, 1H), 4.30 (d, J=10.8Hz, 1H), 3.94 (s, 3H), 3.86-3.6 8 (m, 1H), 3.41 (d, J = 13.6Hz, 1H), 3.12-3.01 (m, 2H), 2.97 (s, 3H), 2.18 (d, J = 13.8Hz, 1H), 1.98-1.83 (m, 1H), 1.46 (s, 9H).

[0621] Step 12: tert-butyl(S)-(8-bromo-6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate

[0622]

[0623] 10 g (25.4 mmol) of tert-butyl(S)-(6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthid-2-yl)methyl)(methyl)carbamate was dissolved in N,N-dimethylformamide (100 mL), and N-bromosuccinimide (13.5 g, 76.1 mmol) was added. The reaction mixture was stirred at 70 °C for 2 h. The mixture was diluted with 200 mL of saturated sodium sulfite aqueous solution and extracted with ethyl acetate (300 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to give the product as a white solid (5.0 g, 42% yield). ESI-MS m / z: 472.1 [M+1] + . 1H NMR (400MHz, Chloroform-d) δ8.45 (s, 1H), 4.31 (brs, 1H), 4.01 (s, 3H), 3.88-3.62 (m, 1H), 3.49-3. 30 (m, 1H), 3.13-3.00 (m, 2H), 2.97 (s, 3H), 2.19 (d, J=14.3Hz, 1H), 1.99-1.85 (m, 1H), 1.46 (s, 9H).

[0624] Step 13: tert-butyl(S)-(8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate

[0625]

[0626] Tert-butyl(S)-(8-bromo-6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate (500 mg, 1.05 mmol) and 1-acetylpiperidin-4-one (596 mg, 4.23 mmol) were dissolved in tetrahydrofuran (20 mL) under nitrogen protection, and samarium iodide (42 mL, 4.23 mmol, 0.1 min THF) was added dropwise at -30 °C. The reaction was stirred at -30 °C for 0.5 h. The mixture was diluted with saturated ammonium chloride aqueous solution (100 mL) at -30 °C and extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give the product as a yellow solid (800 mg, 71% yield). ESI-MS m / z: 479.3 [M-56] + . 1 HNMR (400MHz, Chloroform-d) δ7.92 (s, 1H), 4.61 (s, 1H), 4.30 (s, 1H), 3.97 (s, 3H), 3.92-3.81 (m, 2H), 3.77 (t, J=6.4Hz, 1H), 3.49-3.32 (m, 2H), 3.09 (dd, J=10.0, 6.0Hz, 2H), 2.97 (s, 3H), 2.49 (q, J=6.8Hz, 2H), 2.20-2.15 (m, 7H), 1.99-1.79 (m, 3H), 1.45 (d, J=14.7Hz, 9H).

[0627] Step 14: tert-butyl(((S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate

[0628]

[0629] Tert-butyl(S)-(8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate (260 mg, 0.486 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-trimethylphosphine Isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (44 mg, 0.049 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (277 mg, 1.46 mmol), and sodium tert-butoxide (140 mg, 1.46 mmol) were dissolved in toluene (8 mL). The mixture was reacted under nitrogen protection with stirring 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 = 20:1, v / v) to give the product as a yellow solid (267 mg, 80% yield). ESI-MS m / z: 688.3 [M+1] + .

[0630] Step 15: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-2-((methylamino)methyl)-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one

[0631]

[0632] Tert-butyl(((S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6]naphthidin-2-yl)methyl)(methyl)carbamate (400 mg, 0.580 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 588.3 [M+1]+ .

[0633] Step 16: (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one

[0634]

[0635] The crude product obtained in step 15 was dissolved in tetrahydrofuran (15 mL), and formaldehyde aqueous solution (3 mL, 30% inH2O) was added. Sodium triacetoxyborohydride (246 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The solution was diluted with saturated sodium chloride aqueous solution (100 mL), and extracted with dichloromethane (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 15:1, v / v) to give the product as a yellow solid (300 mg, yield 86%). ESI-MS m / z: 602.3 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ8.21 (s, 1H), 7.55 (s, 1H), 7.53-7.46 (m, 1H), 7.43 (t, J=7.2Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 6.91 (t, J=55.2Hz, 1H), 5.82 (s, 1H), 5.51 (p, J=6.8Hz, 1H), 5.08 (d, J=6.4Hz, 1H), 4.58 (d, J=12.8Hz, 1H), 4.13 (brs, 1H), 3.91 (s, 3H), 3.6 9 (brs, 2H), 3.15 (t, J=11.4Hz, 1H), 3.05 (dd, J=12.8, 7.2Hz, 1H), 2.91 (dd, J=12.8, 3.6Hz, 1H), 2.86-2.67 (m, 2H), 2.50 (d, J=3.7 Hz, 6H), 2.30-2.16 (m, 2H), 2.13 (d, J=2.9Hz, 3H), 2.10-1.99 (m, 2H), 1.99-1.84 (m, 2H), 1.82-1.69 (m, 1H), 1.62 (d, J=6.8Hz, 3H).

[0636] Step 17: (S)-8-(1-acetyl-4-fluoropiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one

[0637]

[0638] (S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (350 mg, 0.581 mmol) was dissolved in dichloromethane (15 mL) under nitrogen protection, and diethylaminosulfur trifluoride (187 mg, 1.16 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 2 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m / z: 604.3 [M+1] + .

[0639] Step 18: (S)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one

[0640]

[0641] The crude product obtained in step 17 was dissolved in methanol (15 mL), and a methanol solution of sodium methoxide (1.08 g, 5.81 mmol, 30% wtin MeOH) was added. The reaction mixture was stirred at 40 °C for 48 hours. After cooling to room temperature, the solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a yellow solid (55 mg, yield 15%). ESI-MS m / z: 616.4 [M+1] + . 1HNMR (400MHz, Chloroform-d) δ8.21 (s, 1H), 7.68 (d, J=2.0Hz, 1H), 7.56-7.39 (m, 2H), 7.15 (t, J=7.6Hz, 1H), 6.90 (t, J=55.2Hz, 1H), 5.50 (s, 1H), 4.93 (s, 1H), 4.58 (d, J=13.0Hz, 1H), 4.18 (s, 1H), 3.85 (d, J=1.7Hz, 2H), 3.70 (d, J =13.5Hz, 1H), 3.58-3.39(m, 1H), 3.27(s, 3H), 2.95(q, J=14.2Hz, 1H), 2.87-2.72(m, 3H), 2.73-2.58(m, 1H), 2.48( d, J=3.9Hz, 6H), 2.19-2.13 (m, 1H), 2.13 (s, 3H), 2.02 (t, J=11.6Hz, 1H), 1.97-1.80 (m, 2H), 1.63 (d, J=7.0Hz, 3H).

[0642] Example 72 (R)-8-(1-acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 72)

[0643]

[0644] Compound 72 was synthesized following the steps of Example 71, except that the starting material (R)-2-((4-methoxybenzyl)oxy)methyl)ethylene oxide in step 1 was replaced with (S)-2-((4-methoxybenzyl)oxy)methyl)ethylene oxide. ESI-MS m / z: 616.4 [M+1] + . 1H NMR (400MHz, Chloroform-d) δ7.68 (s, 1H), 7.50 (q, J=6.8Hz, 1H), 7.43 (t, J=7.2Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 6.90 (t, J= 55.2Hz, 1H), 5.50 (d, J = 7.2Hz, 1H), 4.93 (brs, 1H), 4.58 (d, J = 13.2Hz, 1H), 4.10 (brs, 1H), 3.87 (s, 3H), 3.70 (d, J = 11.2Hz, 1H), 3.49 (t, J=13.2Hz, 1H), 3.26 (s, 3H), 2.98-2.82 (m, 2H), 2.74 (dd, J=13.2, 6.0Hz, 1H), 2.70-2.61 (m, 2H), 2.61-2.44 ( m, 5H), 2.40 (s, 6H), 2.13 (s, 4H), 2.03 (d, J = 13.2Hz, 1H), 1.88 (d, J = 14.0Hz, 1H), 1.85-1.76 (m, 1H), 1.62 (d, J = 7.2Hz, 3H).

[0645] Example 73 (S)-8-(1-acetyl-4-ethoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 73)

[0646]

[0647] Compound 73 was prepared following the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium ethoxide. ESI-MS m / z: 630.3 [M+1] + .

[0648] Example 74 (S)-8-(1-acetyl-4-isopropoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 74)

[0649]

[0650] Compound 74 was prepared following the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium isopropoxide. ESI-MS m / z: 644.3 [M+1] + .

[0651] Example 75 (S)-8-(1-acetyl-4-(2-hydroxyethoxy)piperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 75)

[0652]

[0653] Compound 75 was prepared following the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium hydroxyethanol. ESI-MS m / z: 646.3 [M+1] + .

[0654] Example 76 (S)-8-(1-acetyl-4-(2,2,2,-trifluoroethoxy)piperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthidium-9(10H)-one (Compound 76)

[0655]

[0656] Compound 76 was prepared following the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium trifluoroethoxide. ESI-MS m / z: 684.3 [M+1] + .

[0657] II. Examples of Activity Testing of Compounds of the Invention

[0658] Test Example 1: Inhibitory effect of compounds on the cell growth of NCI-H358 and MIA PaCa-2 tumor cell lines under 3D culture conditions

[0659] Cell source: NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., Ltd.; MIA PaCa-2 was purchased from Shanghai Dior Biotechnology Co., Ltd.

[0660] Cells in the logarithmic growth phase were seeded in ultra-low adsorption 96-well plates (NCI-H358, MIA PaCa-2 cells 4000, 2000 cells / well, 180 μl / well, respectively), and cultured at 37℃ and 5% CO2 to allow cell aggregation into microspheres. One day later, serially diluted test compounds were added. Specifically: The compound stock solution (10 mM) pre-dissolved in DMSO was serially diluted (4-fold) to 10 different concentrations. Each of these 10 concentrations was then diluted 10-fold with culture medium in another 96-well plate. Finally, 20 μl / well of the compound solution was added to each cell-seeded 96-well plate to achieve the target concentrations (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicates were performed for each concentration, and a blank control was included. After incubating at 37°C and 5% CO2 for 6 days, add 50 μl of CellTiter to each well. 3D reagent (luciferase-ATP bioluminescence assay for detecting 3D cell microspheres, purchased from Promega, catalog number G9683), shaken for 10 min, incubated at room temperature for 20 min, and then the fluorescence intensity was measured (collection time was 100 ms). The cell activity inhibition rate of each compound concentration on 3D cell microspheres was calculated as follows: Cell activity inhibition rate (%) = [(luminescence intensity 6...] 天含细胞培养基对照组 -Luminous intensity 6天化合物组 ) / (luminous intensity) 6天化细胞培养基对照组 -Luminous intensity 6天无细胞培养基对照组 The dose-response curve was calculated using GraphPad Prism 8.3 software, with the IC100% calculated. The data was analyzed using nonlinear S-curve regression to fit the data and derive the dose-response curve. 50 Values. The results are shown in Table 4.

[0661] Table 4

[0662]

[0663] "--" indicates that it has not been tested;

[0664] Among them, BI-3406 is an SOS1 inhibitor reported in the literature (Cancer Discovery 2021(11)142-157).

[0665] The compounds of this invention exhibit good cell growth inhibition effects on NCI-H358 and MIA PaCa-2 tumor cell lines.

Claims

1. A fused-ring compound as shown in Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof; characterized in that, I in: X is -O-, -S-, or -CH2-; Y is -O-; for ; L represents a single bond, -C(=O)-, -C(=O)NR 8 -or-(CH2) p -; Ring A is C 6-12 Aryl or 5-10 heteroaryl groups; Each R 1 Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkyl-O- or with one or more R 1a Replacement C 1-6 alkyl; Each R 1a Independently hydroxyl, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; R 2 It is hydrogen; R 3 C 1-6 Alkyl, with one or more R 3a Replacement C 1-6 Alkyl, C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 6-12 aryl, with one or more R 3f Replacement C 6-12 aryl, 5-10 heteroaryl, with one or more R 3g Substituted 5-10 heteroaryl groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl; Each R 3a R 3d R 3e R 3f R 3g and R 3h Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Cyano group, C 1-6 Alkyl, with one or more R 3-a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 aryl, with one or more R 3-g Replacement C 6-12 Aryl, 5-10 heteroaryl, C 3-7 Cycloalkenyl, -C(=O)-N(R) 7 )2、-S(O)2-R 9 -C(=O)-R 9 or -NR 8 C(=O)-R 9 , or two R 3e Together with the attached ring atoms, they form C 3-7 Cycloalkyl, 3-7 membered heterocyclic or C 3-7 Cycloalkenyl; Each R 3-a R 3-b and R 3-g Each is independently a hydroxyl group, halogen, or C. 1-6 Alkyl or C 1-6 Alkyl-O-; Each R 4 Independently hydroxyl, halogen, -N(R) 7 2. Oxygenation, C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups; Each R 4d Independently hydroxyl, halogen or C 1-6 alkyl; R 5 For hydrogen, halogen, C 1-6 Alkyl or with one or more R 5a Replacement C 1-6 alkyl; Each R 5a Independently hydroxyl or halogen; Each R 7 Independently hydrogen or C 1-6 Alkyl, or two R 7 Together with the nitrogen atom it is attached to, it forms a 3-7 membered heterocyclic group; Each R 8 and R 9 Each is independently hydrogen or C 1-6 alkyl; R 11 C 1-6 alkyl; m is 1, 2, or 3; n is 0 or 1; p is 1 or 2; The 3-7 membered heterocyclic groups are each independently selected from N, O and S as heteroatoms, and the number of heteroatoms is 1, 2 or 3. The 5-10 membered heteroaryl groups are each independently selected from N, O and S for the type of heteroatom, and are 5-10 membered heteroaryl groups with 1, 2 or 3 heteroatoms. when When the carbon atoms are chiral, the fused ring compound shown in Formula I is... , Or a mixture thereof.

2. The fused-ring compound of formula I as described in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) X is -O- or -CH2-; (2) L is a single bond; (3) Each R 1 Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O- or with one or more R 1a Replacement C 1-6 alkyl; (4) Each R 1a Independently hydroxyl, halogen or C 1-6 alkyl; (5) R 3 C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl; (6) Each R 3d R 3e and R 3h Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Cyano group, C 1-6 Alkyl, with one or more R 3 -a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkynyl group, -C(=O)-R 9 or -NR 8 C(=O)-R 9 , or two R 3e Together with the attached ring atoms, they form C 3-7 Cycloalkyl, 3-7 membered heterocyclic or C 3-7 Cycloalkenyl; (7) Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups; (8) Each R 4d Independently for C 1-6 Alkyl or halogen; (9) R 5 It is hydrogen or C 1-6 alkyl; (10) Each R 7 Independently hydrogen or C 1-6 alkyl; (11) The 3-7 membered heterocyclic groups are each independently selected from N, O and S as heteroatoms, and the number of heteroatoms is 1, 2 or 3. (12) The 5-10 heteroaryl group is a 5-10 heteroaryl group whose heteroatom species are independently selected from N, O and S, and whose heteroatom number is 1, 2 or 3.

3. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I: X is either -O- or -CH2-; Y is -O-; for ; L represents a single bond; Ring A is C 6-12 Aryl or 5-10 heteroaryl groups; Each R 1 Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O- or with one or more R 1a Replacement C 1-6 alkyl; Each R 1a Independently hydroxyl, halogen or C 1-6 alkyl; R 2 It is hydrogen; R 3 C 3-7 cycloalkyl, with one or more R 3d Replacement C 3-7 cycloalkyl, 3-7 membered heterocyclic group, with one or more R 3e Substituted 3-7 membered heterocyclic groups, C 3-7 Cycloalkenyl or with one or more R 3h Replacement C 3-7 Cycloalkenyl; Each R 3d R 3e and R 3h Each is independently a hydroxyl group, halogen, or -N(R) 7 2. Cyano group, C 1-6 Alkyl, with one or more R 3-a Replacement C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkynyl group, -C(=O)-R 9 or -NR 8 C(=O)-R 9 , or two R 3e Together with the attached ring atoms, they form C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or surrounded by one or more C groups 3-7 Cycloalkenyl; Each R 3-a and R 3-b Each is independently a hydroxyl group, halogen, or C. 1-6 Alkyl or C 1-6 Alkyl-O-; Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups; Each R 4d Independently for C 1-6 Alkyl or halogen; R 5 It is hydrogen or C 1-6 alkyl; Each R 7 Independently hydrogen or C 1-6 alkyl; Each R 8 and R 9 Each is independently hydrogen or C 1-6 alkyl; R 11 C 1-6 alkyl; m is 1, 2, or 3; n is 0 or 1; p is 1 or 2; The 3-7 membered heterocyclic groups are each independently selected from N, O and S as heteroatoms, and the number of heteroatoms is 1, 2 or 3. The 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group whose heteroatom types are independently selected from N, O and S, and whose number of heteroatoms is 1, 2 or 3.

4. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) X is -O- or -CH2-; (2) Ring A is C 6-12 Aryl; (3) Each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl; (4) Each R 1a Halogens are independent of each other; (5) R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups; (6) Each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkynyl or -C(=O)-R 9 ; (7) Each R 3-b Independently hydroxyl or halogen; (8) Each R 9 Independently hydrogen or C 1-6 alkyl.

5. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused ring compound shown in Formula I, each R 3e Independently hydroxyl, C 1-6 Alkyl-O- or -C(=O)-R 9 .

6. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I: X and Y are each independently -O-; Each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl; Each R 1a Halogens are independent of each other; Ring A is C 6-12 Aryl; for ; L represents a single bond; R 2 It is hydrogen; R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups; Each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkynyl or -C(=O)-R 9 ; R 5 It is hydrogen or C 1-6 alkyl; Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups; Each R 4d Independently for C 1-6 Alkyl or halogen; Each R 7 Independent hydrogen or C 1-6 alkyl; Each R 9 Independently hydrogen or C 1-6 alkyl; R 11 C 1-6 alkyl; m is 1, 2, or 3; n is 0 or 1.

7. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I: X is either -O- or -CH2-; Y is -O-; for ; Each R 1 Independent of halogen, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl; Each R 1a Halogens are independent of each other; Ring A is C 6-12 Aryl; L represents a single bond; R 2 It is hydrogen; R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e Substituted 3-7 membered heterocyclic groups; Each R 3e Independently hydroxyl, halogen, -N(R) 7 2. Cyano group, C 1-6 Alkyl, C 1-6 Alkyl-O-, with one or more R 3-b Replacement C 1-6 Alkyl-O-, C 2-6 alkynyl or -C(=O)-R 9 ; Each R 3-b Independently hydroxyl or halogen; R 5 It is hydrogen or C 1-6 alkyl; Each R 4 Independently for C 1-6 Alkyl, -C 1-4 Alkylene-N(R) 7 )2, 3-7 membered heterocyclic groups or surrounded by one or more R 4d Substituted 3-7 membered heterocyclic groups; Each R 4d Independently for C 1-6 Alkyl or halogen; Each R 7 Independent hydrogen or C 1-6 alkyl; Each R 9 Independently hydrogen or C 1-6 alkyl; R 11 C 1-6 alkyl; m is 1, 2, or 3; n is 0 or 1.

8. The fused-ring compound of formula I according to claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I: for ; for , , , , , or ; L represents a single bond; R 3 for or ; R 11 It is a methyl group.

9. The fused-ring compound of formula I according to claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I: for ; for , , , , , , , or ; L represents a single bond; R 3 for or ; R 11 It is a methyl group.

10. The fused-ring compound of Formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) When ring A is C 6-12 When aryl, the C 6-12 The aryl group is phenyl or naphthyl; (2) When ring A is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-10 membered heteroaryl with N heteroatom and 1 or 2 heteroatoms; (3) When R 1 For one or more R 1a Replacement C 1-6 When alkyl, the substance is subjected to one or more R 1a Replacement C 1-6 The alkyl group is -CHF2, -CF3, -CF2CH3, -CF2CH2OH or -CF2C(CH3)2OH; (4) When R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e When a 3-7 membered heterocyclic group is substituted, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group in which the heteroatom species are independently selected from N and O, and the number of heteroatoms is 1 or 2. (5) When R 3 C 3-7 cycloalkyl or with one or more R 3d Replacement C 3-7 When cycloalkyl, the C 3-7 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or... ; (6) When each R 3d and R 3e C independently 2-6 When alkynyl group is used, the C 2-6 The alkynyl group is either ethynyl or propynyl; (7) When R 4 -C 1-4 Alkylene-N(R) 7 At time 2, the two Rs 7 When the -C atom forms a 3-7 membered heterocyclic group together with the attached nitrogen atom, the -C 1-4 Alkylene-N(R) 7 )2 is ; (8) When R 4 -C 1-4 Alkylene-N(R) 7 When )2, the R 7 Independently for C 1-6 When alkyl; the -C 1-4 Alkylene-N(R) 7 )2 is ; (9) When R 4 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 4d The substituted 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group in which the heteroatom type is N and the number of heteroatoms is 1 or 2; (10) Two Rs 7 When a 3-7 membered heterocyclic group is formed together with the nitrogen atom attached thereto, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group in which the heteroatom type is N and the number of heteroatoms is 1 or 2; (11) When R 1 R 1a R 3d R 3e R 3h R 3-a R 3-b R 4 R 4d R 5 R 7 R 8 R 9 or R 11 C 1-6 Alkyl or substituent C 1-6 When alkyl, the C 1-6 Each alkyl group is independently C10. 1-4 alkyl; (12) When R 1 R 1a R 3d R 3e R 3h R 3-a R 3-b or R 4d When the halogen is halogen, each halogen is independently F, Cl, Br or I; (13) When R 1 R 3d R 3e R 3h R 3-a or R 3-b C 1-6 Alkyl-O- or C-substituted with a substituent 1-6 When alkyl-O-, the C 1-6 Alkyl groups -O- are each independently C 1-4 Alkyl-O-.

11. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) When ring A is C 6-12 When aryl, the C 6-12 The aryl group is phenyl; (2) When ring A is a 5-10 member heteroaryl, the 5-10 member heteroaryl is ; (3) When R 3 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 3e When the 3-7 membered heterocyclic group is replaced, the 3-7 membered heterocyclic group is , , , , , , , or ; (4) When R 4 It is a 3-7 membered heterocyclic group or is surrounded by one or more R groups. 4d The substituted 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is , or ; (5) Two Rs 7 When it forms a 3-7 membered heterocyclic group together with the attached nitrogen atom, the 3-7 membered heterocyclic group is... ; (6) When R 1 R 1a R 3d R 3e R 3h R 3-a R 3-b R 4 R 4d R 5 R 7 R 8 R 9 or R 11 C 1-6 Alkyl or substituent C 1-6 When alkyl, the C 1-6 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (7) When R 1 R 1a R 3d R 3e R 3h R 3-a R 3-b or R 4d When the halogen is halogen, each halogen is independently either F or Cl; (8) When R 1 R 3d R 3e R 3h R 3-a or R 3-b C 1-6 Alkyl-O- or C-substituted with a substituent 1-6 When alkyl-O-, the C 1-6 The alkyl-O- groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

12. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) When R 1 R 1a R 3d R 3e R 3h R 3-a R 3-b R 4 R 4d R 5 R 7 R 8 R 9 or R 11 C 1-6 Alkyl or substituent C 1-6 When alkyl, the C 1-6 Each alkyl group is independently methyl, ethyl, or isobutyl; (2) When R 1 R 3d R 3e R 3h R 3-a or R 3-b C 1-6 Alkyl-O- or C-substituted with a substituent 1-6 When alkyl-O-, the C 1-6 The alkyl-O- groups are each independently methoxy, ethoxy, or isopropoxy.

13. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused-ring compound shown in Formula I, when R 1 R 3d R 3e R 3h R 3-a or R 3-b C 1-6 Alkyl-O- or C-substituted with a substituent 1-6 When alkyl-O-, the C 1-6 The alkyl-O- groups are each independently methoxy or ethoxy.

14. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) Ring A is , , or ; (2) R 1 For F, Cl, -CN, -CHF2, -CF3, -CH3, -CF2CH2OH, -CF2CH3, -NH2 or -CF2C(CH3)2OH; (3) R 3 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; (4) R 4 -CH3, , , or ; (5) for The b-end is connected to the Z atom. (6) R 11 It is a methyl group.

15. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1) R 3 for or ; (2) for or ; wherein the b end is connected to the Z atom.

16. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1A) for , , , , , , , , , , , , , or ; (1B) for , , , , , , , , , , or .

17. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (1A) for ; (1B) for , , , , , , , or .

18. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compounds of Formula I satisfy one or more of the following conditions: (2A) for , , , , , , , , , , or ; (2B) The fused-ring compound as shown in Formula I is .

19. The fused-ring compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, In the fused ring compound shown in Formula I, for , , , , , , , or .

20. The fused-ring compound of Formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof; characterized in that, The fused-ring compound represented by Formula I is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

21. A method for preparing a fused-ring compound of formula I as described in any one of claims 1-20, its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising the following steps: When the fused-ring compound as shown in Formula I is compound Ia, compound Ia-6 and Compound Ia was obtained via a Buchwald–Hartwig coupling reaction; 。 22. The preparation method according to claim 21, wherein the Buchwald–Hartwig coupling reaction is carried out in the presence of a catalyst and a base; the catalyst is one or more of RuPhos Pd G3, BrettPhos Pd G3, XPhos Pd G3, XantPhos Pd G3, RuPhos Pd G4, and BrettPhos Pd G4; and the base is one or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

23. The preparation method according to claim 21, further comprising the following steps: ； The compound I-1 and R 5 -NH2 undergoes a substitution reaction to give compound Ia-1; The compound Ia-1 was reacted with an iodination reagent via an iodination reaction to yield compound Ia-2; The compound Ia-2 and Compound Ia-3 was obtained via Heck coupling reaction; The compound Ia-3 was subjected to a cyclization reaction under alkaline conditions to yield compound Ia-4; The compound Ia-4 was reacted with a brominating reagent via a bromination reaction to yield compound Ia-5; The compound Ia-5 reacts with the corresponding substituted ketones, amines, or borate ester derivatives to give compound Ia-6.

24. The preparation method according to claim 23, wherein in the iodination reaction, the iodination reagent is N-iodosuccinimide and / or I2.

25. The preparation method according to claim 23, wherein in the ring-closing reaction, the base is one or more of sodium methanethiol, sodium methoxide, and sodium ethoxide.

26. The preparation method according to claim 23, wherein in the bromination reaction, the brominating agent is N-bromosuccinimide and / or Br2.

27. A pharmaceutical composition; characterized in that, The pharmaceutical composition comprises: (1) Substance X, wherein substance X is a fused-ring compound of formula I as described in any one of claims 1-20, its stereoisomers or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

28. The use of a substance X or the pharmaceutical composition as described in claim 27 in the preparation of an SOS1 inhibitor, characterized in that, The substance X is a fused-ring compound of Formula I as described in any one of claims 1-20, its stereoisomer, or a pharmaceutically acceptable salt thereof.

29. The use of a substance X or the pharmaceutical composition as described in claim 27 in the preparation of a medicament; characterized in that, The substance X is a fused-ring compound of Formula I as described in any one of claims 1-20, its stereoisomer, or a pharmaceutically acceptable salt thereof; the drug is a drug for treating and / or preventing diseases related to SOS1 activity or expression levels.

30. The application as described in claim 29, wherein the diseases associated with SOS1 activity or expression are selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, granulosa cell tumors of the skin, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, squamous cell carcinoma of the head and neck, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, monocytic leukemia, splenomegaly with polycythemia, eosinophilic leukemia syndrome, and multiple myeloma, as well as diseases associated with SOS1 genetic mutations.

31. The application as described in claim 29, wherein the disease associated with SOS1 activity or expression is selected from lung adenocarcinoma, lung squamous cell carcinoma, endometrial carcinoma, and B-cell lymphoma.

32. The application as described in claim 30, wherein the disease associated with the SOS1 hereditary mutation is selected from neurofibromatosis type I, Noonan syndrome, Noonan syndrome with multiple freckles, capillary malformation-arteriovenous malformation syndrome, cardiofacial-skin syndrome, Kristillo syndrome, Reggio Emilia syndrome, and hereditary gingival fibroma type I.

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