A heterocyclic compound, a pharmaceutical composition thereof, and use thereof

Abstract

The application discloses a heterocyclic compound, a pharmaceutical composition thereof and application of the heterocyclic compound. The structure of the heterocyclic compound is shown in formula I. The heterocyclic compound has a strong inhibitory effect on STAT3, and is expected to be applied to treatment and / or prevention of various diseases related to STAT3.

Description

Technical Field

[0001] This invention relates to a heterocyclic compound, its pharmaceutical composition, and its application. Background Technology

[0002] STAT3, a cell signal transducer and activator of transcription, is widely involved in various physiological and pathological processes in vivo through transcriptional regulation. Under normal circumstances, STAT3 is transiently activated by both activating and negative regulators; however, in many malignant tumors and autoimmune diseases, STAT3 signaling is persistently activated and highly expressed. Studies have shown that inhibiting the phosphorylation of STAT3 protein can effectively suppress tumor growth and metastasis.

[0003] Currently, some compounds targeting the STAT3 protein are in preclinical or clinical research stages, but due to poor bioactivity and selectivity, they have not yet achieved good clinical results. There are currently no marketed STAT3 inhibitors, indicating significant room for further research on this target. Summary of the Invention

[0004] The technical problem this invention aims to solve is the lack of effective STAT3 inhibitors in the prior art, by providing a heterocyclic compound, its pharmaceutical composition, and its applications. The heterocyclic compound of this invention can inhibit STAT3 activity, thus holding promise for the treatment of STAT3-mediated diseases.

[0005] This invention provides a heterocyclic compound as shown in Formula I, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules:

[0006]

[0007] in,

[0008] X 1 For NR 4 , O or S;

[0009] R 4 For hydrogen, C 1-6 Alkyl, with one or more R 4-1 Replacement C 1-6 Alkyl, -C(=O)R 4a -C(=O)OR 4b -C(=O)NR 4c1 R 4c2 C 6-20 aryl, with one or more R 4-2 Replacement C 6-20Aryl, "a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 4-3 Substituted "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 3-12 cycloalkyl, with one or more R 4-4 Replacement C 3-12 Cycloalkyl, "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N, 4-12 membered heterocycloalkyl", and surrounded by one or more R 4-5 Substituted "containing 1-3 heteroatoms, the heteroatoms being independently selected from 4-12 membered heterocyclic alkyl groups of O, S, and N", C 5-7 Cycloalkenyl, with one or more R 4-6 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 4-7 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0010] R 4-1 For deuterium, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 41a -NR 41b1 R 41b2 -C(=O)OR 41c -C(=O)NR 41d1 R 41d2 -S(O)2NR 41e1 R 41e2 -S(O)2R 41f C 6-20 aryl, with one or more R 41-1 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 41-2 Substituted "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 3-12 cycloalkyl, with one or more R 41-3 Replacement C 3-12 Cycloalkyl, "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N, 4-12 membered heterocycloalkyl", and surrounded by one or more R 41-4Substituted "containing 1-3 heteroatoms, the heteroatoms being independently selected from 4-12 membered heterocyclic alkyl groups of O, S, and N", C 5-7 Cycloalkenyl, with one or more R 41-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 41-6 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0011] R 4-2 R 4-3 R 4-4 R 4-5 R 4-6 R 4-7 R 41-1 R 41-2 R 41-3 R 41-4 R 41-5 and R 41-6 Independently for C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -C(=O)R 42a -NR 42b1 R 42b2 -C(=O)OR 42c -C(=O)NR 42d1 R 42d2 -S(O)2NR 42e1 R 42e2 -S(O)2R 42f -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms independently selected from O, S, and N", C 3-12 Cycloalkyl, "4-12 membered heterocyclic alkyl groups containing 1-3 heteroatoms independently selected from O, S, and N", C 5-7Cycloalkenyl, or "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N in 5-7 membered heterocyclic alkenyl groups"; when there are multiple substituents, they may be the same or different;

[0012] R 4a R 4b R 4c1 R 4c2 R 41a R 41b1 R 41b2 R 41c R 41d1 R 41d2 R 41e1 R 41e2 R 41f R 42a R 42b1 R 42b2 R 42c R 42d1 R 42d2 R 42e1 R 42e2 and R 42f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0013] X 2 For CR 5 Or N;

[0014] R 5 For hydrogen, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, hydroxyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R 5a -NR 5b1 R 5b2 -C(=O)OR 5c -C(=O)NR 5d1 R 5d2 -S(O)2NR 5e1 R 5e2 , or, -S(O)2R5f When there are multiple substituents, they may be the same or different.

[0015] R 5a R 5b1 R 5b2 R 5c R 5d1 R 5d2 R 5e1 R 5e2 and R 5f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0016] Y 1 and Y 4 Independent for CR 6 Or N;

[0017] Y 2 For CR 8 Y 3 For CR 7 Or N; or Y 3 For CR 8 Y 2 For CR 7 Or N;

[0018] R 6 and R 7 Independently hydrogen, C 1-6 Alkyl groups, halogens, and C atoms substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0019] R 8 for

[0020] n2 is 0, 1, 2 or 3;

[0021] It is a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N; or a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N;

[0022] R 9 It is cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, with one or more R9-1 Replacement C 1-6 Alkyl, halogen, hydroxyl, -OC 1-6 Alkyl, with one or more R 9-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 9-3 Replacement -SC 1-6 Alkyl, -C(=O)R 9a -NR 9b1 R 9b2 -C(=O)OR 9c -C(=O)NR 9d1 R 9d2 -S(O)2NR 9e1 R 9e2 -S(O)2R 9f C 3-12 cycloalkyl, with one or more R 9-4 Replacement C 3-12 Cycloalkyl, "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N", and surrounded by one or more R 9-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 9-6 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 9-7 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0023] R 9-1 R 9-2 R 9-3 R 9-4 R 9-5 R 9-6 R 9-7 R 9-8 and R 9-9 Independently deuterium, azide, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, with one or more R9-1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 9-1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 91a -NR 91b1 R 91b2 -C(=O)OR 91c -C(=O)NR 91d1 R 91d2 -S(O)2NR 91e1 R 91e2 -S(O)2R 91f , C 3-12 cycloalkyl, with one or more R 9-1-4 Replacement C 3-12 Cycloalkyl, "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N", and surrounded by one or more R 9-1-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 9-1-6 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 9-1-7 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 9-1-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-1-9 The substituent is a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N; when there are multiple substituents, they may be the same or different; or, when R 9-4 R 9-5 R 9-8 and R 9-9 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-4 Two Rs 9-5 Two Rs 9-8 Or two Rs 9-9 They connect to each other, forming C atoms with the atoms they are connected to.3-12 Cycloalkanes, or, "containing 1-3 heteroatoms, the heteroatoms being independently selected from 5-7 membered heterocycles selected from O, S, and N"; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N";

[0024] R 9-1-1 R 9-1-2 R 9-1-3 R 9-1-4 R 9-1-5 R 9-1-6 R 9-1-7 R 9-1-8 and R 9-1-9 Independently deuterium, azide, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 911a -NR 911b1 R 911b2 -C(=O)OR 911c -C(=O)NR 911d1 R 911d2 -S(O)2NR 911e1 R 911e2 or -S(O)2R 911f ;

[0025] R 9a R 9b1 R 9b2 R 9c R 9d1 R 9d2 R 9e1 R 9e2 R 9f R 91a R 91b1 R 91b2 R 91c R 91d1 R 91d2 R 91e1 R 91e2 R 91f R 911a R 911b1 R 911b2 R 911c R 911d1 R 911d2 R 911e1 R 911e2 and R911f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0026] n3 can be 0, 1, 2, or 3;

[0027] R 10 It is an azide group, halogen, hydroxyl group, cyano group, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R 10a -NR 10b1 R 10b2 -C(=O)OR 10c -C(=O)NR 10d1 R 10d2 -S(O)2NR 10e1 R 10e2 -S(O)2R 10f C 3-12 Cycloalkyl, "4-12 membered heterocyclic alkyl groups containing 1 to 3 heteroatoms independently selected from O, S, and N", C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl, or "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N in 5-7 membered heterocyclic alkenyl groups"; when there are multiple substituents, they may be the same or different;

[0028] R 10a R 10b1 R 10b2 R 10c R 10d1 R 10d2 R 10e1 R 10e2 and R 10f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0029] L2 is the connection key. C 1-6 Alkylene, by one or more R 11 Replacement C 1-6 Alkylene, O, S or NR 12 ;

[0030] R 11 For deuterium, halogen, cyano, hydroxyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR 11d1 R 11d2 -S(O)2NR 11e1 R 11e2 -S(O)2R 11f =O, -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0031] R 12 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R 12a -NR 12b1 R 12b2 -C(=O)OR 12c -C(=O)NR 12d1 R 12d2 -S(O)2NR 12e1 R 12e2 or -S(O)2R 12f When there are multiple substituents, they may be the same or different.

[0032] R 11a R 11b1 R 11b2 R 11c R 11d1 R 11d2 R 11e1 R 11e2 R 11f R 12a R 12b1 R 12b2 R 12c R 12d1 R 12d2 R 12e1R 12e2 and R 12f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0033] L1 is End b is connected to ring A, and Z is either O or S;

[0034] R 3 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0035] L 11 C 1-6 Alkylene, by one or more R 13 Replacement C 1-6 Alkylene, C 2-6 alkynyl group, with one or more R 14 Replacement C 2-6 alkynyl group, C 2-6 alkenyl or with one or more R 15 Replacement C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different;

[0036] R 13 R 14 and R 15 Independently deuterium, halogen, cyano, hydroxyl, -C(=O)R 13a -NR 13b1 R 13b2 -C(=O)OR 13c -C(=O)NR 13d1 R 13d2 -S(O)2NR 13e1 R 13e2 -S(O)2R 13f -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0037] R 13a R 13b1 R 13b2 R 13c R 13d1 R 13d2 R 13e1 R 13e2 and R 13f Independently hydrogen, C1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0038] Ring A is C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N";

[0039] n1 is 0, 1, 2, 3, 4 or 5;

[0040] R 1 For deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl, with one or more R 1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 1a -NR 1b1 R 1b2 -C(=O)OR 1c -C(=O)NR 1d1 R 1d2 -S(O)2NR 1e1 R 1e2 or -S(O)2R 1f When there are multiple substituents, they may be the same or different.

[0041] R 1-1 R 1-2 and R 1-3 Independently halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR11d1 R 11d2 -S(O)2NR 11e1 R 11e2 or -S(O)2R 11f ;

[0042] R 1a R 1b1 R 1b2 R 1c R 1d1 R 1d2 R 1e1 R 1e2 R 1f R 11a R 11b1 R 11b2 R 11c R 11d1 R 11d2 R 11e1 R 11e2 and R 1f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0043] R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl, -SR 2e , by one or more R 2f Replacement -SC 1-6 Alkyl, -NR 2g1 R 2g2 , or, by one or more R 2h Replacement -NR 2i C 1-6 Alkyl; R 2b OR 2b1 SR 2b2 or -NR 2b31 R 2b32 When there are multiple substituents, they may be the same or different.

[0044] R 2g2 R 2i and R 2b32 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0045] R 2a R 2b1 R 2b2 R 2b31 R 2c R 2d R 2e R 2f R 2g1 and R 2h Independently for C 3-12 cycloalkyl, with one or more R 2-1 Replacement C 3-12 Cycloalkyl, "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N", and surrounded by one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 2-4 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 2-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-6 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0046] R 2-1 R 2-2 R 2-3 R 2-4 R 2-5 and R 2-6 Independently, it is an azide group, halogen, hydroxyl group, cyano group, C 1-6 Alkyl, with one or more R 2-1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6Alkyl, with one or more R 2-1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 21a -NR 21b1 R 21b2 -C(=O)OR 21c -C(=O)NR 21d1 R 21d2 -S(O)2NR 21e1 R 21e2 -S(O)2R 21f C 3-12 cycloalkyl, -OC 3-12 Cycloalkyl, "4-12 membered heterocyclic alkyl groups containing 1 to 3 heteroatoms independently selected from O, S, and N", C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0047] R 2-1-1 R 2-1-2 and R 2-1-3 Independently, it is an azide group, halogen, hydroxyl group, cyano group, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 22a -NR 22b1 R 22b2 -C(=O)OR 22c -C(=O)NR 22d1 R 22d2 -S(O)2NR 22e1 R 22e2 -S(O)2R 22f C 3-12 Cycloalkyl, "4-12 membered heterocyclic alkyl groups containing 1 to 3 heteroatoms independently selected from O, S, and N", C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0048] R 21a R 21b1 R 21b2 R 21c R 21d1R 21d2 R 21e1 R 21e2 R 21f R 22a R 22b1 R 22b2 R 22c R 22d1 R 22d2 R 22e1 R 22e2 and R 22f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0049] R 4c1 and R 4c2 R 41b1 and R 41b2 R 41d1 and R 41d2 R 41e1 and R 41e2 R 42b1 and R 42b2 R 42d1 and R 42d2 R 42e1 and R 42e2 R 5b1 and R 5b2 R 5d1 and R 5d2 R 5e1 and R 5e2 R 9b1 and R 9b2 R 9d1 and R 9d2 R 9e1 and R 9e2 R 91b1 and R 91b2 R 91d1 and R 91d2 R 91e1 and R 91e2 R 911b1 and R 911b2 R 911d1 and R 911d2 R 911e1 and R 911e2 R 10b1 and R 10b2 R 10d1 and R 10d2 R 10e1 and R 10e2 R 11b1 and R 11b2R 11d1 and R 11d2 R 11e1 and R 11e2 R 12b1 and R 12b2 R 12d1 and R 12d2 R 12e1 and R 12e2 R 13b1 and R 13b2 R 13d1 and R 13d2 R 13e1 and R 13e2 R 1b1 and R 1b2 R 1d1 and R 1d2 R 1e1 and R 1e2 R 11b1 and R 11b2 R 11d1 and R 11d2 R 11e1 and R 11e2 R 21b1 and R 21b2 R 21d1 and R 21d2 R 21e1 and R 21e2 R 22b1 and R 22b2 R 22d1 and R 22d2 R 22e1 and R 22e2 Independently, each of them, together with the attached N, forms a 3- to 8-membered heterocycle containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N, or is formed by one or more R... a The substituted ring "contains 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from 3 to 8-membered heterocycles of O, S, and N"; R a Independently, it can be O, hydroxyl, halogen, cyano, or C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)Ra1 -NR a21 R a22 -C(=O)OR a3 -C(=O)NR a41 R a42 -S(O)2NR a51 R a52 or -S(O)2R a6 ;R a1 R a21 R a22 R a3 R a41 R a42 R a51 R a52 and R a6 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 Alkyl group; when there are multiple substituents, they may be the same or different.

[0050] In one embodiment, the structure of the heterocyclic compound as shown in Formula I, its stereoisomers, its pharmaceutically acceptable salt, the stereoisomers of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule is shown in Formula II:

[0051]

[0052] in,

[0053] It can be a single bond or a double bond;

[0054] B is C, CH, or N;

[0055] Y 3 For CR 7 Or N;

[0056] The definitions of other groups are as described above.

[0057] In one embodiment, the structure of the heterocyclic compound, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule as shown in Formula I or II is as shown in Formula III:

[0058]

[0059] in,

[0060] It has aromatic properties;

[0061] It can be a single bond or a double bond;

[0062] B is C, CH, or N;

[0063] Y 3 For CR 7 Or N;

[0064] G1 and G2 are independently C or N;

[0065] G3, G4 and G5 are independently C, CH, NH, N, O or S;

[0066] The definitions of other groups are as described above.

[0067] In one embodiment, the structure of a heterocyclic compound, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule, as shown in Formula I, II, or III, is as shown in Formula IV:

[0068]

[0069] in,

[0070] It has aromatic properties;

[0071] It can be a single bond or a double bond;

[0072] B is C, CH, or N;

[0073] G1 and G2 are independently C or N;

[0074] G3 and G4 are independently C, CH, NH, N, O or S;

[0075] L3 represents O and C. 1-6 Alkylene or NR 2g2 ;R 2g2 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 alkyl;

[0076] Ar is C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 aryl, "a 5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-4 The substituted "contains 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S and N";

[0077] The definitions of other groups are as described above.

[0078] In one scheme, in the heterocyclic compound shown in Formula I,

[0079] X 1 For NR 4 O or S, R 4 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, or, C 3-12 cycloalkyl;

[0080] X 2 For CR 5 Or N, R 5 It is hydrogen;

[0081] Y 1 and Y 4 Independent for CR 6 ;

[0082] Y 2 For CR 8 Y 3 For CR 7 Or N; or Y 3 For CR 8 Y 2 For CR 7 Or N; R 6 and R 7 Independently hydrogen;

[0083] R 8 for

[0084] n2 is 0 or 1;

[0085] n3 is 0;

[0086] The terms are: "a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N", "a 5-membered or 5-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N", or "a 6-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N".

[0087] R 9 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, halogen, or with one or more R9-5 The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in a 4 to 12-membered heterocyclic alkyl group", and is subjected to one or more R 9-6 Replacement C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0088] R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 They connect to each other, forming C atoms with the atoms they are connected to. 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N";

[0089] R 9-1-1 and R 9-1-2 Halogens are independent of each other;

[0090] R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C1-6 alkyl;

[0091] L2 is the connection key. C 1-6 Alkylene, O, S or NR 12 ;R 12 It is hydrogen or C 1-6 alkyl;

[0092] L1 is End b is connected to ring A, and Z is O;

[0093] R 3 It is hydrogen or C 1-6 alkyl;

[0094] L 11 C 1-6 Alkylene or C 2-6 alkynyl group;

[0095] Ring A is C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S and N, 5 to 12-membered heteroaryl" or "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S and N, 5 to 7-membered heterocyclic alkenyl";

[0096] n1 is either 0 or 1;

[0097] R 1 C 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl or with one or more R 1-2 Replacement -OC 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0098] R 1-1 and R 1-2 Halogens are independent of each other;

[0099] R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl, or, -NR 2g1 R 2g2 When there are multiple substituents, they may be the same or different.

[0100] R 2g2 It is hydrogen or C 1-6 alkyl;

[0101] R 2a R 2c R 2d and R 2g1 Independently halogenated, by one or more R 2-2 The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in a 4 to 12-membered heterocyclic alkyl group", and is subjected to one or more R 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 Substitutions are defined as "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different;

[0102] R 2-2 R 2-3 and R 2-4 Independently halogenated, by one or more R 2-1-1 Replacement C 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl or -OC 3-12 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0103] R 2-1-1 and R 2-1-2 Halogens are independent of each other.

[0104] In one scheme, in the heterocyclic compound shown in Formula IV, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules,

[0105] It can be a single bond or a double bond;

[0106] G1 and G2 are independently C or N;

[0107] G3 and G4 are independently C, O, CH, NH or N;

[0108] n2 is 0 or 1;

[0109] R 9 Halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, halogen, C 3-12 cycloalkyl, with one or more R 9-5The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in a 4 to 12-membered heterocyclic alkyl group", and is subjected to one or more R 9-6 Replacement C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0110] R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 Formation C 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N";

[0111] R 9-1-1 and R 9-1-2 Halogens are independent of each other;

[0112] R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C 1-6 alkyl;

[0113] X 1 For NR 4 O or S; R 4 For hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl or C substituted with one or more halogens 1-6 alkyl;

[0114] B is CH, C, or N;

[0115] n1 is either 0 or 1;

[0116] R 1 C 1-6 alkyl;

[0117] L3 represents O and C. 1-6 Alkylene or NR 2g2 ;R 2g2 It is hydrogen or C 1-6 alkyl;

[0118] Ar is a variable that is controlled by one or more R. 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 The substituted "contains 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S and N";

[0119] R 2-3 and R 2-4 C that is independently a halogen, or a C substituted with one or more halogens. 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl or -OC 3-12 Cycloalkyl.

[0120] In one of the proposed solutions, X 1 For NR 4 O or S, R 4 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, or, C 3-12 Cycloalkyl.

[0121] In one of the proposed solutions, X 1 For NR 4 O or S, X 2 For CR 5 ;R 4 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, or, C 3-12 Cycloalkyl.

[0122] In one of the schemes, Y 1 and Y4 Independent for CR 6 Y 2 For CR 8 Y 3 For CR 7 ;R 6 and R 7 It is hydrogen independently.

[0123] In one particular scheme, R 9 Independent of halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, with one or more R 9-5 The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in a 4 to 12-membered heterocyclic alkyl group", and is subjected to one or more R 9-6 Replacement C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0124] R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 Formation C 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N";

[0125] R 9-1-1 and R 9-1-2 Halogens are independent of each other;

[0126] R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C 1-6 alkyl.

[0127] In one scheme, L2 is the connection key. C 1-6 Alkylene, O, S or NR 12 ;R 12 It is hydrogen or C 1-6 alkyl.

[0128] In one scheme, L1 is End b is connected to ring A, and Z is O;

[0129] R 3 It is hydrogen or C 1-6 alkyl;

[0130] L 11 C 1-6 Alkylene, C 2-6 alkynyl or C 2-6 Alkenyl group.

[0131] In one particular scheme, R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl-NR 2g1 R 2g2 When there are multiple substituents, they may be the same or different.

[0132] R 2g2 It is hydrogen or C 1-6 alkyl;

[0133] R 2a R 2c R2d and R 2g1 and independently for one or more R 2-2 The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in a 4 to 12-membered heterocyclic alkyl group", and is subjected to one or more R 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 Substitutions are defined as "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different;

[0134] R 2-2 R 2-3 and R 2-4 Independently halogenated, by one or more R 2-1-1 Replacement C 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl, or, -OC 3-12 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0135] R 2-1-1 and R 2-1-2 Halogens are independent of each other.

[0136] In one scheme, when L 11 C 2-6 When alkynyl group, L 11 for

[0137] In one of the solutions, In this ring, the C ring contains 1 to 4 heteroatoms, which are independently selected from 5- or 6-membered heteroaromatic rings of O, S, and N.

[0138] In one of the solutions, In this structure, both ring C and ring D are aromatic rings.

[0139] In one of the solutions, for

[0140] In one of the solutions, for

[0141] In one scheme, n2 is either 0 or 1.

[0142] In one particular scheme, n3 is 0.

[0143] In one particular scheme, R 9 for Cl, -CN, methyl, Ethyl, In one of the solutions, for

[0144] In one scheme, L1 is End b is connected to ring A, and Z is O.

[0145] In one of the solutions, for

[0146] In one scheme, L2 is -O-, the connector, -CH2-、 -S- or

[0147] In one particular scheme, R 2 For hydrogen,

[0148] In one embodiment, the heterocyclic compound represented by Formula I, its stereoisomer, its pharmaceutically acceptable salt, the stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule has any of the following structures:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] The present invention also provides a pharmaceutical composition comprising substance A and a pharmaceutical excipient; wherein substance A is a therapeutically effective amount of the above-described heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule.

[0155] The present invention also provides the use of substance A in the preparation of STAT3 inhibitors, wherein substance A is a heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule.

[0156] The present invention also provides a method for using substance A to inhibit STAT3, comprising administering an effective amount of substance A to a subject. The substance A is a heterocyclic compound as shown in Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a stereoisomer of a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated compound thereof, or a PROTAC molecule thereof.

[0157] The present invention also provides the use of substance A in the preparation of a drug for inhibiting the phosphorylation of STAT3 protein; wherein substance A is a heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule.

[0158] The present invention also provides a method for treating or preventing STAT3-related diseases using substance A, comprising administering an effective amount of substance A to a subject. The substance A is a heterocyclic compound as shown in Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a stereoisomer of a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated compound thereof, or a PROTAC molecule thereof.

[0159] This invention also provides the use of substance A in the preparation of a medicament for treating or preventing cancer; substance A is a heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, a stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule. The cancer is selected from one or more of the following: colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, hematologic malignancies, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0160] This invention also provides a method for treating or preventing cancer using substance A, comprising administering an effective amount of substance A to a subject. Substance A is a heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, a stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule. The cancer is selected from one or more of the following: colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, hematologic malignancies, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0161] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0162] In this invention, when there are multiple substituents, they may be the same or different. The term "multiple" refers to 2, 3, 4, or 5.

[0163] The term "stereoisomer" refers to isomers of molecules that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements, such as cis-trans isomers, optical isomers, or trans-blocked isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0164] The term "hydroxyl group" refers to a -OH group.

[0165] The term "cyano" refers to a -CN group.

[0166] The term "cycloalkyl" refers to a saturated cyclic group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., C3 to C6), and can be monocyclic, bicyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0167] The term "heterocyclic alkyl" refers to a saturated cyclic group that contains not only carbon atoms but also one or more heteroatoms, which can be monocyclic, bicyclic, bridged, or spirocyclic.

[0168] The term "cycloalkenyl" refers to a non-aromatic cyclic group consisting of only carbon atoms, containing one or more double bonds, having a specified number of carbon atoms, and being monocyclic, bicyclic, bridged, or spirocyclic.

[0169] The term "heterocyclic alkenyl" refers to a non-aromatic cyclic group containing one or more double bonds, consisting of not only carbon atoms but also one or more heteroatoms. It can be monocyclic, bicyclic, bridged, or spirocyclic.

[0170] The term "aryl" refers to an aromatic group consisting of carbon atoms, with each ring possessing aromaticity. Examples include phenyl or naphthyl.

[0171] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are linked to other segments of a molecule through either an aromatic or non-aromatic ring. Heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indoleyl.

[0172] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0173] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0174] In this invention, the term "alkoxy group" refers to the -OR group. X , where R X It is an alkyl group as defined above.

[0175] In this invention, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, wherein the C 2-6 The alkynyl group is C 2-3 Alkyne group, such as ethynyl, propynyl or propynyl.

[0176] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, wherein the C 2-6 The alkenyl group can be vinyl, propenyl, or allyl.

[0177] In this invention, the C 3-12The cycloalkyl group is cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.

[0178] In this invention, the C 6-20 The aryl group is C 6-10 Aryl groups, such as phenyl or naphthyl.

[0179] In this invention, the C 1-6 The alkylene group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2- or -C(CH3)2CH2-.

[0180] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0181] The reagents and raw materials used in this invention are all commercially available.

[0182] The positive and progressive effect of this invention is that the heterocyclic compound provided by this invention has a strong inhibitory effect on STAT3, and is expected to treat and / or prevent a variety of diseases related to STAT3. Detailed Implementation

[0183] 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. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0184] In this invention, room temperature refers to ambient temperature, which is 10℃-35℃. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0185] The following is a list of abbreviations used in the examples:

[0186] DCM dichloromethane

[0187] DMF N,N-dimethylformamide

[0188] EA (ethyl acetate)

[0189] DMSO (dimethyl sulfoxide)

[0190] DIPEA (diisopropylethylamine)

[0191] Pd2(dba)3 Tris(dibenzylacetone dipalladium)

[0192] THF Tetrahydrofuran

[0193] TFA (trifluoroacetic acid)

[0194] DMAC N,N-dimethylacetamide

[0195] HATU 2-(7-Azobenzotriazole)-Tetramethylurea hexafluorophosphate

[0196] TEA Triethylamine

[0197] Boc tert-butyloxycarbonyl

[0198] TBSCl tert-butyldimethylchlorosilane

[0199] PyBOP Benzotriazine-1-yl-oxytripyrrolidinephosphide hexafluorophosphate

[0200] AcOH glacial acetic acid

[0201] MeOH (methanol)

[0202] PE petroleum ether

[0203] tBuXPhos 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0204] Synthetic route of compound 1

[0205]

[0206] Synthesis of compound 1-h

[0207] TBSCl (3.15 g, 20.92 mmol) was added to a solution of methyl 6-hydroxy-1H-indole-2-carboxylate (2.0 g, 10.46 mmol) and imidazole (2.85 g, 41.84 mmol) in dichloromethane (40 mL) under ice-water bath conditions. The mixture was reacted at room temperature for 2 hours under ice-water bath conditions. Water was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane 100 / 0 to 20 / 80) to give compound 1-h (3.10 g, 97% yield). LC-MS (ESI): m / z 304.1 (MH) - .

[0208] Synthesis of compound 1-g

[0209] Compound 1-h (3.10 g, 10.15 mmol), cesium carbonate (1.65 g, 5.07 mmol), and potassium carbonate (3.51 g, 25.37 mmol) were added to a reaction flask. Anhydrous DMF (60 mL) was slowly added under ice-water bath, followed by dropwise addition of iodomethane (1.65 mL, 20.30 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was rotary evaporated at room temperature for 10 minutes, then slowly added to ice water, and extracted twice with ethyl acetate / petroleum ether (2:1). The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (direct loading, mobile phase: petroleum ether / dichloromethane 100 / 0 to 60 / 40) to give compound 1-g (2.8 g, yield 86%).

[0210] Synthesis of compound 1-f

[0211] Compound 1-f (2.8 g, 8.76 mmol), tetrahydrofuran (15 mL), anhydrous methanol (15 mL), and water (15 mL) were added to a reaction flask. Lithium hydroxide monohydrate (1.47 g, 35.06 mmol) was added under ice-water bath conditions. The reaction mixture was stirred overnight at room temperature. Lithium hydroxide monohydrate (0.37 g, 8.76 mmol) was added as a supplement. The reaction mixture was heated and stirred at 45 °C for 6 hours. The reaction mixture was cooled to room temperature, the organic solvent was removed by rotary evaporation, ice water and sodium bisulfate solid were added to make the solution acidic, dichloromethane and petroleum ether were added, the mixture was filtered, the filter cake was washed three times with a small amount of water and twice with petroleum ether, and air-dried overnight to give compound 1-f (1.3 g, 77% yield). LC-MS (ESI): m / z 190.2 (MH) - .

[0212] Synthesis of compound 1-e

[0213] Potassium carbonate (16.7 g, 120.84 mmol) was added to a DMF (120 mL) solution of 4-fluorobenzaldehyde (10 g, 80.57 mmol) and trifluoroethanol (6.44 mL, 88.96 mmol) under ice-water bath conditions. The reaction mixture was reacted at 80 °C for 18 hours. The reaction solution was cooled to room temperature and added to ice water (no solid precipitate). The mixture was extracted twice with ethyl acetate / petroleum ether (2:1). The organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to give compound 1-e (15 g, 91% yield).

[0214] Synthesis of compound 1-d

[0215] N-Boc-piperazine (6.5 g, 34.90 mmol), dichloromethane (100 mL), compound 1-e (6.5 g, 31.84 mmol), and acetic acid (0.2 mL, 3.49 mmol) were added to a reaction flask. The reaction mixture was stirred at room temperature for 1 hour, and sodium borohydride acetate (9.6 g, 45.51 mmol) was added in portions under an ice-water bath. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours and then frozen overnight. The next day, most of the solvent was removed by rotary evaporation, and ethyl acetate and ice water were added. The mixture was separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to give compound 1-d (10.0 g, 84% yield). LC-MS (ESI): m / z 375.2 (M+H) + .

[0216] Synthesis of compound 1-c

[0217] Compound 1-d (1.5 g, 4.01 mmol) and 1,4-dioxane (16 mL) were added to a reaction flask. A 1,4-dioxane hydrochloric acid solution (4 M, 16 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 6 hours (a large amount of solid precipitated). The solution was evaporated to dryness to give compound 1-c (1.3 g, 93% yield). LC-MS (ESI): m / z 275.2 (M+H) + .

[0218] Synthesis of compound 1-b

[0219] Compound 1-f (225 mg, 1.18 mmol), compound 1-c (488 mg, 1.41 mmol), DMF (10 mL), DIPEA (0.62 mL, 3.53 mmol), and HATU (537 mg, 1.41 mmol) were added to the reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 4 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: methanol / dichloromethane, 0% to 10%) to give compound 1-b (400 mg, 76%). LC-MS (ESI): m / z 448.2 [M+H] + .

[0220] Synthesis of compound 1-a

[0221] At room temperature, 2-bromo-4'-(trifluoromethyl)acetophenone (500 mg, 1.87 mmol) and 2-amino-4-bromopyridine (340 mg, 1.97 mmol) were dissolved in ethanol (10 mL). After addition, the reaction mixture was refluxed and stirred overnight. The next day, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 1-a (300 mg, 47%). LC-MS (ESI): m / z 341.0 [M+H] + .

[0222] Synthesis of Compound 1

[0223] Compound 1-b (20 mg, 0.045 mmol), compound 1-a (23 mg, 0.068 mmol), tBuXPhos (4 mg, 0.009 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), potassium phosphate (29 mg, 0.14 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was then purified by Prep-HPLC (alkaline method) to obtain compound 1 (15 mg, 47%). LC-MS (ESI): m / z 708.3 [M+H] + .

[0224] Synthetic route of compound 2

[0225]

[0226] Synthesis of compound 2-b

[0227] 2-Amino-4-bromopyridine (500 mg, 2.89 mmol) and DMF (10 mL) were added to a reaction flask, and sodium hydroxide (60% in oil, 139 mg, 3.47 mmol) was added under an ice-water bath. The reaction mixture was stirred under an ice-water bath for 30 minutes, and p-trifluoromethylbenzonitrile (594 mg, 3.47 mmol) was added. After the addition was complete, the ice-water bath was removed, and the reaction mixture was stirred for another 2 hours. After the reaction was complete, the mixture was quenched with a saturated sodium bicarbonate aqueous solution, stirred for another 30 minutes, and extracted with ethyl acetate. The organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 100%) to give compound 2-b (300 mg, 30%). LC-MS (ESI): m / z = 344.0 [M+H] + .

[0228] Synthesis of compound 2-a

[0229] Compound 2-b (300 mg, 0.87 mmol) and chloramine-T trihydrate (491 mg, 1.74 mmol) were dissolved in ethanol (10 mL) at room temperature. After the addition was complete, the reaction mixture was refluxed and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 40%) to give compound 2-a (200 mg, 67%). LC-MS (ESI): m / z 342.0 [M+H] + .

[0230] Synthesis of Compound 2

[0231] Compound 1-b (30 mg, 0.067 mmol), compound 2-a (35 mg, 0.10 mmol), tBuXPhos (6 mg, 0.013 mmol), Pd2(dba)3 (6 mg, 0.007 mmol), potassium phosphate (43 mg, 0.20 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 2 (20 mg, 42%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 709.2 [M+H] + .

[0232] Synthetic route of compound 3

[0233]

[0234] Synthesis of compound 3-a

[0235] Under ice-water bath conditions, 6-hydroxy-2-indolecarboxylic acid (200 mg, 1.13 mmol), 1-c (471 mg, 1.36 mmol), DMF (10 mL), DIPEA (0.59 mL, 3.39 mmol), and HATU (515 mg, 1.36 mmol) were added to the reaction flask. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: methanol / dichloromethane, 0% to 10%) to give compound 3-a (450 mg, 92%). LC-MS (ESI): m / z 434.3 [M+H]+ .

[0236] Synthesis of Compound 3

[0237] Compound 3-a (70 mg, 0.16 mmol), compound 2-a (83 mg, 0.24 mmol), tBuXPhos (14 mg, 0.032 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), potassium phosphate (103 mg, 0.49 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 3 (20 mg, 18%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 695.2 [M+H] + ; 1 H NMR(DMSO-d6,400MHz): δ11.71(1H,s),8.98(1H,d,J=7.6Hz),7.99(2H,d,J=8.4Hz),8.34(2H,d,J=8.0Hz),7.73(1H,d,J=8.8Hz),7.29(2H ,d,J=8.4Hz),7.23(1H,s),6.93-7.08(5H,m),6.87(1H,s),4.74(2H,q,J=8.8Hz),3.70-3.84(2H,m),3.46-3.52(4H,m),2.39-2.47(4H,m).

[0238] Synthetic route of compound 4

[0239]

[0240] Synthesis of Compound 4

[0241] At room temperature, potassium carbonate (30 mg, 0.22 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (42 μL, 0.29 mmol) were added to a DMF (5 mL) solution of compound 3 (100 mg, 0.14 mmol). After addition, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Compound 4 (40 mg, 36%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z = 777.1 [M+H] + ; 1HNMR(DMSO-d6,400MHz): δ8.98-9.04(1H,m),8.35(2H,d,J=8.0Hz),7.90(2H,d,J=8.0Hz),7.78(1H,d,J=8.4Hz),7.74(1H,s),7.29(2H,d ,J=8.8Hz),6.99-7.13(5H,m),6.95(1H,s),5.29-5.43(2H,m),4.74(2H,q,J=8.8Hz),3.63-3.82(4H,m),3.47(2H,s),2.34-2.46(4H,m).

[0242] Synthetic route of compound 5

[0243]

[0244] Synthesis of Compound 5

[0245] Compound 3 (100 mg, 0.14 mmol), cyclopropylboronic acid (31 mg, 0.36 mmol), copper acetate hydrate (29 mg, 0.14 mmol), 2,2'-bipyridine (22 mg, 0.14 mmol), sodium carbonate (31 mg, 0.29 mmol), and DMF (5 mL) were added to the reaction flask. The reaction solution was heated to 70 °C and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and the organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 5 (50 mg, 47%) was obtained by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 735.2 [M+H] + ; 1 HNMR (DMSO-d6, 400MHz): δ8.99 (1H, d, J = 7.2Hz), 8.34 (2H, d, J = 8.0Hz), 7.90 (2 H,d,J=8.4Hz),7.70(1H,d,J=8.8Hz),7.43(1H,s),7.28(2H,d,J=8.8Hz),6.97 -7.12(5H,m),6.61(1H,s),4.74(2H,q,J=8.8Hz),3.49-3.76(4H,m),3.48(2H, s),3.33-3.43(1H,m),2.33-2.48(4H,m),0.97-1.08(2H,m),0.76-0.86(2H,m).

[0246] Synthetic route of compound 6

[0247]

[0248] Synthesis of compound 6-a

[0249] Under ice-water bath conditions, 6-hydroxybenzothiophene-2-carboxylic acid (150 mg, 0.77 mmol), 1-c (322 mg, 0.93 mmol), DMF (10 mL), DIPEA (0.40 mL, 2.32 mmol), and HATU (353 mg, 0.93 mmol) were added to a reaction flask. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: methanol / dichloromethane, 0% to 10%) to give compound 6-a (250 mg, 72%). LC-MS (ESI): m / z 451.6 [M+H] + .

[0250] Synthesis of Compound 6

[0251] Compound 6-a (50 mg, 0.11 mmol), compound 2-a (57 mg, 0.17 mmol), tBuXPhos (9 mg, 0.022 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), potassium phosphate (71 mg, 0.33 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 6 (30 mg, 38%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 712.1 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.52 (1H, d, J = 7.6Hz), 8.34 (2H, d, J = 8.0Hz), 7.87 (1H, d ,J=8.8Hz),7.73(2H,d,J=8.4Hz),7.63(1H,d,J=2.0Hz),7.50(1H,s),7.31(2H, d,J=8.0Hz),7.22(1H,dd,J=8.8Hz,2.0Hz),7.00(1H,d,J=2.4Hz),6.88-6.93(3 H,m),4.35(2H,q,J=8.0Hz),3.73-3.95(4H,m),3.57(2H,s),2.45-2.71(4H,m).

[0252] Synthetic route of compound 7

[0253]

[0254] Synthesis of compounds 7-a-1 and 7-a-2

[0255] At room temperature, 6-bromoindazole (100 mg, 0.51 mmol), 4-fluorotrifluorotoluene (167 mg, 1.02 mmol), potassium carbonate (210 mg, 1.52 mmol), and DMF (5 mL) were added to a microwave tube. After the addition was complete, the reaction mixture was heated to 120 °C and stirred overnight. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 20%) to give two compounds:

[0256] 7-a-1 (100 mg, 58%) is a white solid. LC-MS (ESI): m / z 341.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.51 (1H, s), 8.19 (1H, s), 8.06 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.4Hz), 7.90 (1H, d, J = 8.4Hz), 7.48 (1H, d, J = 8.4Hz);

[0257] 7-a-2 (50 mg, 29%) is a white solid. LC-MS (ESI): m / z 341.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ9.32 (1H, s), 8.33 (2H, d, J = 8.4Hz), 8.03 (1H, s), 7.99 (2H, d, J = 8.4Hz), 7.79 (1H, d, J = 8.8Hz), 7.24 (1H, d, J = 8.8Hz).

[0258] Synthesis of Compound 7

[0259] Compound 1-b (35 mg, 0.078 mmol), compound 7-a-2 (40 mg, 0.12 mmol), tBuXPhos (7 mg, 0.016 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), potassium phosphate (50 mg, 0.24 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 7 (20 mg, 36%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 708.2 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.43 (1H, s), 8.00 (2H, d, J = 8.4Hz), 7.76 (2H, d, J = 8.4H z),7.67(1H,d,J=9.2Hz),7.59(1H,d,J=8.8Hz),7.29(2H,d,J=8.4Hz),7.08( 2H,s),6.94-7.04(2H,m),6.92(2H,d,J=8.4Hz),6.59(1H,s),4.35(2H,q,J=8 .0Hz),3.71-3.97(4H,m),3.76(3H,s),3.26-3.65(2H,m),2.36-2.67(4H,m).

[0260] Synthetic route of compound 8

[0261]

[0262] Synthesis of Compound 8

[0263] Compound 1-b (35 mg, 0.078 mmol), compound 7-a-1 (40 mg, 0.12 mmol), tBuXPhos (7 mg, 0.016 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), potassium phosphate (50 mg, 0.24 mmol), and toluene (5 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 8 (30 mg, 54%) was obtained by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 708.2 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.19 (1H, s), 7.69-7.85 (5H, m), 7.58 (2H, d, J = 8.4Hz), 7.32-7.38 (2H, m), 6.86-7.04 (5H ,m),6.60(1H,s),4.35(2H,q,J=8.0Hz),3.68-3.95(4H,m),3.75(3H,s),3.36-3.64(2H,m),2.37-2.87(4H,m).

[0264] Synthetic route of compound 9

[0265]

[0266] Synthesis of compound 9-d

[0267] Potassium carbonate (468 mg, 3.39 mmol) and methyl iodide (275 μL, 3.39 mmol) were added to a DMF (10 mL) solution of ethyl 5-benzyloxyindole-2-carboxylate (500 mg, 1.69 mmol) under ice-water bath conditions. After addition, the reaction mixture was brought to room temperature and stirred for 5 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 20%) to give compound 9-d (450 mg, 86%). LC-MS (ESI): m / z = 310.3 [M+H] + .

[0268] Synthesis of compound 9-c

[0269] Pd / C (10%, 155 mg, 0.15 mmol) was added to a solution of compound 9-d (450 mg, 1.46 mmol) in EA (15 mL) and MeOH (15 mL) at room temperature. The mixture was purged three times with hydrogen, and stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Purification was achieved by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 9-c (150 mg, 47%). LC-MS (ESI): m / z = 218.3 [MH] - .

[0270] Synthesis of compound 9-b

[0271] Compound 9-c (50 mg, 0.23 mmol), 2-a (94 mg, 0.27 mmol), tBuXPhos (19 mg, 0.046 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), potassium phosphate (145 mg, 0.68 mmol), and toluene (8 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated overnight at 110 °C. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: methanol / dichloromethane, 0% to 10%) to obtain compound 9-b (90 mg, 82%). LC-MS (ESI): m / z 481.4 [M+H] + .

[0272] Synthesis of compound 9-a

[0273] Compound 9-b (90 mg, 0.19 mmol) and lithium hydroxide monohydrate (31 mg, 0.75 mmol) were dissolved in methanol (40 mL) and water (10 mL) at room temperature. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the pH was carefully adjusted to 5-6 with dilute hydrochloric acid (2N), and the organic solvent was removed by concentration under reduced pressure. The remaining aqueous layer was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 9-a (70 mg, 83%). LC-MS (ESI): m / z 453.6 [M+H] + .

[0274] Synthesis of Compound 9

[0275] Compound 9-a (35 mg, 0.077 mmol), compound 1-c (32 mg, 0.093 mmol), DMF (3 mL), DIPEA (0.067 mL, 0.39 mmol), and HATU (35 mg, 0.093 mmol) were added to a reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by Prep-HPLC (alkaline method) to obtain compound 9 (30 mg, 55%). LC-MS (ESI): m / z 709.2 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.47 (1H, d, J = 8.0Hz), 8.32 (2H, d, J = 8.0Hz), 7.72 (2H ,d,J=8.4Hz),7.41(1H,d,J=8.8Hz),7.38(1H,d,J=2.0Hz),7.29(2H,d,J=8.4 Hz),7.09(1H,dd,J=8.8Hz,2.0Hz),6.86-6.97(4H,m),6.57(1H,s),4.35(2H, q,J=8.0Hz),3.87(3H,s),3.63-3.94(4H,m),3.54(2H,s),2.33-2.72(4H,m).

[0276] Synthetic route of compound 10

[0277]

[0278] Synthesis of compound 10-c

[0279] At room temperature, potassium carbonate (445 mg, 3.22 mmol) and 2-chloro-4-fluorobenzyl bromide (288 mg, 1.29 mmol) were added to a DMF (10 mL) solution of Boc-piperazine (200 mg, 1.07 mmol). After addition, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to give compound 10-c (300 mg, 85%). LC-MS (ESI): m / z = 329.6 [M+H] + .

[0280] Synthesis of compound 10-b

[0281] Compound 10-c (200 mg, 0.61 mmol) and dichloromethane (10 mL) were added to a reaction flask. A solution of 1,4-dioxane (4 M, 7.6 mL, 30.41 mmol) was then added dropwise under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 10-b (180 mg, 98%).

[0282] Synthesis of compound 10-a

[0283] Compound 1-f (90 mg, 0.47 mmol), compound 10-b (171 mg, 0.57 mmol), DMF (10 mL), DIPEA (0.41 mL, 2.35 mmol), and HATU (215 mg, 0.57 mmol) were added to the reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 100%) to give compound 10-a (150 mg, 79%). LC-MS (ESI): m / z 402.7 [M+H] + .

[0284] Synthesis of Compound 10

[0285] Compound 10-a (50 mg, 0.12 mmol), compound 2-a (64 mg, 0.19 mmol), tBuXPhos (11 mg, 0.025 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), potassium phosphate (79 mg, 0.37 mmol), and toluene (3 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 10 (30 mg, 36%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 663.2 [M+H] + ; 1H NMR (DMSO-d6, 400MHz): δ8.99 (1H, d, J = 7.2Hz), 8.35 (2H, d, J = 8.4Hz), 7.90 (2H, d, J = 8.4Hz), 7.73 (1H, d, J = 8.8Hz), 7.40-7.6 0(3H,m),7.19-7.27(1H,m),6.98-7.11(3H,m),6.74(1H,s),3.75(3H,s),3.62-3.73(4H,m),3.61(2H,s),3.36-3.51(4H,m).

[0286] Synthetic route of compound 11

[0287]

[0288] Synthesis of compound 11-c

[0289] 4-(2,2,2-trifluoroethoxy)phenol (100 mg, 0.52 mmol), 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (278 mg, 0.78 mmol), cesium carbonate (509 mg, 1.56 mmol), and N-methylpyrrolidone (3 mL) were added to a 10 mL microwave-safe tube. The reaction mixture was heated to 65 °C and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (mobile phase: EA / PE, 0-20%) to give compound 11-c (152 mg, 78%). LC-MS (ESI): m / z 376.2 (M+H) + .

[0290] Synthesis of compound 11-b

[0291] Hydrogen chloride / 1,4-dioxane (4M, 2 mL, 0.41 mmol) was added to a 10 mL solution of compound 11-c (152 mg, 0.41 mmol) in 1,4-dioxane. The reaction mixture was stirred overnight at room temperature. After evaporating the solution to dryness, compound 11-b (125 mg, 99%) was obtained and used directly in the next reaction without purification. LC-MS (ESI): m / z 276.6 (M+H) + .

[0292] Synthesis of compound 11-a

[0293] Compound 1-f (31 mg, 0.16 mmol), compound 11-b (50 mg, 0.16 mmol), DMF (5 mL), DIPEA (0.14 mL, 0.80 mmol), and PyBOP (167 mg, 0.32 mmol) were added to the reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 100%) to give compound 11-a (50 mg, 70%). LC-MS (ESI): m / z 449.6 [M+H] + .

[0294] Synthesis of Compound 11

[0295] Compound 11-a (50 mg, 0.11 mmol), compound 2-a (57 mg, 0.17 mmol), tBuXPhos (10 mg, 0.022 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), potassium phosphate (71 mg, 0.33 mmol), and toluene (3 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 11 (40 mg, 51%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 710.6 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.99 (1H, d, J = 7.2Hz), 8.35 (2H, d, J = 8.0Hz), 7.90 (2H, d, J = 8.4Hz), 7.73 (1H, d, J = 8.8Hz), 7.50 (1H, s), 6.93-7.10 (7H, m ),6.77(1H,s),4.68(2H,q,J=8.8Hz),4.55-4.65(1H,m),3.85-4.10(2H, m),3.75(3H,s),3.56-3.65(2H,m),1.91-2.07(2H,m),1.58-1.75(2H,m).

[0296] Synthetic route of compound 12

[0297]

[0298] Synthesis of compound 12-c

[0299] At room temperature, 3-trifluoromethoxyaniline (213 mg, 1.20 mmol), AcOH (0.35 mL, 6.03 mmol), and sodium triacetoxyborohydride (529 mg, 2.51 mmol) were added to a DCM (10 mL) solution of N-tert-butoxycarbonyl-4-piperidinone (200 mg, 1.00 mmol) at room temperature. After addition, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. Purification was achieved by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 30%) to give compound 12-c (65 mg, 18%). LC-MS (ESI): m / z = 361.2 [M+H] + .

[0300] Synthesis of compound 12-b

[0301] Compound 12-c (65 mg, 0.18 mmol) and dichloromethane (10 mL) were added to a reaction flask. A solution of 1,4-dioxane hydrogen chloride (4 M, 2.26 mL, 9.02 mmol) was added dropwise under ice-water bath. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 12-b (50 mg, 93%). LC-MS (ESI): m / z 261.3 [M+H] + .

[0302] Synthesis of compound 12-a

[0303] Compound 1-f (32 mg, 0.17 mmol), compound 12-b (50 mg, 0.17 mmol), DMF (5 mL), DIPEA (0.15 mL, 0.84 mmol), and PyBOP (176 mg, 0.34 mmol) were added to a reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 100%) to give compound 12-a (50 mg, 68%). LC-MS (ESI): m / z 434.6 [M+H] + .

[0304] Synthesis of Compound 12

[0305] Compound 12-a (50 mg, 0.12 mmol), compound 2-a (48 mg, 0.14 mmol), tBuXPhos (10 mg, 0.023 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), potassium phosphate (74 mg, 0.35 mmol), and toluene (3 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Compound 12 (40 mg, 50%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 695.3 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.49 (1H, d, J = 7.6Hz), 8.33 (2H, d, J = 8.4Hz), 7.72 (2H ,d,J=8.4Hz),7.67(1H,d,J=8.8Hz),7.11-7.22(2H,m),6.87-7.02(3H,m),6 .65(1H,s),6.49-6.59(2H,m),6.44(1H,s),4.06-5.00(2H,m),3.81(3H,s), 3.51-3.67(1H,m),3.03-3.47(2H,m),2.09-2.31(2H,m),1.42-1.57(2H,m).

[0306] Synthetic route of compound 13

[0307]

[0308] Synthesis of compound 13-f

[0309] Under ice-water bath conditions, potassium carbonate (983 mg, 7.11 mmol) and methyl iodide (577 μL, 7.11 mmol) were added to a DMF (10 mL) solution of methyl 6-(benzyloxy)-1H-indole-2-carboxylic acid (1.0 g, 3.56 mmol). After addition, the reaction mixture was brought to room temperature and stirred for 5 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 20%) to give compound 13-f (900 mg, 86%). LC-MS (ESI): m / z = 296.2 [M+H] + .

[0310] Synthesis of compound 13-e

[0311] Pd / C (10%, 324 mg, 0.31 mmol) was added to a solution of compound 13-f (900 mg, 3.05 mmol) in EA (15 mL) and MeOH (15 mL) at room temperature. The mixture was purged three times with hydrogen, and stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Purification was performed by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 13-e (550 mg, 88%). LC-MS (ESI): m / z = 206.2 [M+H] + .

[0312] Synthesis of compound 13-d

[0313] Compound 13-e (150 mg, 0.73 mmol), compound 2-a (300 mg, 0.88 mmol), tBuXPhos (62 mg, 0.15 mmol), Pd2(dba)3 (67 mg, 0.073 mmol), potassium phosphate (466 mg, 2.19 mmol), and toluene (8 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 110 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with ethyl acetate. The organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by rapid column chromatography (mobile phase: methanol / dichloromethane, 0% to 10%) to obtain compound 13-d (290 mg, 85%). LC-MS (ESI): m / z 467.1 [M+H] + .

[0314] Synthesis of compound 13-c

[0315] Compound 13-d (290 mg, 0.62 mmol) and lithium hydroxide monohydrate (105 mg, 2.49 mmol) were dissolved in methanol (40 mL) and water (10 mL) at room temperature. After addition, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the pH was carefully adjusted to 5-6 with dilute hydrochloric acid (2 M), and the organic solvent was removed by concentration under reduced pressure. The remaining aqueous layer was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 13-c (100 mg, 36%). LC-MS (ESI): m / z 453.7 [M+H] + .

[0316] Synthesis of compound 13-b

[0317] At room temperature, 2-chloro-4-fluoroaniline (175 mg, 1.20 mmol), AcOH (0.35 mL, 6.03 mmol), and sodium triacetoxyborohydride (529 mg, 2.51 mmol) were added to a DCM (10 mL) solution of N-tert-butoxycarbonyl-4-piperidinone (200 mg, 1.00 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. Purification was performed by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 30%) to give compound 13-b (65 mg, 20%). LC-MS (ESI): m / z = 329.2 [M+H] + .

[0318] Synthesis of compound 13-a

[0319] Compound 13-b (65 mg, 0.20 mmol) and dichloromethane (10 mL) were added to a reaction flask. A solution of 1,4-dioxane hydrogen chloride (4 M, 2.47 mL, 9.89 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 13-a (50 mg, 95%). LC-MS (ESI): m / z 229.2 [M+H] + .

[0320] Synthesis of Compound 13

[0321] Compound 13-c (20 mg, 0.044 mmol), compound 13-a (14 mg, 0.053 mmol), DMF (3 mL), DIPEA (0.039 mL, 0.22 mmol), and HATU (20 mg, 0.053 mmol) were added to the reaction flask under ice-water bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 13 (20 mg, 68%) was purified by Prep-HPLC (alkaline method). LC-MS (ESI): m / z 663.2 [M+H] + ; 1H NMR (DMSO-d6, 400MHz): δ8.99 (1H, d, J = 7.2Hz), 8.35 (2H, d, J = 8.0Hz), 7.90 (2H, d, J = 8. 0Hz),7.73(1H,d,J=8.4Hz),7.50(1H,d,J=2.0Hz),7.26(1H,dd,J=8.4Hz,2.8Hz),6.98- 7.11(4H,m),6.85-6.91(1H,m),6.74(1H,s),4.85(1H,d,J=9.2Hz),3.91-4.62(2H,m),3 .75(3H,s),3.62-3.74(1H,m),2.90-3.31(2H,m),1.87-2.06(2H,m),1.46-1.63(2H,m).

[0322] Synthetic route of compound 14

[0323]

[0324] Synthesis of Compound 14

[0325] At room temperature, compound 1-b (500 mg, 1.12 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (357 mg, 1.68 mmol), cuprous iodide (106 mg, 0.56 mmol), N,N-dimethylglycine (115 mg, 1.12 mmol), cesium carbonate (728 mg, 2.24 mmol), and 1,4-dioxane (20 mL) were added to a microwave-safe tube. The reaction mixture was purged with nitrogen three times, and then stirred at 125 °C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by a rapid separation column (DCM / MeOH = 10:1) to give compound 14 (322 mg, 50%). LC-MS (ESI): m / z = 580.3 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ8.17 (1H, d, J = 7.2Hz), 7.61 (1H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.0Hz), 7.09 (1H, d, J = 1.6Hz), 6.93-6.89 (3H, m), 6.69 (1H ,d,J=2.0Hz),6.63(1H,dd,J1=7.6Hz,J2=2.8Hz),6.60(1H,s),4.40-4.30(4H,m),3.80(4H,s),3.78(3H,s),3.58-3.46(2H,m),2.51(4H,s).

[0326] Synthetic route of compound 15

[0327]

[0328] Synthesis of Compound 15

[0329] At room temperature, compound 1-b (30 mg, 0.067 mmol), 7-bromo-[1,2,4]triazole[1,5-a]pyridine (20 mg, 0.10 mmol), cuprous iodide (6.4 mg, 0.034 mmol), N,N-dimethylglycine (6.9 mg, 0.067 mmol), cesium carbonate (44 mg, 0.13 mmol), and 1,4-dioxane (2 mL) were added to a microwave-safe tube. The reaction mixture was purged with nitrogen three times, and then stirred at 125°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (alkaline method, ammonium bicarbonate system) to give compound 15 (18 mg, 48%). LC-MS (ESI): m / z = 565.3 [M+H] + ; 1 HNMR (CDCl3, 400MHz): δ8.48 (1H, d, J = 7.6Hz), 8.21 (1H, s), 7.64 (1H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.8Hz), 7.12 (1H, d, J = 1.6Hz), 6.97 -6.85(5H,m),6.61(1H,s),4.35(2H,q,J1=8.0Hz,J2=8.0Hz),3.92-3.69(7H,m),3.52(2H,s),2.50(4H,s).

[0330] Synthetic route of compound 16

[0331]

[0332] Synthesis of compound 16-a

[0333] At room temperature, compound 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (1.0 g, 4.69 mmol) was dissolved in 10 mL of acetonitrile, and sodium nitrite (810 mg, 11.74 mmol) was added. The mixture was cooled in an ice-water bath, and concentrated hydrochloric acid (1 mL, 12.0 mmol) was slowly added. The reaction mixture was then brought to room temperature and stirred for 2 hours. The reaction solution was diluted with 50 mL of ethyl acetate, and the pH was adjusted to 8 with a solution of saturated sodium bicarbonate. Extraction was performed with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The aqueous phase was then extracted with 100 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residues were combined and purified by rapid separation column (PE / EA = 1:1) to give compound 16-a (367 mg, 34%). LC-MS (ESI): m / z = 232.1 [M+H] + .

[0334] Synthesis of Compound 16

[0335] Compound 1-b (640 mg, 1.43 mmol), compound 16-a (333 mg, 1.43 mmol), potassium phosphate (911 mg, 4.29 mmol), tBuXPhos (121 mg, 0.29 mmol), Pd2(dba)3 (131 mg, 0.14 mmol), and toluene (60 mL) were added to a sealed tube. The mixture was bubbled under nitrogen for 3 minutes, sealed, and stirred at 110 °C for 3 hours. The reaction solution was directly purified by column chromatography (mobile phase: methanol: dichloromethane = 0–2%) to give compound 16 (438 mg, 51%). LC-MS (ESI): m / z 599.2 (M+H) + ;H NMR (400M, CDCl3): δ8.37 (1H, d, J = 7.2Hz), 7.64 (1H, d, J = 8.4Hz), 7.37-7.21 (3H, m), 7.00-6.80 (5H,m),6.62(1H,s),4.35(2H,q,J=8.0Hz),3.93-3.67(7H,m),3.53(2H,s),2.65-2.38(4H,m).

[0336] Synthetic route of compound 17

[0337]

[0338] Synthesis of Compound 17

[0339] Compound 16 (40 mg, 0.067 mmol), 4-fluorophenylboronic acid (19 mg, 0.13 mmol), potassium carbonate (28 mg, 0.20 mmol), tetraphenylphosphine palladium (15 mg, 0.013 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were added to a microwave tube. The tube was sealed, purged three times with nitrogen, and stirred at 120 °C for 24 hours. The reaction mixture was evaporated to dryness, dissolved in 4 mL of methanol, filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate), lyophilized, and compound 17 (16 mg, 36%) was obtained. LC-MS (ESI): m / z 659.2 (M+H) + ; 1 HNMR (400M, CDCl3): δ8.46 (1H, d, J = 7.6Hz), 8.25-8.15 (2H, m), 7.65 (1H, d, J = 8.4Hz), 7.33-7.26 (2H, m), 7.19-7.09 (3H, m), 6.98-6.89(4H,m),6.88-6.83(1H,m),6.62(1H,s),4.35(2H,q,J=8.0Hz),3.88-3.72(7H,m),3.53(2H,s),2.61-2.41(4H,m).

[0340] Synthesis of Compound 18

[0341]

[0342] Following the synthetic method of compound 17, compound 18 was synthesized by replacing 4-fluorophenylboronic acid with 4-methoxyphenylboronic acid, using compound 16 as the starting reactant. LC-MS (ESI): m / z 671.2 (M+H) + ; 1 H NMR (400M, CDCl3): δ8.45(1H,d,J=7.6Hz),8.18-8.10(2H,m),7.64(1H,d,J=8.4Hz),7.37-7.24(2H,m),7.15-7.10(1H,m),7.03 -6.88(6H,m),6.86-6.79(1H,m),6.62(1H,s),4.35(2H,q,J=8.4Hz),3.92-3.72(10H,m),3.67-3.44(2H,m),2.64-2.40(4H,m).

[0343] Synthesis of Compound 19

[0344]

[0345] Following the synthetic method of compound 17, compound 19 was synthesized by replacing 4-fluorophenylboronic acid with 4-pyridineboronic acid pinacol ester, using compound 16 as the starting reactant. LC-MS (ESI): m / z 642.3 (M+H) + ; 1 H NMR (400M, CDCl3) δ8.73 (2H, d, J = 4.4Hz), 8.50 (1H, d, J = 7.2Hz), 8.06 (2H, d, J = 5.2Hz), 7.66 (1H, d, J = 8.4Hz), 7.33 (2H, d, J = 6.4H z),7.14(1H,s),7.03-6.87(5H,m),6.63(1H,s),4.35(2H,q,J=8.0Hz),3.98-3.74(7H,m),3.69-3.49(2H,m),2.78-2.39(4H,m).

[0346] Synthetic route of compound 20

[0347]

[0348] Synthesis of compound 20-a

[0349] Compound 16 (40 mg, 0.067 mmol), 4-(N-BOC-amino)phenylboronic acid (64 mg, 0.27 mmol), cesium carbonate (177 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol), 1,4-dioxane (4 mL), and water (0.5 mL) were added to a microwave-safe tube. The tube was sealed, purged three times with nitrogen, and stirred overnight at 120 °C. The reaction mixture was evaporated to dryness and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–6%) to give compound 20-a (10 mg, 20%). LC-MS (ESI): m / z 756.3 (M+H) + .

[0350] Synthesis of Compound 20

[0351] 20-a (10 mg, 0.013 mmol), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to dryness, purified by HPLC (ammonium bicarbonate), and lyophilized to give compound 20 (1 mg, 12%) as a white solid. LC-MS (ESI): m / z 656.3 (M+H) + ; 1H NMR (400M, CDCl3): δ8.43(1H,d,J=7.2Hz),8.00(2H,d,J=8.4Hz),7.63(1H,d,J=8.4Hz),7.50-7.27(2H,m),7.12(1H,s),7.04 -6.87(4H,m),6.84-6.72(3H,m),6.62(1H,s),4.36(2H,q,J=8.0Hz),3.99-3.71(7H,m),3.66-3.39(2H,m),3.00-2.11(4H,m).

[0352] Synthesis of Compound 21

[0353]

[0354] Following the synthetic method of compound 17, compound 21 was synthesized by replacing 4-fluorophenylboronic acid with 4-chlorophenylboronic acid, using compound 16 as the starting reactant. LC-MS (ESI): m / z 675.1 (M+H) + .

[0355] Synthesis of Compound 22

[0356]

[0357] Following the synthetic method of compound 17, compound 22 was synthesized by replacing 4-fluorophenylboronic acid with 4-cyanophenenoic acid, using compound 16 as the starting reactant. LC-MS (ESI): m / z 666.3 (M+H) + .

[0358] Synthesis of Compound 23

[0359]

[0360] Following the synthetic method of compound 17, compound 23 was synthesized by replacing 4-fluorophenylboronic acid with potassium cyclopropyltrifluoroborate as the starting reactant, using compound 16 as the starting material. LC-MS (ESI): m / z 605.2 (M+H) + ; 1H NMR (400M, CDCl3): δ8.33 (1H, d, J = 7.6Hz), 7.62 (1H, d, J = 8.4Hz), 7.31 (1H, s), 7. 29(1H,s),7.09(1H,d,J=1.6Hz),6.97-6.87(3H,m),6.80(1H,d,J=2.4Hz),6.75(1 H,dd,J=2.4Hz,J=7.2Hz),6.60(1H,s),4.35(2H,q,J=8.4Hz),3.94-3.69(4H,m),3 .78(3H,s),3.55(2H,s),2.67-2.36(4H,m),2.19-2.07(1H,m),1.12-0.97(4H,m).

[0361] Synthesis of Compound 24

[0362]

[0363] Following the synthetic method of compound 17, compound 24 was synthesized by using compound 16 as the starting reactant and replacing 4-fluorophenylboronic acid with 1-(2,2,2-trifluoroethyl)-1,2,3,6-4H-pyridine-4-boronic acid pinacol ester. LC-MS (ESI): m / z 728.3 (M+H) + .

[0364] Synthetic route of compound 25

[0365]

[0366] Synthesis of compound 25-h

[0367] 2-Chloropremine-5-carboxaldehyde (1 g, 7.02 mmol), trifluoroethanol (1.10 mL, 14.73 mmol), and anhydrous dichloromethane (10 mL) were added to a reaction flask. Sodium tert-butoxide (0.81 g, 8.42 mmol) was added to the reaction mixture under ice-water bath conditions. The reaction mixture was stirred for 3 hours after cooling to room temperature in an ice-water bath. Most of the solvent was removed by rotary evaporation at room temperature, diluted with ethyl acetate, washed with 5% sodium bisulfate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 25-h (1.2 g, 83% yield). 1 H NMR (CDCl3, 400MHz): δ10.00 (1H, s), 8.97 (2H, s), 4.86 (2H, q, J = 8.0Hz).

[0368] Synthesis of compound 25-g

[0369] 2-Amino-4-bromopyridine (2.0 g, 11.56 mmol) and pyridine (10 mL) were added to a reaction flask. p-Methoxybenzoyl chloride (2.44 g, 14.30 mmol) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 1 hour under ice-water bath conditions. Ice water was added to the reaction mixture, and a solid precipitated. The supernatant was discarded, and this process was repeated twice. An aqueous solution containing a small amount of sodium bisulfate was added, and the supernatant was discarded. Water was added, and the mixture was filtered. The filter cake was washed twice with water and air-dried overnight to give 25 g (3.0 g, 84% yield) of the compound. LC-MS (ESI): m / z 307.3 (M+H) + .

[0370] Synthesis of compound 25-f

[0371] 25 g (350 mg, 1.14 mmol), diphenylphosphonohydroxylamine (600 mg, 2.57 mmol), and anhydrous 1,4-dioxane (6 mL) were added to a reaction flask. The reaction mixture was heated to 100 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed three times with 5% sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 25-f (320 mg, 92% yield). LC-MS (ESI): m / z 304.2 (M+H) + .

[0372] Synthesis of compound 25-e

[0373] Add 13-f (5.12 g, 17.34 mmol), tetrahydrofuran (15 mL), and anhydrous methanol (15 mL) to a reaction flask. Add a suspension of lithium hydroxide monohydrate (1.82 g, 43.34 mmol) in pure water (15 mL) dropwise under an ice-water bath. After the addition is complete, stir the reaction mixture overnight at room temperature. Remove most of the organic solvent by rotary evaporation, add ice water (60 mL) containing sodium bisulfate (5.6 g, 46.65 mmol), shake for 2 minutes, let stand for 20 minutes, filter, wash the filter cake twice with water, and air dry overnight to give compound 25-e (4.87 g, 100% yield). LC-MS (ESI): m / z 282.3 (M+H) + .

[0374] Synthesis of compound 25-d

[0375] 25-e (4 g, 14.22 mmol), N-Boc-piperazine (2.78 g, 14.93 mmol), and DMF (30 mL) were added to a reaction flask. DIPEA (4.59 g, 35.55 mmol) was added under an ice-water bath. After stirring for 5 minutes under an ice-water bath, HATU (6.49 g, 17.06 mmol) was added. The reaction mixture was stirred under an ice-water bath for 30 minutes. DMF (10 mL) was added. The mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, causing a solid to precipitate. The solid was filtered, the filter cake was washed twice with water, and air-dried over the weekend to give compound 25-d (6.0 g, 94% yield). LC-MS (ESI): m / z 450.3 (M+H) + .

[0376] Synthesis of compound 25-c

[0377] 25-d (2 g, 4.45 mmol), anhydrous methanol (32 mL), and palladium on carbon (10% Pd, containing 40-60% water) (0.4 g, 3.76 mmol) were added to a reaction flask. The reaction mixture was purged with hydrogen three times and stirred under hydrogen atmosphere for 2 hours. Tetrahydrofuran (8 mL) was then added. The reaction mixture was purged with hydrogen three times and stirred under hydrogen atmosphere for 3 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to give compound 25-c (1.4 g, 88% yield). LC-MS (ESI): m / z 360.3 (M+H) + .

[0378] Synthesis of compound 25-b

[0379] Compound 25-c (380 mg, 1.06 mmol), compound 25-f (320 mg, 1.05 mmol), tBuXPhos (60 mg, 0.14 mmol), Pd2(dba)3 (60 mg, 0.066 mmol), and potassium phosphate (700 mg, 3.30 mmol) were added to a microwave-safe tube. The tube was sealed, evacuated, and 10 mL of anhydrous toluene was added. The mixture was purged with nitrogen three times. The reaction mixture was heated to 100 °C and stirred overnight. Anhydrous toluene (5 mL) was added, and the mixture was purged with nitrogen three times. The reaction mixture was heated to 100 °C again and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 20 / 80) to give compound 25-b (310 mg, 51% yield). LC-MS (ESI): m / z 583.7 (M+H) + .

[0380] Synthesis of compound 25-a

[0381] Compound 25-b (310 mg, 0.53 mmol) and dichloromethane (4 mL) were added to a reaction flask. Trifluoroacetic acid (0.8 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred under an ice-water bath for 2 hours. The solvent was removed by evaporation at room temperature, and methyl tert-butyl ether and a small amount of petroleum ether were added and stirred. The supernatant was discarded, and the solid was washed twice with methyl tert-butyl ether and a small amount of petroleum ether, and then evaporated to dryness to give compound 25-a (300 mg, 95% yield). LC-MS (ESI): m / z 483.7 (M+H) + .

[0382] Synthesis of Compound 25

[0383] Compound 25-a (60 mg, 0.10 mmol), compound 25-h (38 mg, 0.18 mmol), and dichloromethane (5 mL) were added to a reaction flask. The reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride acetate (64 mg, 0.30 mmol) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 3 hours. Sodium borohydride acetate (100 mg, 0.47 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the remaining solid was washed with saturated sodium bicarbonate solution. After washing with water, the mixture was purified by HPLC (ammonium bicarbonate) to give compound 25 (16 mg, 24% yield). LC-MS (ESI): m / z 673.4 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ8.90(1H,dd,J=7.2,0.8Hz),8.62(2H,s),8.12–8.04(2H,m),7.72(1H,d,J=8.4Hz),7.48(1H,d,J=2.0Hz),7.11–7.04 (2H,m),7.02–6.94(3H,m),6.72(1H,s),5.04(2H,q,J=9.2Hz),3.82(3 H,s),3.74(3H,s),3.71–3.61(4H,m),3.56(2H,s),2.49–2.39(4H,m).

[0384] Synthetic route of compound 26

[0385]

[0386] Synthesis of compound 26-d

[0387] Compound 25-C (180 mg, 0.50 mmol), 5-bromo-2-nitropyridine (170 mg, 0.84 mmol), and anhydrous DMSO (2.5 mL) were added to a reaction flask. Cesium carbonate (330 mg, 1.01 mmol) was added at room temperature. The reaction mixture was heated and stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and tetrahydrofuran (12 mL) and anhydrous methanol (12 mL) were added to the crude product. Ammonium chloride (450 mg, 8.41 mmol) and zinc powder (480 mg, 7.34 mmol) were added under ice-water bath conditions. The reaction mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation, ethyl acetate and dilute ammonia were added, and the mixture was separated. The aqueous phase was extracted twice with a mixture of ethyl acetate and tetrahydrofuran, and twice with tetrahydrofuran. The organic phases were combined, evaporated to dryness, and dichloromethane and dilute ammonia were added. The mixture was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 20 / 80) to give compound 26-d (150 mg, yield 66%). LC-MS (ESI): m / z 452.7 (M+H) + .

[0388] Synthesis of compound 26-c

[0389] Compound 26-d (150 mg, 0.33 mmol) and pyridine (2 mL) were added to a reaction flask. p-Methoxybenzoyl chloride (85 mg, 0.50 mmol) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then added to ice water and extracted with ethyl acetate. The ethyl acetate phase was washed with aqueous sodium bisulfate solution, water, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 20 / 80) to give compound 26-c (85 mg, 44% yield). LC-MS (ESI): m / z 586.7 (M+H) + .

[0390] Synthesis of compound 26-b

[0391] Compound 26-c (85 mg, 0.15 mmol), diphenylphosphonohydroxylamine (102 mg, 0.44 mmol), and anhydrous 1,4-dioxane (3 mL) were added to a reaction flask. The reaction mixture was heated and stirred at 100 °C for 5 hours. The reaction mixture was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed three times with 5% sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 30 / 70) to give compound 26-b (80 mg, 95% yield). LC-MS (ESI): m / z 583.7 (M+H)+ .

[0392] Synthesis of compound 26-a

[0393] Compound 26-b (85 mg, 0.15 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise under an ice-water bath, and the reaction mixture was stirred under an ice-water bath for 2 hours. The solvent was removed by evaporation at room temperature, and the residue was slurried twice with methyl tert-butyl ether and a small amount of petroleum ether, and evaporated to dryness to give compound 26-a (85 mg, 98% yield). LC-MS (ESI): m / z 483.7 (M+H) + .

[0394] Synthesis of Compound 26

[0395] Compound 26-a (85 mg, 0.14 mmol) and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (42 mg, 0.16 mmol) were added to a reaction flask. Anhydrous tetrahydrofuran (3 mL) and TEA (0.069 mL, 0.49 mmol) were added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 2 hours. 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (18 mg, 0.067 mmol) and TEA (0.041 mL, 0.30 mmol) were then added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation, and the residue was washed once with aqueous sodium bicarbonate solution. Preparative HPLC purification was performed to give compound 26 (32 mg, 33% yield). LC-MS (ESI): m / z 671.4 (M+H) + ; 1 H NMR (CDCl3, 400MHz): δ8.24 (1H, dd, J = 2.4, 0.4Hz), 8.20–8.13 (2H, m), 7.68 (1H ,dd,J=9.6,0.4Hz),7.61(1H,d,J=8.4Hz),7.41(1H,dd,J=9.6,2.0Hz),7.31–7. 27(2H,m),7.05–6.97(3H,m),6.96–6.89(3H,m),6.59(1H,d,J=0.4Hz),4.35(2 H,q,J=8.0Hz),3.87(3H,s),3.83–3.72(7H,m),3.52(2H,s),2.58–2.39(4H,m).

[0396] Synthetic route of compound 27

[0397]

[0398] Synthesis of compound 27-a

[0399] 2-Amino-4-bromopyridine (2.0 g, 11.56 mmol), alpha-bromo-4-methoxyacetophenone (2.65 g, 11.56 mmol), and ethyl acetate (25 mL) were added to a reaction flask. The reaction mixture was heated to 80 °C and stirred for 3 hours. The solvent was removed by rotary evaporation, and cesium carbonate (3.77 g, 11.56 mmol) and 1,4-dioxane (25 mL) were added. The reaction mixture was heated to 80 °C and stirred for 3 hours. The mixture was allowed to stand. Ice water and ethyl acetate were added, and a solid precipitated. The solid was filtered, the filter cake was washed with water and a small amount of ethyl acetate, and then air-dried to give the product. The filtrate was separated, the ethyl acetate phase was evaporated to dryness, and a mixture of methyl tert-butyl ether and petroleum ether was slurried. The slurry was combined with the air-dried product to give compound 27-a (2.6 g, 74% yield). LC-MS (ESI): m / z 303.3 (M+H) + .

[0400] Synthesis of Compound 27

[0401] Compound 1-b (45 mg, 0.10 mmol), compound 27-a (40 mg, 0.13 mmol), tBuXPhos (8.5 mg, 0.020 mmol), Pd2(dba)3 (9.2 mg, 0.010 mmol), potassium phosphate (64 mg, 0.30 mmol), and anhydrous toluene (3 mL) were added to a microwave-safe tube. The tube was sealed and purged with nitrogen three times. The reaction mixture was heated at 100 °C and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and saturated brine, evaporated to dryness, and the residual solid was purified by preparative HPLC (ammonium bicarbonate) to give compound 27 (23.4 mg, 35% yield). LC-MS (ESI): m / z 670.4 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ8.52–8.46(1H,m),8.18(1H,s),7.86–7.79(2H,m),7.68(1H ,d,J=8.4Hz),7.38(1H,d,J=2.0Hz),7.32–7.26(2H,m),7.04–7.00(2H,m),7.00–6.9 7(2H,m),6.95(1H,dd,J=8.4,2.0Hz),6.79–6.74(2H,m),6.70(1H,s),4.74(2H,q,J= 8.8Hz),3.78(3H,s),3.72(3H,s),3.69–3.60(4H,m),3.48(2H,s),2.46–2.37(4H,m).

[0402] Synthetic route of compound 28

[0403]

[0404] Synthesis of compound 28-a

[0405] 2-Amino-5-bromophenol (1.08 g, 5.74 mmol), p-methoxybenzaldehyde (0.68 g, 5.01 mmol), and anhydrous ethanol (20 mL) were added to a reaction flask. The reaction mixture was heated to 80 °C and stirred for 2 hours. The solvent was removed by evaporation, and anhydrous dichloromethane (20 mL) and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (1.25 g, 5.51 mmol) were added under an ice-water bath. The reaction mixture was stirred overnight at room temperature. The solvent was removed by evaporation, and ethyl acetate to petroleum ether (2:1) was added. The mixture was washed twice with saturated sodium bicarbonate solution, filtered, and the filtrate was separated. The organic phase was evaporated to dryness, purified by column chromatography, and combined with the filter cake. The mixture was washed twice with petroleum ether and evaporated to dryness to give compound 28-a (460 mg, 31% yield). LC-MS (ESI): m / z 304.0 (M+H) + .

[0406] Synthesis of Compound 28

[0407] Compound 1-b (45 mg, 0.10 mmol), compound 28-a (42 mg, 0.14 mmol), tBuXPhos (8.5 mg, 0.020 mmol), Pd2(dba)3 (9 mg, 0.010 mmol), potassium phosphate (80 mg, 0.35 mmol), and anhydrous toluene (2.5 mL) were added to a microwave-safe tube. The tube was sealed and purged with nitrogen three times. The reaction mixture was heated to 110 °C and stirred overnight. The reaction mixture was evaporated to dryness, purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 0 / 100), and then purified by preparative HPLC (ammonium bicarbonate) to give compound 28 (34.4 mg, 51% yield). LC-MS (ESI): m / z 671.2 (M+H) + ; 1 HNMR (DMSO-d6, 400MHz): δ8.12–8.06 (2H, m), 7.72 (1H, d, J = 8.4Hz), 7.64 (1H, d, J = 8. 4Hz),7.37(1H,d,J=2.0Hz),7.33–7.24(3H,m),7.18–7.13(2H,m),7.07(1H,dd,J=8.8 ,2.4Hz),7.05–6.99(2H,m),6.89(1H,dd,J=8.4,2.0Hz),6.67(1H,s),4.74(2H,q,J= 8.8Hz),3.86(3H,s),3.69(3H,s),3.67–3.61(4H,m),3.48(2H,s),2.47–2.37(4H,m).

[0408] Synthetic routes of compounds 29 and 30

[0409]

[0410] Synthesis of compound 29-c

[0411] 6-Bromoinazole (5000 mg, 25.38 mmol) and DMF (40 mL) were added sequentially to a reaction flask at room temperature. The mixture was protected by N2 displacement, and sodium hydride (60%, 1015 mg, 25.38 mmol) was added in portions under an ice-water bath, with stirring at room temperature for 1 hour. 2-(chloromethoxy)ethyltrimethylsilane (5077 mg, 30.45 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. 100 mL of water was added to the reaction mixture, and the solution was extracted with 200 mL of ethyl acetate. The organic phase was washed three times with water, washed with brine, dried over anhydrous sodium sulfate, concentrated, stirred into silica gel, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to give compound 29-c (6900 mg, 83%).

[0412] Synthesis of compound 29-b

[0413] Compound 1-b (200 mg, 0.45 mmol), compound 29-c (190 mg, 0.58 mmol), Pd2(dba)3 (41 mg, 0.05 mmol), t-BuXPhos (38 mg, 0.09 mmol), potassium phosphate (285 mg, 1.34 mmol), and toluene (10 mL) were added sequentially to a reaction flask at room temperature. The mixture was protected by N2 displacement and heated to 110 °C overnight. The reaction solution was concentrated, stirred into silica gel, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 0 / 10) to give compound 29-b (270 mg, 87%). LC-MS (ESI): m / z 694.7 (M+H) + .

[0414] Synthesis of compound 29-a

[0415] Compound 29-b (800 mg, 1.15 mmol) and a 1 M, 20 mL solution of tetrabutylammonium fluoride in THF were added sequentially to a reaction flask at room temperature. The mixture was protected by nitrogen displacement and heated to 50 °C for 48 hours. The reaction solution was concentrated, adjusted to alkalinity with sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic phases were combined, washed with water, dried, concentrated, stirred into silica gel, and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 29-a (600 mg, 92%). LC-MS (ESI): m / z 564.7 (M+H) + .

[0416] Synthesis of compounds 29 and 30

[0417] Compound 29-a (50 mg, 0.09 mmol), 4-fluorophenylboronic acid (37 mg, 0.27 mmol), copper acetate (24 mg, 0.13 mmol), 2,2'-bipyridine (28 mg, 0.18 mmol), sodium carbonate (28 mg, 0.27 mmol), and 1,2-dichloroethane (5 mL) were added to a reaction flask at room temperature. The mixture was protected with N2 displacement and reacted overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative HPLC to give compound 29 (0.2 mg, 0.3%) and compound 30 (7.2 mg, 12%). LC-MS (ESI): m / z 658.2 (M+H) + .

[0418] Synthetic route of compound 31

[0419]

[0420] Synthesis of Compound 31

[0421] Compound 26-a (60 mg, 0.10 mmol), 6-(2,2,2-trifluoroethoxy)nicotinaldehyde (43 mg, 0.21 mmol), and dichloromethane (5 mL) were added to a reaction flask. The reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride acetate (64 mg, 0.30 mmol) was added in an ice-water bath. The reaction mixture was stirred in an ice-water bath for 0.5 hours. Sodium borohydride acetate (63 mg, 0.30 mmol) was added as a supplement. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed once with sodium bicarbonate solution and once with water. HPLC purification (ammonium bicarbonate) was performed to give compound 31 (24 mg, 36% yield). LC-MS (ESI): m / z 672.7 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ8.90 (1H, dd, J = 7.2, 0.8Hz), 8.12 (1H, d, J = 1.6Hz), 8.1 0–8.03(2H,m),7.77(1H,dd,J=8.4,2.0Hz),7.71(1H,d,J=8.4Hz),7.47(1H,d,J =1.6Hz),7.12–7.03(2H,m),7.03–6.92(4H,m),6.72(1H,s),4.98(2H,q,J=9.2H z),3.82(3H,s),3.73(3H,s),3.71–3.60(4H,m),3.52(2H,s),2.48–2.38(4H,m).

[0422] Synthetic route of compound 32

[0423]

[0424] Synthesis of Compound 32

[0425] Compound 1-b (50 mg, 0.11 mmol), 6-bromo-2-methyl-2H-indazole (47 mg, 0.22 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), and tBuXPhos (9 mg, 0.11 mmol) were added to the reaction flask at room temperature.

[0426] 0.02 mmol), potassium phosphate (71 mg, 0.33 mmol), and toluene (2 mL). The mixture was protected by N2 displacement and heated to 100 °C overnight. The reaction solution was concentrated and purified by preparative HPLC to give compound 32 (25 mg, 39%). LC-MS (ESI): m / z 578.7 (M+H) + ; 1 H NMR (400MHz, CDCl3): δ7.88(1H,s),7.66-7.52(2H,m),7.37-7.27(2H,m),7.18-7.12(1H,m),7.04-6.99(1H,m),6.99-6.88(4H ,m),6.59(1H,s),4.43-4.30(2H,q,J=8Hz),4.19(3H,s),3.90-3.75(4H,m),3.75(3H,s),3.62-3.44(2H,m),2.68-2.36(4H,m).

[0427] Synthetic route of compound 33

[0428]

[0429] Synthesis of Compound 33

[0430] Compound 29-b (800 mg, 1.15 mmol) and a 1 M, 20 mL solution of tetrabutylammonium fluoride in THF were added sequentially to a reaction flask at room temperature. The mixture was protected by nitrogen displacement and heated to 50 °C for 48 hours. The reaction solution was concentrated, adjusted to alkalinity with aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phases were combined, washed with water, dried, concentrated, and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 33 (600 mg, 92%). LC-MS (ESI): m / z 564.7 (M+H) + ; 1H NMR (400MHz, CDCl3): δ8.04 (1H, s), 7.75-7.66 (1H, d, J = 8.8Hz), 7.64-7.57 (1H, d, J = 8.4Hz), 7.43-7.26 (2H, m), 7.09-6. 87(6H,m),6.61(1H,s),4.43-4.30(2H,q,J=8Hz),3.96-3.76(4H,m),3.77(3H,s),3.70-3.38(2H,m),2.86-2.13(4H,m).

[0431] Synthetic routes of compounds 34 and 35

[0432]

[0433] Synthesis of compounds 34 and 35

[0434] Compound 33 (50 mg, 0.09 mmol), 4-methoxyphenylboronic acid (40 mg, 0.27 mmol), copper acetate (24 mg, 0.13 mmol), 2,2'-bipyridine (28 mg, 0.18 mmol), sodium carbonate (28 mg, 0.27 mmol), and 1,2-dichloroethane (5 mL) were added to a reaction flask at room temperature. The mixture was protected with N2 displacement and reacted overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative HPLC to give compound 34 (2 mg, 3%). LC-MS (ESI): m / z 670.2 (M+H) + Compound 35 (23 mg, 39%). LC-MS (ESI): m / z 670.2 (M+H) + ; 1 H NMR (400MHz, CDCl3): δ8.17-8.12(1H,d,J=1.2Hz),7.80-7.69(1H,d,J=9.2Hz),7.62-7.50(3H,m),7.39-7.26(2H,m),7.24-7.19(1H,m),7. 06-6.88(7H,m),6.59(1H,s),4.43-4.30(2H,q,J=8Hz),3.86(3H,s), 3.90-3.75(4H,m),3.76(3H,s),3.62-3.44(2H,m),2.68-2.36(4H,m).

[0435] Synthetic routes of compounds 36 and 37

[0436]

[0437] Synthesis of compounds 36 and 37

[0438] Compound 33 (50 mg, 0.09 mmol), cyclopropylboronic acid (38 mg, 0.44 mmol), copper acetate (24 mg, 0.13 mmol), 2,2'-bipyridine (28 mg, 0.18 mmol), sodium carbonate (28 mg, 0.27 mmol), and 1,2-dichloroethane (5 mL) were added to a reaction flask at room temperature. The mixture was protected with N2 displacement and reacted overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative HPLC to give compound 36 (0.8 mg, 1%). LC-MS (ESI): m / z 604.6 (M+H) + Compound 37 (14 mg, 26%). LC-MS (ESI): m / z 604.6 (M+H) + ; 1 H NMR (400MHz, CDCl3): δ7.90(1H,s),7.71-7.52(2H,m),7.37-7.27(2H,m),7.18-7.10(1H,m),7.07-6.99(1H,m),6.99-6.87(4H,m),6.61(1H ,s),4.43-4.30(2H,q,J=8Hz),3.90-3.74(4H,m),3.78(3H,s),3.60- 3.50(2H,m),3.54-3.44(1H,m),2.65-2.37(4H,m),1.25-1.03(4H,m).

[0439] Synthetic route of compound 38

[0440]

[0441] Synthesis of Compound 38

[0442] Compound 33 (50 mg, 0.09 mmol), acetonitrile (10 mL), 2-bromoethyl methyl ether (62 mg, 0.44 mmol), and cesium carbonate (289 mg, 0.89 mmol) were added sequentially to a reaction flask at room temperature. The mixture was protected with nitrogen purging and heated to 70 °C overnight. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative HPLC to give compound 38 (18 mg, 33%). LC-MS (ESI): m / z 622.7 (M+H) + .

[0443] Synthetic route of compound 39

[0444]

[0445] Synthesis of Compound 39

[0446] Compound 33 (50 mg, 0.09 mmol), DMF (3 mL), 2,2,2-trifluoroethyl p-toluenesulfonate (113 mg, 0.44 mmol), and cesium carbonate (289 mg, 0.89 mmol) were added sequentially to a reaction flask at room temperature. The mixture was protected with N2 displacement and heated to 95 °C overnight. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give compound 39 (4 mg, 7%). LC-MS (ESI): m / z 646.7 (M+H) + .

[0447] Synthetic route of compound 40

[0448]

[0449] The synthesis of compound 40-c involved adding formic acid (0.54 mL, 14.12 mmol) and acetic anhydride (0.94 mL, 9.99 mmol) to a reaction flask. The reaction mixture was heated to 60 °C and stirred for 2 hours. It was then cooled to room temperature. This mixture (110 mg) was added dropwise to a solution of 26-d (95 mg, 0.21 mmol) in anhydrous tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 4 hours. The solvent was removed by evaporation, dichloromethane was added, and the mixture was evaporated to dryness again. The solution was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 20 / 80) to give compound 40-c (45 mg, 45% yield). LC-MS (ESI): m / z 480.3 (M+H) + .

[0450] Compound 40 was synthesized using the same method as compound 26, but with compound 40-c substituted for compound 26-c. LC-MS (ESI): m / z 565.7 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ8.80(1H,dd,J=2.4,0.8Hz),8.49(1H,s),7.88(1H,dd, J=9.6,0.4Hz),7.63(1H,d,J=8.4Hz),7.56(1H,dd,J=9.6,2.4Hz),7.32–7.24(3H ,m),7.06–6.99(2H,m),6.95(1H,dd,J=8.8,2.4Hz),6.66(1H,d,J=0.8Hz),4.74( 2H,q,J=8.8Hz),3.68(3H,s),3.67–3.60(4H,m),3.47(2H,s),2.45–2.35(4H,m).

[0451] Synthetic route of compound 41

[0452]

[0453] Synthesis of compound 41-a

[0454] 1-Bromo-4-cyclopropylbenzene (1.05 g, 4.93 mmol) and anhydrous tetrahydrofuran (15 mL) were added to a reaction flask. Butyllithium (2.2 mL, 5.50 mmol) was slowly added dropwise over 10 minutes at -78 °C. The reaction mixture was stirred at this temperature for 1.5 hours. Anhydrous DMF (0.79 mL, 9.86 mmol) was slowly added dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 30 minutes, then the dry ice acetone bath was removed, and the mixture was stirred in suspension for 1 hour. The mixture was cooled to -78 °C, and a saturated aqueous solution of ammonium chloride was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then ethyl acetate and a small amount of petroleum ether were added. The mixture was separated, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 41-a (0.75 g, 94% yield). LC-MS (ESI): m / z 163.3 (M+H) + .

[0455] Synthesis of Compound 41

[0456] Compound 25-a (60 mg, 0.10 mmol), compound 41-a (45 mg, 0.28 mmol), and dichloromethane (5 mL) were added to a reaction flask. The reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride acetate (64 mg, 0.30 mmol) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 3 hours. Sodium borohydride acetate (100 mg, 0.47 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residual solid was washed with saturated sodium bicarbonate solution, washed with water, purified by HPLC (ammonium bicarbonate), lyophilized, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 0 / 100) to give compound 41 (10 mg, 16% yield). LC-MS (ESI): m / z 629.4 (M+H) + ; 1H NMR(DMSO-d6,400MHz): δ8.90(1H,dd,J=7.2,1.2Hz),8.11–8.03(2H,m),7.71(1 H,d,J=8.4Hz),7.47(1H,d,J=2.0Hz),7.24(2H,d,J=8.8Hz),7.10–7.04(2H,m),7 .04–6.93(5H,m),6.71(1H,d,J=0.4Hz),3.83–3.78(4H,m),3.73(3H,s),3.69–3. 62(4H,m),3.46(2H,s),2.47–2.38(4H,m),0.81–0.72(2H,m),0.67–0.58(2H,m).

[0457] Synthetic route of compound 42

[0458]

[0459] Synthesis of Compound 42

[0460] Compound 1-b (45 mg, 0.101 mmol), 4-bromo-1,2-methylenedioxybenzene (31 mg, 0.154 mmol), tBuXPhos (8.5 mg, 0.020 mmol), Pd2(dba)3 (9.2 mg, 0.010 mmol), potassium phosphate (700 mg, 3.298 mmol), and anhydrous toluene (3 mL) were added to a microwave-safe tube. The tube was sealed and purged with nitrogen three times. The reaction mixture was heated at 100 °C and stirred overnight. The mixture was diluted with ethyl acetate, washed with water and saturated brine, evaporated to dryness, and the residual solid was purified by preparative HPLC (ammonium bicarbonate) to give compound 42 (4.6 mg, 8.1% yield). LC-MS (ESI): m / z 568.6 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ7.57 (1H, d, J = 8.8Hz), 7.33–7.24 (2H, m), 7.11 (1H, d, J = 2. 0Hz),7.07–6.97(2H,m),6.88(1H,d,J=8.8Hz),6.79(1H,dd,J=8.8,2.0Hz),6.69(1 H,d,J=2.4Hz),6.62(1H,d,J=0.4Hz),6.44(1H,dd,J=8.4,2.4Hz),6.02(2H,s),4.7 3(2H,q,J=8.8Hz),3.67(3H,s),3.67–3.58(4H,m),3.47(2H,s),2.46–2.37(4H,m).

[0461] Synthetic route of compound 43

[0462]

[0463] Synthesis of compound 43-d

[0464] Compound 26-d (1.9 g, 4.21 mmol), diphenylphosphonohydroxylamine (1.47 g, 6.31 mmol), and anhydrous 1,4-dioxane (20 mL) were added to a reaction flask. The reaction mixture was heated to 50 °C and stirred for 2 hours. Anhydrous 1,4-dioxane (10 mL) was added, and the reaction mixture was stirred at 50 °C for another hour. After cooling to room temperature, CDI (2.73 g, 16.83 mmol) and DBU (1.41 g, 9.26 mmol) were added under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water, and a small amount of sodium bisulfate and sodium sulfate solids were added. The mixture was extracted three times with ethyl acetate / tetrahydrofuran (1:1). The organic phases were combined, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 93 / 7) to give compound 43-d (2.0 g, 97% yield). LC-MS(ESI): m / z 493.4(M+H) + .

[0465] Synthesis of compound 43-c

[0466] Under ice-water bath conditions, triethylamine (127 μL, 0.67 mmol) and trifluoromethanesulfonic anhydride (113 μL, 0.67 mmol) were added to a DCM (10 mL) solution of compound 43-d (300 mg, 0.61 mmol). After addition, the reaction mixture was brought to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was quenched with cold water, extracted with DCM, and the combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 43-c (200 mg, 53%). LC-MS (ESI): m / z = 625.2 [M+H] + .

[0467] Synthesis of compound 43-b

[0468] Compound 43-c (50 mg, 0.080 mmol), 2-(trifluoromethyl)phenylboronic acid (30 mg, 0.16 mmol), bis(diphenylphosphine phenyl ether)palladium(II) dichloride (6 mg, 0.008 mmol), cesium carbonate (78 mg, 0.24 mmol), and toluene (2 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction mixture was heated overnight at 100 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 43-b (30 mg, 60%). LC-MS (ESI): m / z 621.8 [M+H] + .

[0469] Synthesis of compound 43-a

[0470] Compound 43-b (30 mg, 0.048 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by the dropwise addition of TFA (2 mL) under an ice-water bath. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 43-a (29 mg, 97%). LC-MS (ESI): m / z 521.3 [M+H] + .

[0471] Synthesis of Compound 43

[0472] Under ice-water bath conditions, potassium carbonate (13 mg, 0.094 mmol) and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (15 mg, 0.056 mmol) were added to a DMF (2 mL) solution of compound 43-a (29 mg, 0.047 mmol). After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by Prep-HPLC (alkaline method) to give compound 43 (25 mg, 75%). LC-MS (ESI): m / z 709.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.83 (1H, s), 7.57-8.03 (7H, m), 7.36 (1H, s), 7.27 (2H, d, J = 8.4Hz), 7.02 (2H, d, J = 8.4Hz), 6 .95-7.00(1H,m),6.67(1H,s),4.73(2H,q,J=8.8Hz),3.70(3H,s),3.57-3.68(4H,m),3.48(2H,m),2.35-2.46(4H,m).

[0473] Synthesis of Compound 44

[0474]

[0475] Following the synthetic method for compound 26, compound 44 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 4-trifluoromethylbenzoyl chloride. LC-MS (ESI): m / z 709.3 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.89 (1H, d, J = 2.4Hz), 8.39 (2H, d, J = 8.0Hz), 7.89-7.98 (3H, m), 7.58-7.68 (2H, m), 7.23-7.35 (3H ,m),6.93-7.05(3H,m),6.67(1H,s),4.74(2H,q,J=8.8Hz),3.68(3H,s),3.57-3.67(4H,m),3.48(2H,m),2.35-2.46(4H,m).

[0476] Synthetic route of compound 45

[0477]

[0478] Synthesis of compound 45-c

[0479] Compound 43-d (2 g, 4.06 mmol), dichloromethane (25 mL), and trifluoroacetic acid (5 mL) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and the mixture was slurried three times with methyl tert-butyl ether and dried under vacuum to give compound 45-c (2.05 g, 100% yield). LC-MS (ESI): m / z 393.2 (M+H) + .

[0480] Synthesis of compound 45-b

[0481] Compound 45-C (2.05 g, 4.05 mmol), dichloromethane (20 mL), anhydrous methanol (4 mL), and 1-E (1.15 g, 5.63 mmol) were added to a reaction flask. Sodium cyanoborohydride (0.47 g, 7.48 mmol) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 1 hour. 1-E (0.75 g, 3.67 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (0.15 g, 2.39 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. 1-E (0.50 g, 2.45 mmol) and sodium cyanoborohydride (0.15 g, 2.39 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred with silica gel and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 90 / 10) to give compound 45-b (1.25 g, yield 53%). LC-MS (ESI): m / z 581.4 (M+H) + .

[0482] Synthesis of compound 45-a

[0483] Under ice-water bath conditions, N,N-diisopropylethylamine (1.20 mL, 6.89 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (615 mg, 1.72 mmol) were added to an anhydrous DMF (10 mL) solution of compound 45-b (1.0 g, 1.72 mmol). After addition, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the reaction was quenched with cold water, extracted with methyl tert-butyl ether, and the combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give compound 45-a (600 mg, 49%). LC-MS (ESI): m / z = 713.6 [M+H] + .

[0484] Synthesis of Compound 45

[0485] Compound 45-a (50 mg, 0.070 mmol), 4-fluorophenylboronic acid (15 mg, 0.11 mmol), bis(diphenylphosphine ether)palladium(II) dichloride (5 mg, 0.007 mmol), cesium carbonate (69 mg, 0.21 mmol), and toluene (2 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction solution was heated at 100 °C overnight. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The crude product was purified by Prep-HPLC (alkaline method) to obtain compound 45 (15 mg, 32%). LC-MS (ESI): m / z 659.2 [M+H] + ; 1H NMR(DMSO-d6,400MHz): δ8.83-8.86(1H,m),8.18-8.24(2H,m),7.88(1H,d,J =9.6Hz),7.64(1H,d,J=8.4Hz),7.58(1H,dd,J=9.6Hz,2.4Hz),7.23-7.43(5H ,m),6.99-7.05(2H,m),6.96(1H,dd,J=8.4Hz,2.4Hz),6.66(1H,s),4.74(2H, q,J=8.8Hz),3.68(3H,s),3.58-3.66(4H,m),3.47(2H,s),2.34-2.47(4H,m).

[0486] Synthesis of Compound 46

[0487]

[0488] Following the synthetic method for compound 43, compound 46 was synthesized using compound 43-c as the starting reactant and replacing 2-(trifluoromethyl)phenylboronic acid with 2-methoxyphenylboronic acid. LC-MS (ESI): m / z 671.5 [M+H] + .

[0489] Synthesis of Compound 47

[0490]

[0491] Following the synthetic method for compound 43, compound 47 was synthesized using compound 43-c as the starting reactant, with 4-methoxy-2-(trifluoromethyl)phenylboronic acid replaced by 2-(trifluoromethyl)phenylboronic acid. LC-MS (ESI): m / z 739.0 [M+H] + .

[0492] Synthesis of Compound 48

[0493]

[0494] Following the synthetic method for compound 43, compound 48 was synthesized using compound 43-c as the starting reactant and replacing 2-(trifluoromethyl)phenylboronic acid with 4-cyanopentenylboronic acid. LC-MS (ESI): m / z 666.2 [M+H] + ; 1H NMR(DMSO-d6,400MHz): δ8.87-8.88(1H,m),8.33(2H,d,J=8.8Hz),8.01(2H,d ,J=8.4Hz),7.94(1H,d,J=9.6Hz),7.60-7.66(2H,m),7.32(1H,d,J=2.0Hz),7 .25-7.31(2H,m),6.99-7.05(2H,m),6.94-6.99(1H,m),6.67(1H,s),4.73(2H ,q,J=8.8Hz),3.68(3H,s),3.58-3.67(4H,m),3.48(2H,m),2.35-2.45(4H,m).

[0495] Synthetic routes of compounds 49 and 50

[0496]

[0497] Synthesis of compounds 49 and 50

[0498] Compound 45-a (40 mg, 0.056 mmol), 2-cyanobenzoboric acid (12 mg, 0.084 mmol), tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol), sodium carbonate (18 mg, 0.17 mmol), ethylene glycol dimethyl ether (10 mL), and water (1 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction mixture was heated and stirred at 80 °C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The crude product was purified by Prep-HPLC (alkaline method) to obtain two compounds: compound 49 (3 mg, 8%), LC-MS (ESI): m / z 666.2 [M+H] + Compound 50 (10 mg, 26%), LC-MS (ESI): m / z 684.5 [M+H] + .

[0499] Synthesis of Compound 51

[0500]

[0501] Following the synthetic method for compound 45, compound 51 was synthesized using compound 45-a as the starting material, with 1-(2,2,2-trifluoroethyl)-1,2,3,6-4H-pyridine-4-boronate pinacol ester replaced by 4-fluorophenylboronic acid. LC-MS (ESI): m / z 728.3 [M+H] + ; 1H NMR (DMSO-d6, 400MHz): δ8.77 (1H, dd, J = 2.4Hz, 0.8Hz), 7.78 (1H, dd, J = 9.6Hz, 0.8Hz), 7.62 (1H, d, J = 8.4Hz),7.51(1H,dd,J=9.6Hz,2.4Hz),7.24-7.31(3H,m),6.98-7.05(2H,m),6.93(1H,dd,J=8.8Hz,2 .4Hz),6.80-6.85(1H,m),6.65(1H,s),4.74(2H,q,J=8.8Hz),3.67(3H,s),3.57-3.66(4H,m),3.47(2 H,s),2.38-2.44(2H,m),3.27-3.37(2H,m),2.85-2.92(2H,m),2.58-2.66(2H,m),2.35-2.44(4H,m).

[0502] Synthetic route of compound 52

[0503]

[0504] Synthesis of Compound 52

[0505] At room temperature, Pd / C (10%, 7 mg, 0.007 mmol) was added to a THF (5 mL) solution of compound 51 (5 mg, 0.007 mmol). After the addition was complete, the mixture was purged with hydrogen three times, and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. This crude product was purified by Prep-TLC (electrolyte: 100% ethyl acetate) to obtain compound 52 (2 mg, 40%). LC-MS (ESI): m / z 730.6 [M+H] + .

[0506] Synthetic route of compound 53

[0507]

[0508] Synthesis of compound 53-b

[0509] Compound 26-d (500 mg, 1.11 mmol), diphenylphosphonohydroxylamine (388 mg, 1.66 mmol), and anhydrous 1,4-dioxane (15 mL) were added to a reaction flask. The reaction mixture was heated to 60 °C and stirred for 3 hours. It was then cooled to room temperature. The solvent was evaporated, and methyl tert-butyl ether was added and stirred twice. The methyl tert-butyl ether solution was discarded, and the mixture was evaporated to dryness to give compound 53-b (0.75 g, 99% yield). LC-MS (ESI): m / z 467.7 (M+H) + .

[0510] Synthesis of compound 53-a

[0511] Cyclopropylformic acid (38 mg, 0.44 mmol), HOBt (59 mg, 0.44 mmol), and dichloromethane (2.5 mL) were added to a reaction flask. EDCI (72 mg, 0.38 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Compound 53-b (100 mg, 0.15 mmol) and DIPEA (75 mg, 0.58 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation, and the mixture was extracted with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Potassium carbonate (80 mg, 0.58 mmol) and anhydrous ethanol (2 mL) were added to the reaction flask containing the crude product. The reaction mixture was heated and stirred at 80 °C for 5 hours. The mixture was cooled to room temperature. The solvent was removed by evaporation, and ethyl acetate and water were added. The mixture was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 53-a (60 mg, 80% yield). LC-MS (ESI): m / z 517.7 (M+H) + .

[0512] Synthesis of Compound 53

[0513] Compound 53-a (62 mg, 0.12 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.7 mL) was added dropwise in an ice bath. The reaction mixture was stirred in an ice-water bath for 1 hour. The solvent was removed by evaporation at room temperature. Anhydrous tetrahydrofuran (3 mL), triethylamine (0.3 mL, 2.16 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (48 mg, 0.18 mmol) were added to the crude product. The reaction mixture was stirred at room temperature for 2 hours, and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (15 mg, 0.056 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (1 drop) was added, the solvent was removed by evaporation, water was added, the mixture was shaken, the supernatant was discarded, and the solid was washed once with water. HPLC purification yielded compound 53 (32 mg, yield 37%). LC-MS (ESI): m / z 605.2 (M+H) + ; 1H NMR(DMSO-d6,400MHz)δ10.09(1H,bs),8.71(1H,dd,J=2.4,0.8Hz),7.70(1H,dd,J=9.6,0.8Hz),7 .65(1H,d,J=8.8Hz),7.54–7.41(3H,m),7.26(1H,d,J=2.0Hz),7.23–7.14(2H,m),6.95(1H,dd,J=8 .4,2.0Hz),6.80(1H,d,J=0.4Hz),4.82(2H,q,J=8.8Hz),4.55–4.40(2H,m),4.33(2H,s),3.71(3H, s),3.45–3.26(4H,m),3.24–3.06(2H,m),2.20–2.09(1H,m),1.09–0.99(2H,m),1.00–0.91(2H,m).

[0514] Synthesis of Compound 54

[0515]

[0516] Following the synthetic method for compound 26, compound 54 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 4-bromobenzoyl chloride. LC-MS (ESI): m / z 719.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ8.85(1H,d,J=2.0Hz), 8.11(2H,d,J=8.8Hz), 7.90(1H,d,J=9 .6Hz),7.75(2H,d,J=9.6Hz),7.64(1H,d,J=8.4Hz),7.59(1H,dd,J=9.6,2.0Hz),7.32 –7.26(3H,m),7.02(2H,d,J=8.8Hz),6.97(1H,dd,J=8.4,2.0Hz),6.67(1H,s),4.74(2 H,dd,J=18Hz,8.8Hz),3.68(3H,s),3.67–3.59(4H,m),3.47(2H,s),2.45–2.36(4H,m).

[0517] Synthesis of Compound 55

[0518]

[0519] Following the synthetic method for compound 45, compound 55 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with 4-(2,2,2-trifluoroethoxy)phenylboronic acid. LC-MS (ESI): m / z 739.2 (M+H) + .

[0520] Synthetic route of compound 56

[0521]

[0522] Synthesis of compound 56-a

[0523] Add CDI (59 mg, 0.36 mmol) and anhydrous tetrahydrofuran (3 mL) to a reaction flask. Add a solution of 1-(2,2,2-trifluoroethyl)piperazine (74 mg, 0.44 mmol) in anhydrous tetrahydrofuran (1 mL) dropwise with stirring at room temperature. Stir the reaction mixture at room temperature for 1 hour. Add compound 53-b (100 mg, 0.15 mmol) and DIPEA (150 mg, 1.16 mmol). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent by evaporation, and add potassium carbonate (170 mg, 0.36 mmol) to the reaction flask containing the crude product.

[0524] Acetonitrile (1.23 mmol) and anhydrous ethanol (6 mL). The reaction mixture was heated and stirred at 80 °C for 5 hours. It was then cooled to room temperature. The solvent was evaporated, ethyl acetate and water were added, the mixture was separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product. Acetonitrile (5 mL) and DIPEA (0.25 mL, 1.44 mmol) were added to the crude product. Phosphorus oxychloride (0.12 mL, 1.29 mmol) was added dropwise at room temperature. The reaction mixture was heated to 70 °C and stirred for 2 hours. It was cooled to room temperature, the solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated sodium bicarbonate solution, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 56-a (40 mg, yield 43%). LC-MS (ESI): m / z 643.4 (M+H) + .

[0525] Synthesis of Compound 56

[0526] Compound 56-a (80 mg, 0.12 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (0.75 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation at room temperature. Tetrahydrofuran (3 mL), triethylamine (0.2 mL, 1.44 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (80 mg, 0.30 mmol) were added to the crude product. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (1 drop) was added, the solvent was removed by evaporation, water was added, and the product was extracted once with ethyl acetate. The organic phase was washed once with saturated sodium bicarbonate solution and evaporated to dryness to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate, developed twice) to give compound 56 (2.4 mg, yield 2.6%). LC-MS (ESI): m / z 731.5 (M+H) + .

[0527] Synthesis of Compound 57

[0528]

[0529] Following the synthetic method for compound 45, compound 57 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with 4-ethoxyphenylboronic acid. LC-MS (ESI): m / z 685.5 [M+H] + .

[0530] Synthesis of Compound 58

[0531]

[0532] Following the synthetic method of compound 45, compound 58 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with 4-trifluoromethoxyphenylboronic acid. LC-MS (ESI): m / z 725.2 [M+H] + .

[0533] Synthesis of Compound 59

[0534]

[0535] Following the synthetic method for compound 45, compound 59 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with vinylboronic acid pinacol ester. LC-MS (ESI): m / z 591.6 [M+H] + .

[0536] Synthetic route of compound 60

[0537]

[0538] Synthesis of compound 60-a

[0539] Compound 53-b (125 mg, 0.18 mmol), potassium carbonate (100 mg, 0.72 mmol), anhydrous ethanol (3 mL), and methyl acetate (0.032 mL, 0.40 mmol) were added to a microwave-safe tube. The reaction mixture was heated to 80 °C and stirred for 2 hours. Methyl acetate (0.032 mL, 0.40 mmol) was then added. The reaction mixture was heated to 60 °C and stirred for 0.5 hours. After cooling to room temperature, ethyl acetate was added, followed by washing with water, then saturated brine, drying over anhydrous sodium sulfate, filtering, and evaporation to dryness to give compound 60-a (85 mg, 95% yield). LC-MS (ESI): m / z 491.2 (M+H) + .

[0540] Synthesis of Compound 60

[0541] Compound 60-a (85 mg, 0.17 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation at room temperature. The crude product was then added to a solution of tetrahydrofuran (3 mL), triethylamine (0.25 mL, 1.80 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (80 mg, 0.30 mmol) under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (1 drop) was added, the solvent was removed by evaporation, water was added, the aqueous phase was discarded, and the residue was purified by HPLC (ammonium bicarbonate) to give compound 60 (14 mg, yield 14%). LC-MS (ESI): m / z 579.4 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ8.72(1H,dd,J=2.4,0.8Hz),7.73(1H,dd,J=9.6,0.8Hz ),7.62(1H,d,J=8.4Hz),7.49(1H,dd,J=9.6,2.4Hz),7.33–7.23(3H,m),7.07–6. 99(2H,m),6.92(1H,dd,J=8.4,2.0Hz),6.65(1H,d,J=0.4Hz),4.74(2H,q,J=8.8H z),3.67(3H,s),3.67–3.60(4H,m),3.47(2H,s),2.46(3H,s),2.44–2.34(4H,m).

[0542] Synthetic route of compound 61

[0543]

[0544] Synthesis of compound 61-a

[0545] Compound 53-b (150 mg, 0.22 mmol), dichloromethane (3 mL), and triethylamine (0.2 mL, 1.44 mmol) were added to a reaction flask. Acryloyl chloride (80 mg, 0.88 mmol) was added dropwise to the reaction solution under ice bath conditions. The reaction solution was stirred for 1 hour under ice-water bath conditions. The solvent was removed by evaporation, ethyl acetate was added, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and potassium carbonate (240 mg, 1.74 mmol) and anhydrous ethanol (5 mL) were added to the crude product reaction flask. The reaction solution was heated to 60 °C and stirred for 4 hours. It was cooled to room temperature. Ethyl acetate was added, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and 1,4-dioxane (3 mL) was added to the crude product. The reaction solution was heated to 100 °C and stirred for 2 hours. The solvent was removed by evaporation to give compound 61-a (70 mg, 64% yield). LC-MS (ESI): m / z 503.4 (M+H) + .

[0546] Synthesis of Compound 61

[0547] Compound 61-a (70 mg, 0.14 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed by evaporation at room temperature. Anhydrous tetrahydrofuran (3 mL), triethylamine (0.2 mL, 1.44 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (70 mg, 0.26 mmol) were added to the crude product under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 1 minute. The solvent was removed by evaporation, and the residue was washed twice with pure water. The mixture was dried. Tetrahydrofuran (3 mL) and palladium on carbon (10% Pd, containing 40-60% water) (90 mg, 0.85 mmol) were added to the crude product. The reaction mixture was purged with hydrogen three times and then stirred at room temperature for 1.5 hours under hydrogen atmosphere. The reaction solution was filtered and evaporated to dryness to obtain the crude product. HPLC purification (ammonium bicarbonate) yielded compound 61 (14.4 mg, yield 17.4%). LC-MS (ESI): m / z 593.4 (M+H) + ; 1H NMR (DMSO-d6, 400MHz): δ8.74 (1H, dd, J = 2.4, 0.4Hz), 7.74 (1H, dd, J = 6.4, 0.4Hz), 7.62 ( 1H,d,J=8.8Hz),7.49(1H,dd,J=9.6,2.0Hz),7.31–7.23(3H,m),7.05–7.00(2H,m),6.92( 1H,dd,J=8.4,2.0Hz),6.65(1H,d,J=0.4Hz),4.74(2H,q,J=8.8Hz),3.67(3H,s),3.66–3 .60(4H,m),3.47(2H,s),2.83(2H,q,J=7.6Hz),2.45–2.34(4H,m),1.31(3H,t,J=7.6Hz).

[0548] Synthetic route of compound 62

[0549]

[0550] Synthesis of compound 62-a

[0551] Compound 53-b (101 mg, 0.15 mmol), anhydrous methanol (3 mL), and triethylamine (0.075 mL, 0.54 mmol) were added to a reaction flask. Trifluoroacetic anhydride (0.038 mL, 0.28 mmol) was added dropwise under an ice-water bath. The reaction mixture was stirred for 10 minutes under an ice-water bath and then stirred overnight at room temperature. The solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was added to 1,4-dioxane (3 mL). The reaction mixture was heated to 80 °C and stirred for 1.5 hours. After cooling to room temperature, the solvent was removed by rotary evaporation to give compound 62-a (70 mg, 87% yield). LC-MS (ESI): m / z 545.2 (M+H) + .

[0552] Synthesis of Compound 62

[0553] Compound 62-a (70 mg, 0.13 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation at room temperature. The crude product was then added to a solution of tetrahydrofuran (3 mL), triethylamine (0.2 mL, 1.44 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (63 mg, 0.23 mmol) under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation, water was added, the aqueous phase was discarded, and the residue was purified by preparative HPLC (ammonium bicarbonate) to give compound 62 (20.4 mg, 25% yield). LC-MS (ESI): m / z 633.2 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ8.99 (1H, d, J = 2.0Hz), 8.05 (1H, d, J = 9.6Hz), 7.76 (1 H,dd,J=10.0,2.4Hz),7.65(1H,d,J=8.4Hz),7.32(1H,d,J=2.0Hz),7.31–7.24 (2H,m),7.06–7.00(2H,m),6.97(1H,dd,J=8.4,2.0Hz),6.67(1H,s),4.74(2H ,q,J=8.8Hz),3.68(3H,s),3.67–3.57(4H,m),3.47(2H,s),2.46–2.35(4H,m).

[0554] Synthesis of Compound 63

[0555]

[0556] Following the synthetic method for compound 26, compound 63 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-trifluoromethylbenzoyl chloride. LC-MS (ESI): m / z 709.3 [M+H] + ; 1 HNMR(DMSO-d6,400MHz): δ8.88-8.89(1H,m),8.42-8.50(2H,m),7.76-7.97(3H,m),7.58-7.68(2H,m),7.25-7.35(3H,m) ,6.94-7.05(3H,m),6.67(1H,s),4.74(2H,q,J=9.2Hz),3.69(3H,s),3.58-3.68(4H,m),3.48(2H,s),2.36-2.47(4H,m).

[0557] Synthetic route of compound 64

[0558]

[0559] Synthesis of compound 64-b

[0560] Compound 45-a (90 mg, 0.13 mmol), tert-butyl 5-methyl-4-(tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (62 mg, 0.19 mmol), tetra(triphenylphosphine)palladium (29 mg, 0.025 mmol), sodium carbonate (40 mg, 0.38 mmol), ethylene glycol dimethyl ether (10 mL), and water (1 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction mixture was heated and stirred at 80 °C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The crude product was purified by preparative TLC (electrolyte: EA 100%) to give compound 64-b (35 mg, 36%). LC-MS (ESI): m / z 760.7 [M+H] + .

[0561] Synthesis of compound 64-a

[0562] Compound 64-b (35 mg, 0.046 mmol) and dichloromethane (20 mL) were added to a reaction flask, followed by the dropwise addition of TFA (4 mL) under an ice-water bath. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 64-a (35 mg, 98%). LC-MS (ESI): m / z 660.7 [M+H] + .

[0563] Synthesis of Compound 64

[0564] TEA (0.031 mL, 0.23 mmol) was added to a THF (20 mL) solution of compound 64-a (35 mg, 0.045 mmol), and the mixture was stirred for 10 minutes. Then, 2,2,2,-trifluoroethyltrifluoromethanesulfonate (0.013 mL, 0.090 mmol) was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by Prep-HPLC (alkaline method) to obtain compound 64 (20 mg, 60%). LC-MS (ESI): m / z 742.3 [M+H] + ; 1H NMR (DMSO-d6, 400MHz): δ8.75 (1H, d, J = 1.6Hz), 7.82 (1H, d, J = 9.6Hz), 7.62 (1H, d, J = 8.8Hz ),7.52(1H,dd,J=8.8Hz,2.4Hz),7.24-7.32(3H,m),6.98-7.06(2H,m),6.94(1H,dd,J=8.8 Hz,2.4Hz),6.66(1H,s),4.74(2H,q,J=8.8Hz),3.68(3H,s),3.57-3.66(4H,m),3.47(2H,s ),3.22-3.33(4H,m),2.81-2.88(2H,m),2.58-2.68(2H,m),2.35-2.46(4H,m),2.10(3H,s).

[0565] Synthetic route of compound 65

[0566]

[0567] Synthesis of Compound 65

[0568] Compound 45-a (40 mg, 0.056 mmol), tributylpropynyl stanane (20 mg, 0.062 mmol), tetrakis(triphenylphosphine)palladium (13 mg, 0.011 mmol), lithium chloride (7 mg, 0.17 mmol), and THF (10 mL) were added to a microwave tube. After purging with nitrogen three times, the reaction mixture was heated and stirred overnight at 90 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The crude product was purified by Prep-HPLC (alkaline method) to obtain compound 65 (4 mg, 12%). LC-MS (ESI): m / z 603.2 [M+H] + .

[0569] Synthetic route of compound 66

[0570]

[0571] Synthesis of compound 66-f

[0572] In a reaction flask, methyl 6-hydroxy-1H-indole-2-carboxylate (1.18 g, 6.17 mmol), 5-fluoro-2-nitropyridine (1.05 g, 7.39 mmol), potassium carbonate (2.13 g, 15.43 mmol), and anhydrous DMSO (10 mL) were added. The reaction mixture was heated to 60 °C and stirred for 2 hours. Potassium carbonate (0.43 g, 3.09 mmol) was added, and the mixture was stirred at 60 °C for another 2 hours. The mixture was cooled to room temperature. Iodimethane (0.76 mL, 12.21 mmol) and cesium carbonate (2.41 g, 7.41 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, during which a large amount of solid precipitated. DMF (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly added to ice water, followed by the addition of petroleum ether. The mixture was filtered, the filter cake was washed with water and then with petroleum ether again, and finally dissolved in tetrahydrofuran. The solution was then evaporated to dryness to give compound 66-f (2.0 g, 99% yield). LC-MS (ESI): m / z 328.2 (M+H) + .

[0573] Synthesis of compound 66-e

[0574] Compound 66-f (2.0 g, 6.11 mmol), tetrahydrofuran (100 mL), anhydrous methanol (50 mL), and palladium on carbon (10% Pd, containing 40-60% water) (0.9 g, 8.46 mmol) were added to a reaction flask. After three purgings with hydrogen, the reaction mixture was heated to 22 °C and stirred under hydrogen atmosphere for 54 hours. Ammonium formate (0.50 g, 7.93 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the solvent was removed by rotary evaporation, and the mixture was slurried with water and petroleum ether, filtered, washed with water and petroleum ether, and the filter cake was dissolved in tetrahydrofuran and evaporated to dryness to give compound 66-e (1.65 g, 91% yield). LC-MS (ESI): m / z 298.3 (M+H) + .

[0575] Synthesis of compound 66-d

[0576] In a reaction flask, compound 66-e (50 mg, 0.17 mmol), diphenylphosphonohydroxylamine (67 mg, 0.29 mmol), and 1,4-dioxane (3 mL) were added. The reaction mixture was heated to 60 °C and stirred for 3 hours. It was then cooled to room temperature. The solvent was removed by rotary evaporation. Solution A was obtained by dissolving the compound in dichloromethane (1 mL). In another reaction flask, 1-BOC-1,2,3,6-tetrahydropyridine-4-carboxylic acid (48 mg, 0.21 mmol), HOBt (37 mg, 0.27 mmol), and dichloromethane (3 mL) were added. EDCI (45 mg, 0.24 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Solution A and DIPEA (150 mg, 1.16 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation, followed by addition of ethyl acetate, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and evaporating to dryness. The crude product was then added to anhydrous ethanol (5 mL) and potassium carbonate (90 mg, 0.65 mmol). The reaction mixture was heated to 60 °C and stirred overnight, then heated to 80 °C and stirred for 2 hours. The solvent was removed by rotary evaporation, followed by addition of ethyl acetate, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and evaporating to dryness to give compound 66-d (75 mg, 86% yield). LC-MS (ESI): m / z 518.8 (M+H) + .

[0577] Synthesis of compound 66-c

[0578] Compound 66-d (75 mg, 0.14 mmol), tetrahydrofuran (2 mL), and anhydrous methanol (1 mL) were added to a reaction flask. A solution of lithium hydroxide monohydrate (21 mg, 0.50 mmol) in water (1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and water and sodium bisulfate solid (61 mg) were added. The mixture was extracted twice with ethyl acetate, and the combined organic phases were evaporated to dryness to give compound 66-c (65 mg, 92% yield). LC-MS (ESI): m / z 490.8 (M+H) + .

[0579] Synthesis of compound 66-b

[0580] Compound 66-c (65 mg, 0.13 mmol), 1-c (69 mg, 0.20 mmol), DMF (3 mL), and DIPEA (100 mg, 0.77 mmol) were added to a reaction flask under ice bath conditions. HATU (60 mg, 0.16 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. The mixture was extracted with ice water and ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 66-b (95 mg, 96% yield). LC-MS (ESI): m / z 746.6 (M+H) + .

[0581] Synthesis of compound 66-a

[0582] Compound 66-b (95 mg, 0.13 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (0.75 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation, and methyl tert-butyl ether and a small amount of petroleum ether were added and slurryed. The solid was slurryed with methyl tert-butyl ether and evaporated to dryness to give compound 66-a (110 mg, 99% yield). LC-MS (ESI): m / z 646.2 (M+H) + .

[0583] Synthesis of Compound 66

[0584] Compound 66-a (110 mg, 0.13 mmol) and triethylenediamine (10 mg, 0.089 mmol) were added to a reaction flask. Anhydrous acetonitrile (5 mL), tetramethyltrifluoromethanethiol ammonium (41 mg, 0.23 mmol), and silver fluoride (91 mg, 0.72 mmol) were added in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. After filtration, the solvent was removed by rotary evaporation, ethyl acetate was added, and the mixture was washed once with water. Saturated brine was added, and the mixture was stirred for 5 minutes. The upper layer changed from black to light brown. The mixture was filtered, separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by HPLC to give compound 66 (6.7 mg, yield 7.5%). LC-MS (ESI): m / z 714.4 (M+H) + ; 1 HNMR (DMSO-d6, 400MHz): δ8.79 (1H, dd, J = 2.4Hz, 0.8Hz), 7.80 (1H, dd, J = 9.6Hz, 0.8Hz), 7.62 (1H, d,J=8.4Hz),7.53(1H,dd,J=9.6Hz,2.4Hz),7.33–7.23(3H,m),7.07–6.98(2H,m),6.94(1H,dd,J= 8.4Hz,2.0Hz),6.91–6.84(1H,m),6.66(1H,s),4.74(2H,q,J=8.8Hz),3.75–3.70(2H,m),3.67(3H ,s),3.66–3.56(4H,m),3.47(2H,s),3.17(2H,t,J=5.6Hz),2.76–2.64(2H,m),2.46–2.35(4H,m).

[0585] Synthesis of Compound 67

[0586]

[0587] Following the synthetic method for compound 53, compound 67 was synthesized using compound 53-b as the starting reactant and replacing cyclopropionic acid with 4-methoxycyclohexyl-1-enic acid. LC-MS (ESI): m / z 675.3 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.74 (1H, d, J = 2.0Hz), 7.77 (1H, d, J = 9.6Hz), 7.62 (1H, d, J = 8.4Hz), 7.50 (1H, dd ,J=9.6Hz,2.4Hz),7.24-7.32(3H,m),6.99-7.05(2H,m),6.93(1H,dd,J=8.8Hz,2.4Hz),6.78-6.82(1H,m ),6.65(1H,s),4.74(2H,q,J=8.8Hz),3.67(3H,s),3.58-3.66(4H,m),3.50-3.59(1H,m),3.47(2H,s),3. 30(3H,s),2.50-2.73(3H,m),2.34-2.45(4H,m),2.11-2.22(1H,m),1.93-2.03(1H,m),1.62-1.76(1H,m).

[0588] Synthesis of Compound 68

[0589]

[0590] Following the synthetic method for compound 53, compound 68 was synthesized using compound 53-b as the starting reactant and replacing cyclopropionic acid with 3,6-dihydro-2H-pyran-4-carboxylic acid. LC-MS (ESI): m / z 647.2 (M+H) + .

[0591] Synthesis of Compound 69

[0592]

[0593] Following the synthetic method for compound 43, compound 69 was synthesized using compound 43-c as the starting reactant and replacing 2-(trifluoromethyl)phenylboronic acid with 4-dimethylaminophenylboronic acid. LC-MS (ESI): m / z 684.2 [M+H] + .

[0594] Synthesis of Compound 70

[0595]

[0596] Following the synthetic method for compound 43, compound 70 was synthesized using compound 43-c as the starting reactant, with 4-cyano-2-fluorophenylboronic acid replacing 2-(trifluoromethyl)phenylboronic acid. LC-MS (ESI): m / z 684.2 [M+H] + .

[0597] Synthesis of Compound 71

[0598]

[0599] Following the synthetic method of compound 43, compound 71 was synthesized using compound 43-c as the starting reactant and replacing 2-(trifluoromethyl)phenylboronic acid with 4-methylthiophenylboronic acid. LC-MS (ESI): m / z 687.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.82(1H,d,J=2.4Hz),8.10(2H,d,J=8.4Hz),7.86(1H,d,J =10.0Hz),7.64(1H,d,J=8.4Hz),7.56(1H,dd,J=9.6Hz,2.4Hz),7.40(2H,d,J=8.4 Hz),7.31–7.26(3H,m),7.01(2H,d,J=8.8Hz),6.96(1H,dd,J=8.4Hz,2.0Hz),6.67 (1H,s),4.73(2H,q,J=8.8Hz),3.69–3.61(9H,m),2.54(3H,s),2.44–2.36(4H,m).

[0600] Synthesis of Compound 72

[0601]

[0602] Following the synthetic method of compound 43, compound 72 was synthesized using compound 43-c as the starting reactant and replacing 2-(trifluoromethyl)phenylboronic acid with 2-fluoro-4-methoxyphenylboronic acid. LC-MS (ESI): m / z 689.3 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.84(1H,dd,J=2.4Hz,0.8Hz),8.10(1H,t,J=8.4Hz),7.88(1H,dd,J=9.6Hz,0.8Hz),7.64(1H,d,J=8.8Hz),7.57(1H,dd,J=8. 8Hz,2.4Hz),7.31–7.25(3H,m),7.04–6.94(5H,m),6.67(1H,s),4.73(2H,q ,J=8.8Hz),3.85(3H,s),3.68(3H,s),3.66–3.58(6H,m),2.44–2.36(4H,m).

[0603] Synthesis of Compound 73

[0604]

[0605] Following the synthetic method for compound 26, compound 73 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 4-chlorobenzoyl chloride. LC-MS (ESI): m / z 675.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.82(1H,d,J=1.6Hz),8.17(2H,d,J=8.4Hz),7.88(1H,d,J=10.0Hz),7.66–7.56(4H,m),7.29(2H,d,J=2.8Hz),7. 27(1H,s),7.01(2H,d,J=8.4Hz),6.96(1H,dd,J=8.4Hz,2.0Hz),6.67(1H,s),4.72(2H,q,J=8.8Hz),3.69–3.61(9H,m),2.44–2.36(4H,m).

[0606] Synthesis of Compound 74

[0607]

[0608] Following the synthetic method of compound 45, compound 74 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with 3-methoxyphenylboronic acid. LC-MS (ESI): m / z 671.3 (M+H) + ; 1H NMR (DMSO-d6, 400MHz): δ8.85 (1H, d, J = 2.4Hz), 7.89 (1H, d, J = 9.6Hz), 7.77 (1H, d, J = 8.0Hz), 7.6 8-7.73(1H,m),7.64(1H,d,J=8.8Hz),7.58(1H,dd,J=9.6Hz,2.0Hz),7.45(1H,d,J=8.0Hz),7.24- 7.34(3H,m),7.05-7.10(1H,m),6.99-7.05(2H,m),6.97(1H,dd,J=8.8Hz,2.0Hz),6.67(1H,s),4. 74(2H,q,J=8.8Hz),3.85(3H,s),3.68(3H,s),3.57-3.67(4H,m),3.47(2H,s),2.34-2.45(4H,m).

[0609] Synthesis of Compound 75

[0610]

[0611] Following the synthetic method for compound 45, compound 75 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with (6-methoxypyridin-3-yl)boronic acid. LC-MS (ESI): m / z 672.3 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ8.94 (1H, d, J = 2.0Hz), 8.86 (1H, d, J = 2.0Hz), 8.38 (1H, dd ,J=8.4Hz,2.4Hz),7.89(1H,d,J=9.6Hz),7.64(1H,d,J=8.4Hz),7.58(1H,dd,J=9. 6Hz,2.0Hz),7.24-7.32(3H,m),6.93-7.05(4H,m),6.66(1H,s),4.74(2H,q,J=8.8 Hz),3.94(3H,s),3.68(3H,s),3.58-3.67(4H,m),3.47(2H,s),2.34-2.45(4H,m).

[0612] Synthesis of Compound 76

[0613]

[0614] Following the synthetic method of compound 45, compound 76 was synthesized using compound 45-a as the starting reactant and replacing 4-fluorophenylboronic acid with 3-fluoro-4-methoxyphenylboronic acid. LC-MS (ESI): m / z 689.3 (M+H) + ; 1 H NMR (400M, DMSO-d6) δ8.81 (1H, d, J = 2.0Hz), 7.97 (1H, d, J = 8.4Hz), 7.91-7.83 (2H, m),7.64(1H,d,J=8.4Hz),7.56(1H,dd,J=2.4Hz,J=9.6Hz),7.38-7.24(4H,m),7.0 2(2H,d,J=8.4Hz),6.96(1H,dd,J=2.4Hz,J=8.4Hz),6.67(1H,s),4.73(2H,q,J=8. 8Hz),3.92(3H,s),3.68(3H,s),3.67-3.58(4H,m),3.47(2H,s),2.46-2.32(4H,m).

[0615] Synthesis of Compound 77

[0616]

[0617] Following the synthetic method for compound 53, compound 77 was synthesized using compound 53-b as the starting reactant and replacing cyclopropionic acid with imidazole [1,5-a]pyridine-7-carboxylic acid. LC-MS (ESI): m / z 681.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.86(1H,dd,J=2.0,0.4Hz),8.49(1H,s),8.46(1H,d,J=7.2Hz),8.38(1H,s) ,7.89(1H,dd,J=9.6Hz,0.4Hz),7.65(1H,d,J=8.8Hz),7.61–7.57(2H,m),7.36(1H,dd,J=7.6Hz,2.0H z),7.31(1H,d,J=2.4Hz),7.28(2H,d,J=8.4Hz),7.02(2H,d,J=8.8Hz),6.98(1H,dd,J=8.4Hz,2.4H) ,6.67(1H,s),4.74(2H,q,J=8.8Hz),3.69(3H,s),3.67–3.61(4H,m),3.48(2H,s),2.45–2.39(4H,m).

[0618] Synthesis of Compound 78

[0619]

[0620] Following the synthetic method for compound 53, compound 78 was synthesized using compound 53-b as the starting reactant and replacing cyclopropionic acid with p-trifluoromethylthiobenzoic acid. LC-MS (ESI): m / z 741.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.86 (1H, d, J = 1.6Hz), 8.30 (2H, d, J = 8.0Hz), 7.92 (1H, d, J = 10 .0Hz),7.89(2H,d,J=8.4Hz),7.64(1H,d,J=8.4Hz),7.60(1H,dd,J=9.6Hz,2.4Hz),7.3 2(1H,s),7.28(2H,d,J=8.0Hz), 7.01(2H,d,J=8.4Hz), 6.97(1H,dd,J=8.4Hz,2.0Hz), 6.87(1H,s),4.73(2H,q,J=8.8Hz),3.68(3H,s),3.66–3.61(6H,m),2.45–2.37(4H,m).

[0621] Synthetic route of compound 80

[0622]

[0623] Synthesis of Compound 80

[0624] At room temperature, acetaldehyde (40% aqueous solution) (0.5 mL) and sodium cyanoborohydride (49 mg, 0.77 mmol) were added to a methanol (5 mL) solution of compound 66-a (100 mg, 0.16 mmol), and the reaction mixture was allowed to react overnight at room temperature. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative HPLC to give compound 80 (81.6 mg, 78%). LC-MS (ESI): m / z 674.3 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.74 (1H, dd, J = 2.4, 0.8 Hz), 7.76 (1H, dd, J = 9.6 Hz, 0.4 Hz), 7.62 (1H, d, J = 8.8Hz),7.50(1H,dd,J=9.6Hz,2.0Hz),7.29(1H,s),7.27–7.25(2H,m),7.01(2H,d,J=8.4Hz),6.93 (1H,dd,J=8.4Hz,2.0Hz),6.86–6.82(1H,m),6.65(1H,s),4.72(2H,q,J=8.8Hz),3.67(3H,s),3.6 5–3.52(6H,m),3.12(2H,d,J=2.8Hz),2.65–2.56(4H,m),2.49–2.35(6H,m),1.06(3H,t,J=7.2Hz).

[0625] Synthesis of Compound 81

[0626]

[0627] Following the synthetic method for compound 26, compound 81 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-fluorobenzoyl chloride. LC-MS (ESI): m / z 659.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.83 (1H, d, J = 2.0Hz), 8.02 (1H, d, J = 8.0Hz), 7.92–7. 85(2H,m),7.67–7.56(3H,m),7.39–7.32(1H,m),7.31(1H,d,J=1.6Hz),7.27(2 H,d,J=8.8Hz),7.01(2H,d,J=8.4Hz),6.96(1H,dd,J=8.8Hz,2.0Hz),6.67(1H ,s),4.72(2H,q,J=8.8Hz),3.68(3H,s),3.66–3.51(6H,m),2.45–2.35(4H,m).

[0628] Synthesis of Compound 82

[0629]

[0630] Following the synthetic method for compound 26, compound 82 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-chlorobenzoyl chloride. LC-MS (ESI): m / z 675.3 (M+H) + ;1 H NMR(400MHz,DMSO-d6)δ8.83(1H,d,J=2.0Hz),8.16–8.10(2H,m),7.90(1H,d,J =9.6Hz),7.64(1H,d,J=8.8Hz),7.62–7.55(3H,m),7.31(1H,d,J=2.0Hz),7.27 (2H,d,J=8.4Hz),7.01(2H,d,J=8.4Hz),6.96(1H,dd,J=8.8Hz,2.0Hz),6.67(1 H,s),4.72(2H,q,J=8.8Hz),3.68(3H,s),3.66–3.51(6H,m),2.45–2.35(4H,m).

[0631] Synthesis of Compound 83

[0632]

[0633] Following the synthetic method for compound 26, compound 83 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-bromobenzoyl chloride. LC-MS (ESI): m / z 719.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.81(1H,d,J=2.0Hz),8.28(1H,s),8.15(1H,d,J=8.0Hz),7.88(1H,d,J=10 .0Hz),7.70(1H,dd,J=8.0Hz,0.8Hz),7.63(1H,d,J=8.4Hz),7.58(1H,dd,J=9.6Hz,2.0Hz),7.50(1 H,t,J=8.0Hz),7.30(1H,d,J=2.0Hz),7.27(2H,d,J=8.8Hz),7.01(2H,d,J=8.8Hz),6.96(1H,dd,J= 8.4,2.0Hz),6.66(1H,s),4.72(2H,q,J=8.8Hz),3.68(3H,s),3.66–3.51(6H,m),2.45–2.35(4H,m).

[0634] Synthesis of Compound 84

[0635]

[0636] Following the synthetic method for compound 26, compound 84 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-(trifluoromethoxy)benzoyl chloride. LC-MS (ESI): m / z 725.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.88(1H,dd,J=2.4,0.8Hz),8.21(1H,d,J=6.8Hz),8.06(1H,s),7.93(1H,dd,J=1 0.0Hz,0.8Hz),7.71(1H,t,J=8.0Hz),7.64(1H,d,J=8.4Hz),7.61(1H,dd,J=12.0Hz,2.0Hz),7.53(1H,dd, J=8.0,0.8Hz),7.32(1H,d,J=2.4Hz),7.28(2H,d,J=8.8Hz),7.02(2H,d,J=8.8Hz),6.97(1H,dd,J=8.4,2. 0Hz),6.67(1H,s),4.74(2H,q,J=8.8Hz),3.69(3H,s),3.67–3.59(4H,m),3.48(2H,s),2.46–2.36(4H,m).

[0637] Synthesis of Compound 85

[0638]

[0639] Following the synthetic method of compound 53, compound 85 was synthesized using compound 53-b as the starting reactant and replacing cyclopropionic acid with 4-(2,2,2-trifluoroethyl)benzoic acid. LC-MS (ESI): m / z 723.3 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.84 (1H, d, J = 2.0Hz), 8.18 (2H, d, J = 8.4Hz), 7.89 (1H, d, J = 10.0Hz), 7 .64(1H,d,J=8.8Hz),7.58(1H,dd,J=9.6Hz,2.4Hz),7.53(2H,d,J=8.0Hz),7.30(1H,d,J=2.0Hz ),7.28(2H,d,J=8.4Hz),7.01(2H,d,J=8.8Hz),6.97(1H,dd,J=8.4Hz,2.0Hz),6.67(1H,s),4. 73(2H,q,J=8.8Hz), 3.74(2H,q,J=11.6Hz), 3.68(3H,s), 3.66–3.57(6H,m), 2.45–2.36(4H,m).

[0640] Synthetic route of compound 86

[0641]

[0642] Synthesis of compound 86-b

[0643] 6-Iodopyridazine-3-amine (221 mg, 1.00 mmol), 2-bromo-1-(4-(trifluoromethyl)phenyl)ethyl-1-one (268 mg, 1.00 mmol), and anhydrous ethanol (5 mL) were added to a reaction flask. The reaction mixture was heated and stirred at 80 °C for 3 hours. Sodium bicarbonate (126 mg, 1.50 mmol) was added. The reaction mixture was heated and stirred at 80 °C for 5 hours. Most of the solvent was removed by rotary evaporation, and water and ethyl acetate were added. The aqueous phase was separated, the organic suspension was washed once with water, evaporated to dryness, and lyophilized for 30 minutes to give compound 86-b (0.38 g, 98%). LC-MS (ESI): m / z 390.0 (M+H) + .

[0644] Synthesis of compound 86-a

[0645] Compound 25-c (100 mg, 0.28 mmol), compound 86-b (180 mg, 0.46 mmol), anhydrous potassium carbonate (154 mg, 1.11 mmol), and DMSO (4 mL) were added to a reaction flask. The reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 86-a (0.16 g, 93%). LC-MS (ESI): m / z 621.6 (M+H) + .

[0646] Synthesis of Compound 86

[0647] Compound 86-a (160 mg, 0.26 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (0.75 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation at room temperature. Methyl tert-butyl ether was added and the mixture was stirred three times, then evaporated to dryness to obtain the crude product. 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (108 mg, 0.40 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamine (0.34 mL, 2.45 mmol) were added to the crude product under ice-water bath conditions. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 1 minute. The solvent was removed by evaporation, and the residue was washed twice with pure water. The mixture was dried overnight. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 20 / 80; dichloromethane / methanol, 100 / 0 to 97 / 3), evaporated to dryness, and then purified by preparative HPLC (ammonium bicarbonate) to give compound 86 (66 mg, 36%). LC-MS (ESI): m / z 709.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ8.76(1H,s),8.22(1H,dd,J=10.0Hz,0.4Hz),8.18–8.12 (2H,m),7.81–7.75(2H,m),7.68(1H,d,J=8.4Hz),7.54(1H,d,J=2.0Hz),7.32–7. 25(2H,m),7.20(1H,d,J=9.6Hz),7.08–7.00(3H,m),6.70(1H,d,J=0.4Hz),4.74 (2H,q,J=8.8Hz),3.73(3H,s),3.70–3.62(4H,m)3.49(2H,s),2.47–2.36(4H,m).

[0648] Synthetic route of compound 87

[0649]

[0650] Synthesis of compound 87-b

[0651] Add 6-bromo-[1,2,4]triazole[1,5-a]pyridine-2-amine (3.65 g, 17.13 mmol), acetonitrile (80 mL), isoamyl nitrite (6.8 mL, 50.79 mmol), and anhydrous copper(II) chloride (6.9 g, 51.32 mmol) to a reaction flask. Heat the reaction mixture to 70 °C and stir for 3 hours. Filter, evaporate the filtrate to dryness, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 0 / 100, DCM, 100) to obtain the crude product. Add dichloromethane, water, and concentrated ammonia, separate the layers, and extract the aqueous phase once with dichloromethane. Combine the organic phases, wash once with water, and evaporate to dryness. Add dichloromethane, water, and concentrated ammonia to the filter cake, separate the layers, extract the aqueous phase once with dichloromethane, combine the organic phases, wash once with water, and evaporate to dryness. The two solids were combined, a small amount of anhydrous ethanol was added, the mixture was filtered, the filter cake was washed with a small amount of anhydrous ethanol, and dried overnight to give compound 87-b (1.7 g, 43%).

[0652] Synthesis of compound 87-a

[0653] 6-Bromo-1-methyl-2-indolecarboxylic acid (254 mg, 1.00 mmol) and 1-c (348 mg, 1.00 mmol) were added to a reaction flask. DMF (3 mL) and DIPEA (517 mg, 4.00 mmol) were added under ice-water bath conditions. After stirring the mixture for 5 minutes under ice-water bath conditions, HATU (456 mg, 1.20 mmol) was added. The reaction mixture was stirred under ice-water bath conditions for 2 hours. Ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 87-a (480 mg, 94% yield). LC-MS (ESI): m / z 510.0 (M+H) + .

[0654] Synthesis of Compound 87

[0655] Compound 87-b (120 mg, 0.52 mmol), bis-pinacolborate (180 mg, 0.71 mmol), Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.024 mmol), potassium acetate (190 mg, 1.94 mmol), and 1,4-dioxane (5 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, and the reaction solution was heated to 80 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, and compound 87-a (156 mg, 0.31 mmol), Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.024 mmol), and 1,4-dioxane (5 mL) were added.

[0656] 0.024 mmol), potassium phosphate (280 mg, 1.22 mmol), and water (1 mL). The reaction mixture was purged with nitrogen three times, and the reaction solution was heated to 90 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, ethyl acetate and water were added, and the mixture was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 96 / 4) to give compound (150 mg, yield 84%). 60 mg of the sample was taken and purified by preparative HPLC to give compound 87 (15.5 mg, yield 22%). LC-MS (ESI): m / z 583.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ9.37(1H,s),8.25(1H,dd,J=9.6Hz,1.6Hz),8.02(1H,s),7.92(1H,d,J=9.2Hz),7.72(1H,d,J=8.4Hz),7.54(1H,dd,J=8.4Hz ,1.6Hz),7.35–7.25(2H,m),7.08–6.95(2H,m),6.68(1H,s),4.74(2H,q,J =8.8Hz),3.85(3H,s),3.74–3.55(4H,m),3.48(2H,s),2.48–2.37(4H,m).

[0657] Synthetic route of compound 88

[0658]

[0659] Synthesis of Compound 88

[0660] Compound 87-a (53 mg, 0.10 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (40 mg, 0.16 mmol), and Pd(dppf)Cl2 were added to a microwave tube. . CH₂Cl₂ (18 mg, 0.022 mmol) and potassium phosphate (72 mg, 0.31 mmol) were added. The mixture was sealed, evacuated, and 1,4-dioxane (2.5 mL) and water (0.5 mL) were added. The reaction mixture was purged with nitrogen three times, and the reaction solution was heated to 90 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, and ethyl acetate and water were added. The mixture was separated, the organic phase was washed with water, evaporated to dryness, and purified by preparative HPLC to give compound 88 (16.6 mg, 29% yield) as a white solid. LC-MS (ESI): m / z 549.3 (M+H) + ;1 HNMR(DMSO-d6,400MHz)δ9.03(1H,d,J=7.2Hz),8.52(1H,s),8.29–8.23(1H,m),8.12(1H,s),7.77–7.68(2H,m),7.64(1H,dd,J=8.0Hz,1.6Hz ),7.32–7.24(2H,m),7.08–6.98(2H,m),6.69(1H,s),4.74(2H,q,J=8. 8Hz),3.86(3H,s),3.75–3.54(4H,m),3.48(2H,s),2.48–2.36(4H,m).

[0661] Synthetic route of compound 89

[0662]

[0663] Synthesis of Compound 89

[0664] Compound 87 (90 mg, 0.15 mmol), 4-trifluoromethylphenylboronic acid (62 mg, 0.33 mmol), potassium carbonate (64 mg, 0.46 mmol), and Pd(PPh3)4 (18 mg, 0.016 mmol) were added to a microwave-safe tube. The tube was sealed and evacuated. 1,4-Dioxane (4.5 mL) and water (0.5 mL) were added. The mixture was purged with nitrogen three times, and the reaction mixture was heated to 120 °C and stirred overnight. After cooling to room temperature, the mixture was evaporated to dryness, and ethyl acetate and water were added. The mixture was separated, the organic phase was washed with water, and the residue was evaporated to dryness. The crude product was purified by preparative HPLC (TFA) to give compound 89 (31.4 mg, 25% yield). LC-MS (ESI): m / z 693.3 (M+H) + ; 1 HNMR(DMSO-d6,400MHz)δ10.05(1H,bs),9.53–9.48(1H,m),8.49–8.40(2H,m),8.25(1H,dd ,J=9.2,1.6Hz),8.10(1H,s),8.03(1H,dd,J=9.2Hz,0.4Hz),7.99–7.92(2H,m),7.77(1H,d, J=8.4Hz),7.62(1H,dd,J=8.0,1.2Hz),7.53–7.45(2H,m),7.23–7.15(2H,m),6.84(1H,s),4 .83(2H,q,J=8.8Hz),4.61–4.27(4H,m),3.90(3H,s),3.49–3.31(4H,m),3.26–3.15(2H,m).

[0665] Synthetic route of compound 90

[0666]

[0667] Synthesis of compound 90-c

[0668] Compound 25-c (150 mg, 0.42 mmol), 2-bromo-5-fluoropyrimidine (110 mg, 0.62 mmol), anhydrous potassium carbonate (174 mg, 1.26 mmol), and DMSO (3 mL) were added to a reaction flask. The reaction mixture was heated to 80 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 90-c (200 mg, 93%). LC-MS (ESI): m / z 459.8 (Mt-Bu+H) + .

[0669] Synthesis of compound 90-b

[0670] Compound 90-c (200 mg, 0.39 mmol), Pd2dba3 (17 mg, 0.019 mmol), Xantphos (18 mg, 0.031 mmol), benzophenone imine (115 mg, 0.64 mmol), anhydrous 1,4-dioxane (5 mL), and cesium carbonate (352 mg, 1.08 mmol) were added to a microwave-safe tube. The tube was sealed and purged with nitrogen three times. The reaction mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed by evaporation, and the solution was diluted with ethyl acetate and washed once with saturated ammonium chloride. The aqueous phase was extracted once more with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and methanol (5 mL) and hydroxylamine hydrochloride (110 mg, 1.58 mmol) were added to the crude product. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 96 / 4) to give compound 90-b (30 mg, 17%). LC-MS (ESI): m / z 453.4 (M+H) + .

[0671] Synthesis of compound 90-a

[0672] Compound 90-b (30 mg, 0.066 mmol), 2-bromo-1-(4-(trifluoromethyl)phenyl)-1-ethyl-one (26 mg, 0.097 mmol), sodium bicarbonate (8.4 mg, 0.10 mmol), and anhydrous ethanol (3 mL) were added to a reaction flask. The reaction mixture was heated to 90 °C and stirred overnight. 2-bromo-1-(4-(trifluoromethyl)phenyl)-1-ethyl-one (42 mg, 0.16 mmol), sodium bicarbonate (15 mg, 0.18 mmol), and anhydrous ethanol (3 mL) were then added. The reaction mixture was heated to 90 °C and stirred for 8 hours. The reaction mixture was cooled to room temperature, the solvent was removed by evaporation, diluted with ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 90-a (40 mg, 97% yield). LC-MS (ESI): m / z 621.3 (M+H) + .

[0673] Synthesis of Compound 90

[0674] Compound 90-a (40 mg, 0.064 mmol) and dichloromethane (1.5 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation at room temperature. Methyl tert-butyl ether and a small amount of petroleum ether were added and stirred twice. The mixture was then evaporated to dryness to obtain the crude product. 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (36 mg, 0.13 mmol), anhydrous tetrahydrofuran (2 mL), and triethylamine (0.12 mL, 0.86 mmol) were added to the crude product under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (1 drop) was added and the mixture was stirred for 1 minute. The solvent was removed by evaporation. The residue was washed twice with pure water and purified by HPLC (ammonium bicarbonate) to give compound 90 (3.4 mg, yield 7.4%). LC-MS (ESI): m / z 709.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ8.84(1H,d,J=2.8Hz),8.60(1H,d,J=2.8Hz),8.44(1H,s ),8.20(2H,d,J=8.4Hz),7.83(2H,d,J=8.4Hz),7.65(1H,d,J=8.8Hz),7.37(1H, d,J=2.0Hz),7.31–7.24(2H,m),7.05–6.98(3H,m),6.67(1H,d,J=0.4Hz),4.74( 2H,q,J=8.8Hz),3.69(3H,s),3.67–3.59(4H,m),3.48(2H,s),2.45–2.35(4H,m).

[0675] Synthesis of Compound 91

[0676]

[0677] Following the synthetic method of compound 26, compound 91 was synthesized using compound 26-d as the starting reactant and replacing p-methoxybenzoyl chloride with 3-cyanobenzoyl chloride. LC-MS (ESI): m / z 666.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ8.88(1H,dd,J=2.4,0.8Hz),8.51–8.45(2H,m),7.99(1H,dt,J=8.0,1.2 Hz),7.93(1H,dd,J=10.0Hz,0.8Hz),7.77(1H,td,J=7.6Hz,1.2Hz),7.67–7.57(2H,m),7.32(1H, d,J=2.4Hz),7.30–7.25(2H,m),7.06–7.00(2H,m),6.97(1H,dd,J=8.4Hz,2.0Hz),6.67(1H,d,J =0.8Hz),4.74(2H,q,J=8.8Hz),3.69(3H,s),3.67–3.59(4H,m),3.47(2H,s),2.46–2.37(4H,m).

[0678] Synthetic route of compound 92

[0679]

[0680] Synthesis of compound 92-b

[0681] 1H-pyrazole-4-carboxaldehyde (2.0 g, 20.81 mmol) and anhydrous DMF (20 mL) were added to a reaction flask. Cesium carbonate (13.56 g, 41.63 mmol) was added under an ice-water bath. After stirring the reaction mixture under an ice-water bath for 5 minutes, 2,2,2-trifluoroethyltrifluoromethanesulfonate (7.55 g, 32.53 mmol) was added dropwise. The reaction mixture was reacted at 40 °C for 2 hours. After cooling to room temperature, it was placed in a freezer. Ice water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 40 / 60) to give compound 92-b (3.4 g, 92% yield). LC-MS (ESI): m / z 179.2 (M+H) + .

[0682] Synthesis of compound 92-a

[0683] Compound 26-d (70 mg, 0.16 mmol) and pyridine (1.5 mL) were added to a reaction flask. After stirring for 5 minutes in an ice-water bath, p-cyanobenzoyl chloride (42 mg, 0.25 mmol) was added. The reaction mixture was stirred for 5 minutes in an ice-water bath, then stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was discarded, and the residue was washed once with a saturated ammonium chloride solution. Ethyl acetate was added, and the mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Diphenylphosphonic hydroxylamine (92 mg, 0.39 mmol) and anhydrous 1,4-dioxane (2.5 mL) were added to the crude product. The mixture was heated to 100 °C and stirred for 3 hours. Diphenylphosphonic hydroxylamine (92 mg, 0.39 mmol) was added, and stirring was continued at 100 °C for 2 hours. The mixture was cooled to room temperature. The solvent was removed by rotary evaporation, the mixture was diluted with ethyl acetate, washed twice with a 5% sodium bicarbonate aqueous solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 92-a (85 mg, 95%). LC-MS (ESI): m / z 578.5 (M+H) + .

[0684] Synthesis of Compound 92

[0685] Compound 92-a (85 mg, 0.15 mmol) and dichloromethane (1.5 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed by rotary evaporation, and the methyl tert-butyl ether was slurried twice. The residue was evaporated to dryness. Compound 92-b (55 mg, 0.31 mmol) and 1,2-dichloroethane (4 mL) were added to the crude product. After stirring at room temperature for 5 minutes, sodium borohydride acetate (128 mg, 0.61 mmol) was added under an ice-water bath. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and saturated sodium bicarbonate aqueous solution, a small amount of sodium carbonate solid, and ethyl acetate were added. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine. The solution was evaporated to dryness and purified by preparative HPLC to give compound 92 (23.1 mg, 25%). LC-MS (ESI): m / z 640.3 (M+H) + ; 1H NMR(DMSO-d6,400MHz)δ8.88(1H,dd,J=2.0Hz,0.4Hz),8.39–8.30(2H,m),8.06– 7.99(2H,m),7.94(1H,dd,J=9.6Hz,0.4Hz),7.75(1H,s),7.68–7.59(2H,m),7.49 (1H,s),7.32(1H,d,J=2.0Hz),6.97(1H,dd,J=8.4Hz,2.0Hz),6.66(1H,s),5.08( 2H,q,J=9.2Hz),3.68(3H,s),3.67–3.57(4H,m),3.43(2H,s),2.47–2.34(4H,m).

[0686] Synthetic route of compound 93

[0687]

[0688] Synthesis of compound 93-d

[0689] Under ice-water bath conditions, potassium hydroxide (3.92 g) was slowly added dropwise to a 4 mL solution of 1,4-cyclohexanedione monoethylene glycol ketal (1.56 g, 9.99 mmol) and benzyltriethylammonium bromide (0.27 g, 1.00 mmol) in tribromomethane.

[0690] A 4 mL solution of water containing 69.92 mmol was prepared, and the reaction mixture was reacted at this temperature for 4 hours. Water and dichloromethane were added to the reaction mixture, the dichloromethane phase was separated, and the aqueous phase was washed once more with dichloromethane. Concentrated hydrochloric acid (2 mL) was slowly added to the aqueous phase to adjust the pH to 3, and then the mixture was extracted with dichloromethane (30 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 93-d (800 mg, 43%). LC-MS (ESI): m / z 183.0 (MH) - .

[0691] Synthesis of compound 93-c

[0692] Compound 66-e (200 mg, 0.67 mmol), diphenylphosphonohydroxylamine (267 mg, 1.14 mmol), and anhydrous 1,4-dioxane (5 mL) were added to a reaction flask. The reaction mixture was heated to 60 °C and stirred for 3 hours. After cooling to room temperature, the solvent was removed by evaporation to give compound 93-c (355 mg, 99% yield).

[0693] Synthesis of compound 93-b

[0694] Compound 93-d (230 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and dichloromethane (5 mL) were added to a reaction flask. EDCI (143 mg, 0.75 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. 93-c (270 mg, 0.50 mmol) and DIPEA (740 mg, 5.72 mmol) were added under an ice-water bath. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the mixture was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was added to anhydrous ethanol (10 mL) and potassium carbonate (274 mg, 1.98 mmol). The reaction mixture was heated to 70 °C and stirred overnight. The solvent was evaporated, and the mixture was washed twice with water to give compound 93-b (230 mg, 98% yield). LC-MS (ESI): m / z 475.7 (M+H) + .

[0695] Synthesis of compound 93-a

[0696] Compound 93-b (230 mg, 0.48 mmol), tetrahydrofuran (4 mL), and anhydrous methanol (2 mL) were added to a reaction flask. A solution of lithium hydroxide monohydrate (72 mg, 1.72 mmol) in water (2 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and water and citric acid solid (300 mg) were added. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 93-a (190 mg, 88% yield). LC-MS (ESI): m / z 447.0 (M+H) + .

[0697] Synthesis of Compound 93

[0698] Compounds 93-a (190 mg, 0.43 mmol) and 1-c (163 mg, 0.47 mmol) were added to a reaction flask. DMF (3 mL) and DIPEA (220 mg, 1.70 mmol) were added in an ice bath. After stirring in an ice bath for 5 minutes, HATU (194 mg, 0.51 mmol) was added. The reaction mixture was stirred in an ice-water bath for 2 hours. Ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude compound (280 mg, 94% yield). 40 mg of this crude compound was purified by preparative HPLC to obtain compound 93 (11.0 mg, 25% yield). LC-MS (ESI): m / z 703.3 (M+H) + ; 1H NMR(DMSO-d6,400MHz)δ8.75(1H,d,J=2.4Hz),7.78(1H,d,J=9.6Hz),7.62(1H,d,J=8.8Hz) ,7.50(1H,dd,J=9.6Hz,2.0Hz),7.31–7.24(3H,m),7.05–6.98(2H,m),6.93(1H,dd,J=8.4, 2.0Hz),6.82–6.75(1H,m),6.65(1H,s),4.74(2H,q,J=8.8Hz),3.93(4H,s),3.67(3H,s),3 .66–3.58(4H,m),3.47(2H,s),2.74–2.64(2H,m),2.45–2.37(6H,m),1.83(2H,t,J=6.8Hz).

[0699] Synthesis of Compound 94

[0700]

[0701] Following the synthetic method of compound 93, compound 94 was synthesized by using compound 93-c as the starting reactant and replacing compound 93-d with piperic acid. LC-MS (ESI): m / z 685.2 (M+H)+; 1 H NMR(DMSO-d6,400MHz)δ8.81(1H,dd,J=2.0,0.4Hz),7.85(1H,dd,J=9.6,0.8Hz),7.74(1H,dd,J=8.0 ,1.6Hz),7.64(1H,d,J=8.8Hz),7.61(1H,d,J=1.6Hz),7.55(1H,dd,J=9.6Hz,2.4Hz),7.34–7.24(3H ,m),7.07(1H,d,J=8.0Hz),7.04–6.99(2H,m),6.96(1H,dd,J=8.4Hz,2.0Hz),6.66(1H,d,J=0.8Hz), 6.12(2H,s),4.74(2H,q,J=8.8Hz),3.68(3H,s),3.66–3.58(4H,m),3.47(2H,s),2.46–2.36(4H,m).

[0702] Synthetic route of compound 95

[0703]

[0704] Synthesis of compound 95-a

[0705] Add methyl 3-iodobenzoate (525 mg, 2.00 mmol) and nickel iodide (48 mg, 2.00 mmol) to a microwave tube.

[0706] 0.15 mmol), 4,4-di-tert-butylbipyridine (40 mg, 0.15 mmol), 1,1'-bis(diisopropylphosphine)ferrocene (60 mg, 0.14 mmol), and manganese powder (360 mg, 6.55 mmol). The mixture was sealed, evacuated, and DMAc (8 mL) was added. After purging twice with nitrogen, 1,1,1-trifluoro-2-iodoethane (0.59 mL, 6.04 mmol) was added. The reaction mixture was heated to 80 °C and stirred overnight. The reaction solution was cooled to room temperature. Ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Tetrahydrofuran (5 mL) and anhydrous methanol (5 mL) were added to the crude product. A solution of lithium hydroxide monohydrate (84 mg, 2.00 mmol) in water (5 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation, and ice water and 900 mg of solid sodium bisulfate were added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 95-a (190 mg, 46%). LC-MS (ESI): m / z 202.9 (MH) - .

[0707] Synthesis of Compound 95

[0708] Following the synthetic method for compound 53, compound 53-b was used as the starting reactant, and compound 95-a was used to replace cyclopropionic acid to synthesize compound 95. LC-MS (ESI): m / z 723.3 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ8.88(1H,dd,J=2.0Hz,0.4Hz),8.21(1H,s),8.20–8.12(1H,m),7.90(1H,d d,J=9.6Hz,0.4Hz),7.64(1H,d,J=8.4Hz),7.61–7.53(2H,m),7.53–7.46(1H,m),7.31(1H,d,J=2.0 Hz),7.32–7.24(2H,m),7.08–6.98(2H,m),6.97(1H,dd,J=8.8Hz,2.0Hz),6.67(1H,s),4.74(2H,q, J=8.8Hz),3.80(2H,q,J=11.6Hz),3.68(3H,s),3.67–3.57(4H,m),3.48(2H,s),2.47–2.35(4H,m).

[0709] Synthetic route of compound 96

[0710]

[0711] Synthesis of compound 96-a

[0712] In a reaction flask, methyl 3-hydroxybenzoate (761 mg, 5.00 mmol), anhydrous potassium carbonate (2080 mg, 15.05 mmol), DMF (10 mL), and 1,1,1-trifluoro-2-iodoethane (1 mL, 10.24 mmol) were added. The reaction mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Tetrahydrofuran (8 mL) and anhydrous methanol (8 mL) were added to the crude product. Lithium hydroxide monohydrate (500 mg, 10 mL) was added dropwise under an ice-water bath.

[0713] A solution of 11.92 mmol / L sodium bisulfate (8 mL) was added to an aqueous solution. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation, and ice water and 900 mg of sodium bisulfate solid were added. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 96-a (800 mg, 73%). LC-MS (ESI): m / z 218.9 (MH) - .

[0714] Synthesis of Compound 96

[0715] Following the synthetic method for compound 53, compound 53-b was used as the starting reactant, and compound 96-a was used to replace cyclopropionic acid to synthesize compound 96. LC-MS (ESI): m / z 739.3 (M+H) + ; 1H NMR(DMSO-d6,400MHz)δ8.84(1H,dd,J=2.4Hz,0.8Hz),7.90(1H,dd,J=10.0Hz,0.8Hz),7.87(1H,dt,J=8.0Hz,0.8Hz),7 .82–7.76(1H,m),7.64(1H,d,J=8.4Hz),7.59(1H,dd,J=9.6Hz,2.4Hz),7.51(1H,t,J=8.0Hz),7.32(1H,d,J=2.4Hz),7. 30–7.25(2H,m),7.21(1H,ddd,J=8.4Hz,2.8Hz,0.8Hz),7.05–7.00(2H,m),6.97(1H,dd,J=8.4Hz,2.0Hz),6.67(1H,d,J =0.4Hz),4.89(2H,q,J=8.8Hz),4.74(2H,q,J=8.8Hz),3.69(3H,s),3.67–3.58(4H,m),3.47(2H,s),2.48–2.35(4H,m).

[0716] Synthetic route of compound 97

[0717]

[0718] Synthesis of compound 97-a

[0719] Compound 93 (240 mg, 0.34 mmol) and tetrahydrofuran (6 mL) were added to a reaction flask. Hydrochloric acid (1.5 mL, 3 M) aqueous solution was added dropwise under nitrogen protection in an ice-water bath. The reaction mixture was stirred at room temperature for 6 hours. Ethyl acetate, water, and sodium carbonate solid (260 mg) were added, and the mixture was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 97-a (190 mg, 84%). LC-MS (ESI): m / z 659.4 (M+H) + .

[0720] Synthesis of Compound 97

[0721] Compound 97-a (82 mg, 0.12 mmol), anhydrous ethanol (3 mL), and methoxyamine hydrochloride (21 mg, 0.25 mmol) were added to a reaction flask. The reaction mixture was sonicated for 1 minute and then stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation, and the mixture was washed twice with saturated sodium bicarbonate solution and once with water. The residual solid was purified by preparative HPLC to give compound 97 (20.2 mg, 24%). LC-MS (ESI): m / z 688.3 (M+H) + ; 1H NMR (DMSO-d6, 400MHz) δ8.77 (1H, dd, J = 2.4Hz, 0.4Hz), 7.79 (1H, dt, J = 9.6Hz, 1.0Hz), 7.62 (1H, d, J = 8 .8Hz),7.52(1H,dd,J=9.6Hz,2.4Hz),7.30–7.25(3H,m),7.07–6.99(2H,m),6.93(1H,dd,J=8.4Hz,2.0 Hz),6.88–6.84(1H,m),6.65(1H,d,J=0.4Hz),4.74(2H,q,J=8.8Hz),3.78(3H,s),3.67(3H,s),3.66– 3.59(4H,m),3.47(2H,s),3.26–3.03(2H,m),2.80–2.66(3H,m),2.51–2.44(1H,m),2.45–2.36(4H,m).

[0722] Synthetic routes of compounds 98 and 79

[0723]

[0724] Synthesis of compound 98-b

[0725] In a reaction flask, 4-cyano-3-fluorobenzoic acid (48 mg, 0.29 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), and dichloromethane (10 mL) were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) was added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. Compound 53-b (100 mg, 0.15 mmol) and N,N-diisopropylethylamine (94 mg, 0.73 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with dichloromethane (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in anhydrous ethanol (10 mL), and potassium carbonate (202 mg, 1.46 mmol) was added. The mixture was heated to 100°C and reacted overnight at this temperature. LC-MS monitoring showed that the intermediate state was almost cyclized. The reaction solution was evaporated to dryness, saturated brine was added, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-100%) to give compound 98-b (82 mg, 94%). The mixture contained two compounds. LC-MS (ESI): m / z 596.2 (M+H). + , 622.3(M+H) + .

[0726] Synthesis of compound 98-a

[0727] Trifluoroacetic acid (1 mL) was added to an 8 mL solution of compound 98-b (82 mg, 0.14 mmol) in dichloromethane at room temperature, and the mixture was reacted overnight at this temperature. The reaction mixture was evaporated to dryness to give compound 98-a (68 mg, 100%), which was used directly in the next reaction without purification. LC-MS (ESI): m / z 496.2 (M+H) + , 522.2(M+H) + .

[0728] Synthesis of compounds 98 and 79

[0729] To a tetrahydrofuran (8 mL) solution of compound 98-a (68 mg, 0.14 mmol), 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (55 mg, 0.21 mmol) and triethylamine (69 mg, 0.69 mmol) were added, and the mixture was reacted overnight at this temperature. The reaction solution was evaporated to dryness, and the crude product was purified by preparative HPLC to give compound 98 (13.1 mg, 14%) and compound 79 (16.9 mg, 17%). Compound 98: LC-MS (ESI): m / z 684.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.90(1H,d,J=2.0Hz),8.20–8.09(3H,m),7.97(1H,d,J=9.6Hz ),7.66(1H,s),7.64(1H,d,J=2.4Hz),7.33(1H,d,J=1.6Hz),7.28(2H,d,J=8.4Hz),7.0 2 (2H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 8.8 Hz, 2.4 Hz), 6.68 (1H, s), 4.74 (2H, q, J = 8.8 Hz), 3.69 (3H, s), 3.67–3.61 (4H, m), 3.48 (2H, s), 2.44–2.38 (4H, m). Compound 79: LC-MS (ESI): m / z 710.2 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ8.90(1H,d,J=2.0Hz),7.95(1H,d,J=9.6Hz),7.92–7.85(3H,m) ,7.66–7.62(2H,m),7.33(1H,d,J=1.6Hz),7.28(2H,d,J=8.4Hz),7.02(2H,d,J=8.4Hz), 6.98(1H,dd,J=8.8Hz,2.4Hz),6.68(1H,s),4.74(2H,q,J=8.8Hz),4.33(2H,q,J=6.8Hz) ,3.69(3H,s),3.67–3.61(4H,m),3.48(2H,s),2.44–2.38(4H,m),1.43(3H,t,J=6.8Hz).

[0730] Synthetic route of compound 99

[0731]

[0732] Synthesis of compound 99-b

[0733] Add 2-amino-5-bromopyridine (1.05 g, 6.07 mmol) and pyridine (6 mL) to a reaction flask. Add 4-trifluoromethylbenzoyl chloride (1.8 g, 8.63 mmol) under an ice-water bath. Stir the reaction mixture under an ice-water bath for 1 hour. Add saturated ammonium chloride aqueous solution; a solid precipitates out. Discard the supernatant. Repeat once. Dissolve the residue in dichloromethane, wash with saturated ammonium chloride aqueous solution, wash with saturated sodium bicarbonate aqueous solution, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and add 1,4-dioxane (15 mL) and diphenylphosphonic hydroxylamine (2.05 g, 8.79 mmol) to the crude product. Heat the reaction mixture to 60 °C and stir overnight. Add diphenylphosphonic hydroxylamine (0.70 g, 3.00 mmol). Heat the reaction mixture to 60 °C and stir overnight. Add diphenylphosphonic hydroxylamine (0.45 g, 1.93 mmol). Heat the reaction mixture from 60 °C to 100 °C and stir for 3 hours. Cool to room temperature. Remove the solvent by rotary evaporation, add dichloromethane and a saturated aqueous solution of sodium bicarbonate, separate the layers, wash the organic phase twice with the saturated aqueous solution of sodium bicarbonate, and evaporate to dryness to give compound 99-b (2.0 g, 96% yield). LC-MS (ESI): m / z 341.9 (M+H) + .

[0734] Synthesis of compound 99-a

[0735] Compound 99-b (380 mg, 1.11 mmol), benzophenone imine (310 mg, 1.71 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), sodium tert-butoxide (180 mg, 1.87 mmol), and BINAP (20 mg, 0.032 mmol) were added to a microwave-safe tube. The tube was sealed, evacuated, and anhydrous toluene (5 mL) was added. After purging with nitrogen three times, the reaction mixture was heated to 75 °C and stirred overnight. The reaction mixture was cooled to room temperature. Ethyl acetate was added, the tube was washed with water, the organic phase was evaporated to dryness, and the crude product was added to anhydrous methanol (10 mL) and hydroxylamine hydrochloride (210 mg, 3.02 mmol) in an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 97 / 3) to give compound 99-a (205 mg, 66% yield). LC-MS(ESI): m / z 279.0(M+H) + .

[0736] Synthesis of Compound 99

[0737] Compound 87-a (61 mg, 0.12 mmol) and compound 99-a (50 mg, 0.12 mmol) were added to a microwave tube.

[0738] 0.18 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), sodium tert-butoxide (28 mg, 0.29 mmol), and BINAP (12 mg, 0.019 mmol). The mixture was sealed, evacuated, and 5 mL of anhydrous toluene was added. After purging with nitrogen three times, the reaction mixture was heated to 85 °C and stirred overnight. The reaction mixture was cooled to room temperature. Ethyl acetate was added, the mixture was washed with water, the organic phase was evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 98 / 2) to give compound 99 (40 mg, 47% yield). 20 mg was then purified by preparative HPLC to give compound 99 (6.5 mg, 15% yield). LC-MS (ESI): m / z 708.3 (M+H) + ; 1H NMR(DMSO-d6,400MHz)δ8.61(1H,d,J=1.6Hz),8.46(1H,s),8.36(2H,d,J=8.0Hz),7.95–7 .86(2H,m),7.82(1H,d,J=9.6Hz),7.60(1H,dd,J=9.6Hz,2.0Hz),7.54(1H,d,J=8.4Hz),7. 33–7.25(2H,m),7.24(1H,s),7.07–6.99(2H,m),6.96(1H,dd,J=8.4Hz,2.0Hz),6.60(1H, s),4.74(2H,q,J=8.8Hz),3.71(3H,s),3.69–3.61(4H,m),3.48(2H,s),2.44–2.38(4H,m).

[0739] Synthetic route of compound 100

[0740]

[0741] Synthesis of compound 100-c

[0742] 6-Bromo-1-methyl-2-indolecarboxylic acid (1 g, 3.94 mmol) and N-Boc-piperazine (0.88 g, 4.72 mmol) were added to a reaction flask. DMF (10 mL) and DIPEA (1.27 g, 9.84 mmol) were added under ice-water bath conditions. After stirring for 5 minutes under ice-water bath conditions, HATU (1.80 g, 4.72 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to cold water, filtered, the filter cake was washed three times with water, and dried overnight to give compound 100-c (1.55 g, 93% yield). LC-MS (ESI): m / z 422.0 (M+H) + .

[0743] Synthesis of compound 100-b

[0744] Compound 100-c (100 mg, 0.24 mmol) and compound 99-a (82 mg, 0.24 mmol) were added to a microwave tube.

[0745] 0.30 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), sodium tert-butoxide (56 mg, 0.58 mmol), and BINAP (20 mg, 0.032 mmol). The mixture was sealed, evacuated, and 5 mL of anhydrous toluene was added. After purging with nitrogen three times, the reaction mixture was heated to 85 °C and stirred overnight. The reaction mixture was cooled to room temperature. Ethyl acetate was added, followed by washing with saturated ammonium chloride, water, and saturated brine. The organic suspension was evaporated to dryness to give crude compound 100-b (145 mg, 99% yield). LC-MS (ESI): m / z 620.3 (M+H) + .

[0746] Synthesis of compound 100-a

[0747] Compound 100-b (155 mg, 0.25 mmol) and anhydrous DMF (6 mL) were added to a reaction flask. Potassium tert-butoxide (84 mg, 0.75 mmol) was added in an ice bath. The reaction mixture was stirred in an ice-water bath for 10 minutes. Iodimethane (0.060 mL, 0.74 mmol) was added. The reaction mixture was stirred in an ice-water bath for 1.5 hours. A small amount of concentrated ammonia was added, and the mixture was stirred for 5 minutes. Ice water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 100-a (150 mg, 95% yield). LC-MS (ESI): m / z 634.3 (M+H) + .

[0748] Synthesis of Compound 100

[0749] Compound 100-a (150 mg, 0.24 mmol) and dichloromethane (2.5 mL) were added to a reaction flask. Trifluoroacetic acid (0.8 mL) was added dropwise in an ice bath. The reaction mixture was stirred in an ice-water bath for 1.5 hours. The solvent was removed by evaporation at room temperature. Ice water, ethyl acetate, and sodium bicarbonate solid were added, and the mixture was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Anhydrous tetrahydrofuran (3 mL) and triethylamine (0.2 mL, 1.44 mmol) were added at room temperature. After stirring the reaction mixture in an ice-water bath for 5 minutes, 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (128 mg, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Add 2 drops of concentrated ammonia, stir for 3 minutes, evaporate the solvent, wash the residue twice with pure water to obtain the crude product, and purify by preparative HPLC (ammonium bicarbonate) to give compound 100 (53.0 mg, yield 31%). LC-MS (ESI): m / z 722.3 (M+H) + ; 1H NMR(CDCl3,400MHz)δ8.41–8.33(2H,m),8.14(1H,d,J=2.0Hz),7.77–7.70(2H,m) ,7.60(1H,d,J=8.4Hz),7.52(1H,d,J=9.6Hz),7.31–7.21(3H,m),7.13–7.08(1H, m),6.96(1H,dd,J=8.4Hz,2.0Hz),6.95–6.88(2H,m),6.58(1H,d,J=0.4Hz),4.35 (2H,q,J=8.0Hz),3.86–3.74(7H,m),3.52(2H,s),3.40(3H,s),2.56–2.39(4H,m).

[0750] Synthetic route of compound 101

[0751]

[0752] Synthesis of compound 101-b

[0753] Compound 100-c (300 mg, 0.88 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), Xantphos (20 mg, 0.035 mmol), 1,4-dioxane (6 mL), DIPEA (220 mg, 1.70 mmol), and methyl 3-mercaptopropionate (68 mg, 0.57 mmol) were added to a reaction flask. After purging twice with nitrogen, the reaction mixture was heated to 90 °C and stirred overnight. The reaction mixture was then cooled to room temperature. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 97 / 3) to give compound 101-b (215 mg, 98% yield). LC-MS (ESI): m / z 462.2 (M+H) + .

[0754] Synthesis of compound 101-a

[0755] Compound 99-b (110 mg, 0.32 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (18 mg, 0.031 mmol), compound 101-b (215 mg, 0.47 mmol), and potassium tert-butoxide (73 mg, 0.65 mmol) were added to a microwave-safe tube. The tube was sealed, evacuated, and 10 mL of anhydrous toluene was added. After purging with nitrogen three times, the reaction mixture was stirred at room temperature for 30 minutes, then heated to 110 °C and stirred for 4.5 hours. The mixture was cooled to room temperature. It was diluted with ethyl acetate, washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 40 / 60) to give compound 101-a (200 mg, 98% yield). LC-MS (ESI): m / z 637.2 (M+H) + .

[0756] Synthesis of Compound 101

[0757] Compound 101-a (150 mg, 0.24 mmol) and dichloromethane (2.5 mL) were added to a reaction flask. Trifluoroacetic acid (0.8 mL) was added dropwise in an ice bath. The reaction mixture was stirred in an ice-water bath for 1.5 hours. The solvent was removed by evaporation at room temperature. Ethyl acetate and sodium bicarbonate aqueous solution were added, and the mixture was separated. A large amount of solid precipitated during washing with saturated brine. The solvent was removed by evaporation, and a small amount of saturated sodium bicarbonate aqueous solution was added. The mixture was extracted twice with tetrahydrofuran. The organic phases were combined, evaporated to dryness, and lyophilized for 10 minutes. Anhydrous tetrahydrofuran (5 mL) was added at room temperature. After stirring the reaction mixture in an ice-water bath for 5 minutes, 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (124 mg, 0.46 mmol) and triethylamine (0.3 mL, 2.16 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (18 mg, 0.067 mmol) was added as a supplement. The reaction mixture was stirred at room temperature for 0.5 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 3 minutes. The solvent was evaporated, and the residue was washed twice with pure water to obtain crude product 101 (200 mg, yield 88%). 100 mg of the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 101 (33.2 mg, yield 29%). 100 mg of the crude product was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 0 / 100) to obtain compound 101 (55 mg, yield 48%). LC-MS (ESI): m / z

[0758] 725.3(M+H) + ; 1H NMR(CDCl3,400MHz)δ8.39(1H,dd,J=1.6Hz,0.8Hz),8.37–8.30(2H,m),7.73(2H,d,J=8.0Hz), 7.66(1H,dd,J=9.2Hz,0.8Hz),7.62(1H,d,J=8.0Hz),7.58–7.54(1H,m),7.47(1H,dd,J=9.6Hz ,2.0Hz),7.30–7.27(2H,m),7.24(1H,dd,J=8.4Hz,1.6Hz),6.94–6.86(2H,m),6.59(1H,d,J=0 .9Hz),4.35(2H,q,J=8.0Hz),3.82(3H,s),3.81–3.62(4H,m),3.52(2H,s),2.62–2.36(4H,m).

[0759] Synthetic routes of compounds 102 and 103

[0760]

[0761] Synthesis of compounds 102 and 103

[0762] Compound 101 (60 mg, 0.083 mmol) and acetone (3 mL) were added to a reaction flask. A solution of Oxone (100 mg, 0.163 mmol) in water (1.5 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by adding sodium bisulfite solid. The mixture was extracted with ethyl acetate, washed with saturated brine, evaporated to dryness, and the crude product was purified by preparative HPLC to give compound 102 (15.2 mg, 25% yield) and compound 103 (14.2 mg, 23% yield).

[0763] Compound 102: LC-MS (ESI): m / z 741.2 (M+H) + ; 1H NMR(CDCl3,400MHz)δ9.05(1H,dd,J=1.6,0.8Hz),8.44–8.35(2H,m),7.95–7.89(1H ,m),7.79–7.72(3H,m),7.70(1H,dd,J=8.4,0.4Hz),7.51(1H,dd,J=9.2Hz,1.6Hz), 7.29–7.27(2H,m),7.26–7.25(1H,m),6.94–6.86(2H,m),6.61(1H,d,J=0.8Hz),4.3 4(2H,q,J=8.0Hz),3.90(3H,s),3.86–3.61(4H,m),3.51(2H,s),2.62–2.33(4H,m).

[0764] Compound 103: LC-MS (ESI): m / z 757.2 (M+H) + ; 1 H NMR(CDCl3,400MHz)δ9.33(1H,dd,J=2.0,0.8Hz),8.39(2H,d,J=8.0Hz),8.17–8 .09(1H,m),7.89(1H,dd,J=9.6Hz,1.6Hz),7.82–7.72(4H,m),7.67(1H,dd,J=8. 4Hz,1.6Hz),7.30–7.23(2H,m),6.95–6.86(2H,m),6.62(1H,d,J=0.8Hz),4.34( 2H,q,J=8.0Hz),3.92(3H,s),3.89–3.56(4H,m),3.50(2H,s),2.62–2.32(4H,m).

[0765] Synthetic route of compound 104

[0766]

[0767] Synthesis of compound 104-d

[0768] 2-(trifluoromethyl)benzoyl chloride (542 mg, 2.60 mmol) was slowly added dropwise to a pyridine (3 mL) solution of 2-amino-4-bromopyridine (300 mg, 1.73 mmol) in an ice-water bath. The temperature was slowly raised to room temperature, and the reaction was allowed to proceed overnight at room temperature. The solution was evaporated to dryness, and the mixture was extracted with 30 mL of saturated ammonium chloride solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 104-d (598 mg, 100%). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z 344.7 (M+H) +.

[0769] Synthesis of compound 104-c

[0770] Diphenylphosphonohydroxylamine (404 mg, 1.73 mmol) was added to a 20 mL solution of compound 104-d (598 mg, 1.73 mmol). The reaction mixture was heated to 100 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and diphenylphosphonohydroxylamine (404 mg, 1.73 mmol) was added. The mixture was stirred overnight at 100 °C. LCMS showed a significant amount of starting material remaining. The reaction mixture was cooled to room temperature, and diphenylphosphonohydroxylamine (404 mg, 1.73 mmol) was added. The mixture was stirred overnight at 100 °C. LCMS showed an increase in product. The reaction mixture was cooled to room temperature, and diphenylphosphonohydroxylamine (404 mg, 1.73 mmol) was added. The mixture was stirred overnight at 100 °C. The extract was evaporated to dryness, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid separation column chromatography (mobile phase: EA / PE: 0% to 30%) to give compound 104-c (264 mg, 45%). LC-MS (ESI): m / z 341.9 (M+H) + .

[0771] Synthesis of compound 104-b

[0772] Compound 25-c (50 mg, 0.14 mmol), compound 104-c (71 mg, 0.21 mmol), tris(dibenzylacetone)dipalladium (13 mg, 0.014 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.028 mmol), potassium phosphate (89 mg, 0.42 mmol), and toluene (3 mL) were added to a 10 mL microwave-safe tube. The tube was sealed, purged with nitrogen several times, heated to 110 °C, and stirred overnight. The solution was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column flash chromatography (mobile phase: EA / PE, 0-50%) to give compound 104-b (41 mg, 47%). LC-MS (ESI): m / z 621.2 (M+H) + .

[0773] Synthesis of compound 104-a

[0774] Trifluoroacetic acid (0.5 mL) was added to a solution of compound 104-b (41 mg, 0.066 mmol) in dichloromethane (3 mL) at room temperature, and the mixture was reacted overnight at this temperature. The solution was then evaporated to dryness to give compound 104-a (34 mg, 99%). LC-MS (ESI): m / z 521.2 (M+H) + .

[0775] Synthesis of Compound 104

[0776] To a tetrahydrofuran (6 mL) solution of compound 104-a (34 mg, 0.065 mmol), 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (35 mg, 0.13 mmol) and triethylamine (33 mg, 0.33 mmol) were added, and the mixture was reacted overnight at this temperature. The reaction solution was evaporated to dryness, and the crude product was purified by preparative HPLC to give compound 104 (35.5 mg, 77%). LC-MS (ESI): m / z 709.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.97(1H,d,J=7.6Hz),7.91(1H,d,J=7.6Hz),7.87(1H,d,J= 7.2Hz),7.81(1H,t,J=7.2Hz),7.77–7.70(2H,m),7.49(1H,d,J=1.6Hz),7.28(2H,d, J=8.8Hz),7.08(1H,dd,J=7.6,2.8Hz),7.04–6.99(3H,m),6.96(1H,d,J=2.8Hz),6. 72(1H,s),4.72(2H,q,J=8.8Hz),3.73(3H,s),3.70–3.58(6H,m),2.45–2.38(4H,m).

[0777] Synthesis of Compound 105

[0778]

[0779] Following the synthetic method for compound 104, compound 105 was synthesized using 2-amino-4-bromopyridine as the starting reactant and replacing 2-(trifluoromethyl)benzoyl chloride with 3-(trifluoromethyl)benzoyl chloride. LC-MS (ESI): m / z 709.2 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ9.00(1H,d,J=7.2Hz),8.43(1H,d,J=7.2Hz),8.40(1H,s),7.9 0(1H,d,J=8.0Hz),7.80(1H,t,J=8.0Hz),7.73(1H,d,J=8.4Hz),7.50(1H,d,J=1.6Hz) ,7.29(2H,d,J=8.4Hz),7.08(1H,dd,J=7.2,2.4Hz),7.06–6.99(4H,m),6.73(1H,s),4 .74(2H,q,J=8.8Hz),3.74(3H,s),3.71–3.61(4H,m),3.49(2H,s),2.46–2.38(4H,m).

[0780] Synthetic route of compound 106

[0781]

[0782] Synthesis of compound 106-b

[0783] Add 500 mg (2.12 mmol) of 5-hydroxyisoindoline-2-carboxylic acid tert-butyl ester and 6 mL of dichloromethane to a reaction flask. Add 2 mL of trifluoroacetic acid dropwise under an ice-water bath. Stir the reaction mixture under an ice-water bath for 1.5 hours. Remove the solvent by evaporation at room temperature. Pulverize twice with methyl tert-butyl ether and petroleum ether, and evaporate to dryness to give compound 106-b (520 mg, 98% yield). LC-MS (ESI): m / z 136.0 (M+H) + .

[0784] Synthesis of compound 106-a

[0785] In a microwave-safe tube, 4-iodotrifluorotoluene (360 mg, 1.32 mmol), compound 106-b (220 mg, 0.88 mmol), palladium acetate (20 mg, 0.089 mmol), RuPhos (82 mg, 0.18 mmol), cesium carbonate (950 mg, 2.92 mmol), and anhydrous dioxane (11 mL) were added. The tube was sealed and purged with nitrogen three times. The reaction mixture was heated to 80 °C and stirred overnight. It was then cooled to room temperature. Most of the solvent was evaporated. A saturated aqueous solution of ammonium chloride, ethyl acetate, and a small amount of sodium bisulfate solid were added. The mixture was separated, the organic phase was evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 75 / 25) to give compound 106-a (140 mg, 57% yield). LC-MS (ESI): m / z 280.0 (M+H) + .

[0786] Synthesis of Compound 106

[0787] Compound 87-a (45 mg, 0.088 mmol) and compound 106-a (32 mg, 0.088 mmol) were added to a microwave tube.

[0788] 0.12 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), tBuXPhos (10 mg, 0.024 mmol), and potassium phosphate (80 mg, 0.35 mmol). The mixture was sealed, evacuated, and 5 mL of anhydrous toluene was added. Nitrogen was purged three times. The reaction mixture was heated to 110 °C and stirred overnight. It was cooled to room temperature. Ethyl acetate was added, followed by washing with water, then saturated brine, drying over anhydrous sodium sulfate, filtering, evaporating to dryness, and HPLC purification to give compound 106 (8.9 mg, 14% yield). LC-MS (ESI): m / z 709.2 (M+H) + ; 1 H NMR(CDCl3,400MHz)δ7.57(1H,d,J=8.4Hz),7.55–7.48(2H,m),7.32–7.25(3H,m),7.02–6.96(3H,m),6.94–6.88(3H,m),6.69–6.62(2 H,m),6.58(1H,d,J=0.8Hz),4.70–4.60(4H,m),4.35(2H,q,J=8.4Hz),3.85–3.77(4H,m),3.76(3H,s),3.51(2H,s),2.58–2.40(4H,m).

[0789] Synthetic route of compound 107

[0790]

[0791] Synthesis of compound 107-f

[0792] 3-Fluoro-4-nitrophenol (800 mg, 5.09 mmol) and potassium carbonate (1.76 g, 12.74 mmol) were added to a reaction flask. Anhydrous DMF (10 mL) was added under an ice-water bath. SEMCl (1.10 g, 6.60 mmol) was added dropwise under an ice-water bath. The reaction mixture was stirred under an ice-water bath for 2 hours. The mixture was extracted with ice water, ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was added to a reaction flask, along with anhydrous DMF (10 mL), potassium carbonate (2.80 g, 20.26 mmol), and methylamine hydrochloride (1.03 mg, 15.26 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with ice water, ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 107-f (900 mg, 59% yield). LC-MS(ESI): m / z 299.0(M+H) + .

[0793] Synthesis of compound 107-e

[0794] Compound 107-f (900 mg, 3.02 mmol), tetrahydrofuran (15 mL), methanol (10 mL), palladium on carbon (10% Pd), water containing 40-60% (200 mg), and ammonium formate (800 mg, 12.69 mmol) were added to a reaction flask. The reaction mixture was heated to 50 °C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered and evaporated to dryness to give crude compound 107-e (800 mg, 99% yield). LC-MS (ESI): m / z 269.0 (M+H) + .

[0795] Synthesis of compound 107-d1

[0796] Compound 107-e (800 mg, 2.98 mmol) and acetic acid (10 mL) were added to a reaction flask with stirring in an ice-water bath. Methyl 2,2,2-trichloroacetyliminolate (1.05 g, 5.96 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate and a small amount of petroleum ether were added to dilute the reaction mixture. The mixture was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residual acetic acid was removed by nitrogen purging. Ethyl acetate (20 mL) was added, followed by N-Boc-piperazine (1.11 g, 5.96 mmol) in an ice-water bath, and then DIPEA (1.40 g, 10.83 mmol) was added dropwise in an ice-water bath. The reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation, and acetonitrile (20 mL), water (10 mL), and sodium bicarbonate (250 mg, 2.98 mmol) were added. The reaction mixture was heated to 50 °C and stirred overnight. Cool to room temperature, remove organic solvent by vortexing, add water, extract twice with ethyl acetate, dry to anhydrous sodium sulfate, filter, evaporate to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 0 / 100) to give compound 107-d1 (750 mg, yield 51%), LC-MS (ESI): m / z 491.4 (M+H). + Compound 107-d2 (300 mg, yield 36%), LC-MS (ESI): m / z 279.1 (M+H) + .

[0797] Synthesis of compound 107-c

[0798] Compound 107-d1 (370 mg, 0.75 mmol) and dichloromethane (4 mL) were added to a reaction flask. Trifluoroacetic acid (1.3 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was dried under nitrogen, and sodium carbonate (500 mg, 4.72 mmol), water (6 mL), tetrahydrofuran (6 mL), and di-tert-butyl dicarbonate (340 mg, 1.56 mmol) were added. The reaction mixture was stirred at room temperature overnight. Most of the organic solvent was evaporated, ethyl acetate and citric acid solid were added, the mixture was separated, the organic phase was evaporated to dryness, and methanol (6 mL), water (6 mL), and lithium hydroxide monohydrate (220 mg, 5.24 mmol) were added. The reaction mixture was stirred at room temperature overnight. Methanol (6 mL) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation, water and citric acid were added, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 96 / 4) to give compound 107-c (180 mg, yield 66%). LC-MS (ESI): m / z 361.1 (M+H) + .

[0799] Synthesis of compound 107-b

[0800] Compound 107-c (120 mg, 0.33 mmol), 5-fluoro-2-nitropyridine (57 mg, 0.40 mmol), potassium carbonate (138 mg, 1.00 mmol), and anhydrous DMSO (2.5 mL) were added to a reaction flask. The reaction mixture was heated to 60 °C and stirred for 3 hours. It was then cooled to room temperature. Ice water was added, followed by extraction with ethyl acetate, washing with water, and evaporation to obtain the crude product. Ammonium formate (80 mg, 1.27 mmol), anhydrous methanol (2.5 mL), tetrahydrofuran (2.5 mL), and 10% Pd palladium on carbon containing 40-60% water (40 mg) were added to the crude product. The reaction mixture was heated to 60 °C and stirred for 1 hour. Ammonium formate (80 mg, 1.27 mmol) and 10% Pd palladium on carbon containing 40-60% water (40 mg) were added as needed. The reaction mixture was heated to 60 °C and stirred for 2 hours. It was then cooled to room temperature. The mixture was filtered, the filtrate was evaporated to dryness, acetonitrile and water were added, and the solution was lyophilized to give compound 107-b (0.15 g, 100% yield). LC-MS (ESI): m / z 453.3 (M+H) + .

[0801] Synthesis of compound 107-a

[0802] Compound 107-b (150 mg, 0.33 mmol) and pyridine (2.5 mL) were added to a reaction flask. After stirring for 5 minutes in an ice-water bath, 4-(trifluoromethyl)benzoyl chloride (138 mg, 0.66 mmol) was added. The reaction mixture was stirred in an ice-water bath for 20 minutes. The reaction mixture was added dropwise to a mixture of saturated ammonium chloride aqueous solution and ice, extracted twice with ethyl acetate, and the organic phases were combined, washed twice with citric acid aqueous solution (5%), washed with water, washed with saturated sodium bicarbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Diphenylphosphonic hydroxylamine (152 mg, 0.65 mmol) and 1,4-dioxane (5 mL) were added to the crude product. The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling to 60 °C, diphenylphosphonic hydroxylamine (152 mg, 0.65 mmol) was added, and the mixture was heated to 100 °C and stirred for another hour. The mixture was cooled to 60°C, and 152 mg (0.65 mmol) of diphenylphosphonic hydroxylamine was added. The mixture was then heated to 100°C and stirred for 1 hour. The mixture was then cooled to 60°C, and 152 mg (0.65 mmol) of diphenylphosphonic hydroxylamine was added. The mixture was then heated to 100°C and stirred for 3 hours. The mixture was cooled to room temperature. The solvent was removed by rotary evaporation, and the mixture was washed twice with ethyl acetate, followed by washing with 5% sodium bicarbonate aqueous solution, water, saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and evaporated to dryness to give compound 107-a (200 mg, 97% yield). LC-MS (ESI): m / z 622.2 (M+H) + .

[0803] Synthesis of Compound 107

[0804] Compound 107-a (200 mg, 0.32 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (0.75 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation at room temperature. Anhydrous tetrahydrofuran (4 mL), triethylamine (0.5 mL, 3.60 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (169 mg, 0.63 mmol) were added under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 3 minutes. The solvent was removed by evaporation, the residue was washed twice with water, extracted with ethyl acetate, the organic phase was washed with water, evaporated to dryness, slurried with anhydrous ethanol, filtered, and the filter cake was lyophilized to give compound 107 (91 mg, 40% yield). LC-MS (ESI): m / z 710.2 (M+H) + ; 1 H NMR (CDCl3, 400MHz) δ8.36 (2H, d, J = 8.0Hz), 8.29 (1H, dd, J = 2.0Hz, 0.4Hz), 7.82–7.72 (4H, m), 7.47 (1H, dd, J = 9.6Hz, 2.4Hz), 7.31 (2H, d, J = 8. 4Hz),7.14–7.09(2H,m),6.96–6.88(2H,m),4.35(2H,q,J=8.4Hz),4.07 –3.94(2H,m),3.93–3.82(5H,m),3.63–3.49(2H,m),2.69–2.50(4H,m).

[0805] Synthetic route of compound 108

[0806]

[0807] Synthesis of compound 108-e

[0808] 5-Fluoro-2-nitropyridine (152 mg, 1.07 mmol) and cesium carbonate (348 mg, 1.07 mmol) were added to a solution of ethyl 6-hydroxybenzofuran-2-carboxylate (200 mg, 0.97 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The mixture was heated to 60 °C and reacted for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 108-e (305 mg, 96%). LC-MS (ESI): m / z 329.0 (M+H) + .

[0809] Synthesis of compound 108-d

[0810] Palladium on carbon 10% (300 mg) was added to a 20 mL solution of compound 108-e (305 mg, 0.93 mmol) in ethyl acetate at room temperature. The mixture was purged with hydrogen several times and stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated to dryness to give compound 108-d (257 mg, 93%). LC-MS (ESI): m / z 299.0 (M+H) + .

[0811] Synthesis of compound 108-c

[0812] 4-Trifluoromethylbenzoyl chloride (94 mg, 0.45 mmol) was slowly added dropwise to a pyridine (6 mL) solution of compound 108-d (90 mg, 0.30 mmol) at room temperature, and the mixture was reacted overnight at room temperature. The solution was evaporated to dryness, extracted with 30 mL of saturated ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 108-c (140 mg, 99%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 471.1 (M+H) + .

[0813] Synthesis of compound 108-b

[0814] Diphenylphosphonyl hydroxylamine (104 mg, 0.45 mmol) was added to a 1,4-dioxane (10 mL) solution of compound 108-c (140 mg, 0.30 mmol), and the reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and diphenylphosphonyl hydroxylamine (104 mg, 0.45 mmol) was added again, followed by stirring overnight at 80 °C. LC-MS showed that the starting material was almost completely reacted. The mixture was evaporated to dryness, and extracted with ethyl acetate (40 mL) by adding saturated sodium bicarbonate solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column flash chromatography (mobile phase: EA / PE: 0% to 100%) to give compound 108-b (102 mg, 73%). LC-MS (ESI): m / z 468.1 (M+H) + .

[0815] Synthesis of compound 108-a

[0816] At room temperature, lithium hydroxide monohydrate (92 mg, 2.18 mmol) was added to a tetrahydrofuran (12 mL) and water (2 mL) solution of compound 108-b (102 mg, 0.22 mmol), and the mixture was reacted overnight at room temperature. The pH was adjusted to 5-6 with dilute hydrochloric acid, and ethyl acetate (30 mL) was added. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 108-a (94 mg, 98%). LC-MS (ESI): m / z 440.1 (M+H) + .

[0817] Synthesis of Compound 108

[0818] HATU (163 mg, 0.43 mmol) was added to a solution of compound 108-a (94 mg, 0.21 mmol) and compound 1-c (89 mg, 0.26 mmol) in dichloromethane (20 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (138 mg, 1.070 mmol). The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative HPLC to give compound 108 (86 mg, 58%). LC-MS (ESI): m / z 696.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ9.09 (1H, d, J = 1.6Hz), 8.40 (2H, d, J = 8.0Hz), 7.97 (1H, d, J = 9.6H z),7.93(2H,d,J=8.0Hz),7.76(1H,d,J=8.4Hz),7.66(1H,dd,J=9.6Hz,2.0Hz),7.46(1H ,d,J=1.6Hz),7.41(1H,s),7.27(2H,d,J=8.4Hz),7.20(1H,dd,J=8.8Hz,2.4Hz),7.01(2 H,d,J=8.4Hz),4.74(2H,q,J=8.8Hz),3.79–3.58(4H,m),3.47(2H,s),2.45–2.38(4H,m).

[0819] Synthetic route of compound 109

[0820]

[0821] Synthesis of compound 109-d

[0822] Compound 107-d2 (250 mg, 0.90 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a reaction flask. A solution of n-butyllithium in n-hexane (2.5 M, 0.72 mL, 1.80 mmol) was added dropwise while cooling at -78 °C. After stirring at -78 °C for 30 min, a solution of 1-Boc-4-[methoxy(methyl)carbamoyl]piperidine (489 mg, 1.80 mmol) in anhydrous tetrahydrofuran (2.5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 4 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to give compound 109-d (200 mg, 45% yield). LC-MS (ESI): m / z 490.3 (M+H) + .

[0823] Synthesis of compound 109-c

[0824] Compound 109-d (200 mg, 0.41 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was dried under nitrogen, and sodium carbonate (300 mg, 2.83 mmol), water (4 mL), tetrahydrofuran (4 mL), and di-tert-butyl dicarbonate (200 mg, 0.92 mmol) were added. The reaction mixture was stirred at room temperature overnight. A small amount of tetrahydrofuran, methanol (4 mL), and potassium carbonate (200 mg, 1.45 mmol) were added. The reaction mixture was heated to 50 °C and stirred for 1 hour. Concentrated ammonia (0.3 mL) was added, and the reaction mixture was heated to 50 °C and stirred overnight. Most of the organic solvent was evaporated, ethyl acetate and citric acid solid were added, the mixture was separated, and the organic phase was evaporated to dryness to give compound 109-c (145 mg, 99% yield). LC-MS (ESI): m / z

[0825] 360.1(M+H) + .

[0826] Synthesis of compound 109-b

[0827] Compound 109-c (145 mg, 0.40 mmol), 5-fluoro-2-nitropyridine (95 mg, 0.67 mmol), potassium carbonate (231 mg, 1.67 mmol), and anhydrous DMSO (3 mL) were added to a reaction flask. The reaction mixture was stirred at room temperature for 2 hours, then heated to 60 °C and stirred for 6 hours. The mixture was cooled to room temperature. Ice water was added, and the mixture was extracted with ethyl acetate, washed with water, and evaporated to dryness to give the crude product. Anhydrous methanol (10 mL), tetrahydrofuran (15 mL), and 10% Pd palladium on carbon (containing 40-60% water, 100 mg) were added to the crude product. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 5 hours. The mixture was filtered, and the filtrate was evaporated to dryness to give compound 109-b (180 mg, 99% yield). LC-MS (ESI): m / z 452.5 (M+H) + .

[0828] Synthesis of compound 109-a

[0829] Compound 109-b (180 mg, 0.40 mmol) and pyridine (2 mL) were added to a reaction flask. After stirring for 5 minutes in an ice-water bath, 4-(trifluoromethyl)benzoyl chloride (250 mg, 1.20 mmol) was added. The reaction mixture was stirred in an ice-water bath for 40 minutes. The reaction mixture was added dropwise to a mixture of saturated ammonium chloride aqueous solution and ice, and extracted twice with ethyl acetate. The organic phases were combined, washed twice with citric acid aqueous solution (5%), washed with water, washed with saturated sodium bicarbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was added to diphenylphosphonic hydroxylamine (206 mg, 0.88 mmol) and 1,4-dioxane (5 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling to 60 °C, diphenylphosphonic hydroxylamine (103 mg, 0.44 mmol) was added, and the mixture was heated to 100 °C and stirred for another hour. The mixture was cooled to 60°C, and diphenylphosphonohydroxylamine (103 mg, 0.44 mmol) was added. The mixture was then heated to 100°C and stirred for 1 hour. The mixture was cooled to room temperature. The solvent was removed by rotary evaporation, and the mixture was washed twice with ethyl acetate, sodium bicarbonate aqueous solution (5%), water, saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 96 / 4) to give compound 109-a (120 mg, 48% yield). LC-MS (ESI): m / z 621.2 (M+H) + .

[0830] Synthesis of Compound 109

[0831] Compound 109-a (200 mg, 0.32 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation at room temperature. Anhydrous tetrahydrofuran (4 mL), triethylamine (0.5 mL, 3.60 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (130 mg, 0.48 mmol) were added under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 3 minutes. The solvent was removed by evaporation, and the residue was washed twice with water. The mixture was purified by HPLC to give compound 109 (9.7 mg, yield 7.1%). LC-MS (ESI): m / z 709.2 (M+H) + ; 1 HNMR(DMSO-d6,400MHz)δ9.04(1H,d,J=2.0Hz),8.40(2H,d,J=8.0Hz),7.98–7.86 (4H,m),7.65(1H,dd,J=9.6Hz,2.4Hz),7.46(1H,d,J=2.4Hz),7.31–7.22(3H,m), 7.04–6.99(2H,m),4.74(2H,q,J=8.8Hz),3.99(3H,s),3.78–3.67(1H,m),3.45(2 H,s),2.93–2.81(2H,m),2.13–2.01(2H,m),1.93–1.83(2H,m),1.71–1.55(2H,m).

[0832] Synthetic route of compound 110

[0833]

[0834] Synthesis of compound 110-b

[0835] Compound 25-c (200 mg, 0.56 mmol), bromo-5-nitropyrazine (138 mg, 0.68 mmol), potassium carbonate (196 mg, 1.42 mmol), and DMSO (3 mL) were added to a reaction flask. The reaction mixture was stirred overnight at room temperature. Ice water was added, and the mixture was extracted twice with ethyl acetate, washed with water, and evaporated to dryness to give the crude product. Ammonium formate (100 mg, 1.59 mmol), anhydrous methanol (2.5 mL), tetrahydrofuran (2.5 mL), and 10% Pd palladium on carbon containing 40–60% water (100 mg) were added to the crude product. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to room temperature. The mixture was filtered, the filtrate was evaporated to dryness, the residue was washed with water, dichloromethane was added, and the mixture was separated. The aqueous phase was extracted twice with tetrahydrofuran, the organic phases were combined, evaporated to dryness, and lyophilized to give compound 110-b (185 mg, 73% yield). LC-MS(ESI):m / z

[0836] 453.1(M+H) + .

[0837] Synthesis of compound 110-a

[0838] Compound 110-b (120 mg, 0.26 mmol) and pyridine (3 mL) were added to a reaction flask. After stirring for 5 minutes in an ice-water bath, 4-(trifluoromethyl)benzoyl chloride (120 mg, 0.58 mmol) was added. The reaction mixture was stirred in an ice-water bath for 40 minutes. A saturated ammonium chloride aqueous solution was added, and the mixture was filtered. The filter cake was washed twice with a saturated ammonium chloride aqueous solution, dissolved in ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution, and evaporated to dryness. Diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol) and 1,4-dioxane (5 mL) were added to the crude product. The reaction mixture was heated to 100 °C and stirred for 30 minutes. After cooling to 60 °C, diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol) was added, and the mixture was heated to 100 °C and stirred for another 30 minutes. After cooling to 60 °C, diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol) was added, and the mixture was stirred at 60 °C for 30 minutes, then heated to 100 °C and stirred for another 30 minutes. Cool to 70°C, add diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol), and heat to 100°C with stirring for 30 minutes. Cool to 70°C, add diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol), and heat to 100°C with stirring for 30 minutes. Cool to 70°C, add diphenylphosphonic hydroxylamine (90 mg, 0.39 mmol), and heat to 100°C with stirring for 30 minutes. Cool to room temperature. Remove solvent by rotary evaporation, add ethyl acetate, wash twice with saturated sodium bicarbonate solution, wash with saturated brine, dry to anhydrous sodium sulfate, filter, evaporate to dryness to give compound 110-a (160 mg, 97% yield). LC-MS (ESI): m / z 622.2 (M+H) + .

[0839] Synthesis of Compound 110

[0840] Compound 110-a (160 mg, 0.26 mmol) and dichloromethane (3 mL) were added to a reaction flask. Trifluoroacetic acid (0.7 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation at room temperature. Anhydrous tetrahydrofuran (5 mL), triethylamine (0.5 mL, 3.60 mmol), and 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (137 mg, 0.51 mmol) were added under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Concentrated ammonia (2 drops) was added, and the mixture was stirred for 3 minutes. The solvent was removed by evaporation, and the residue was washed twice with water. The mixture was purified by HPLC to give compound 110 (18.0 mg, yield 9.9%). LC-MS (ESI): m / z 710.2 (M+H) + ; 1 HNMR(DMSO-d6,400MHz)δ9.23(1H,d,J=1.2Hz),9.09(1H,d,J=1.6Hz),8.44(2H,d,J= 8.0Hz),7.97(2H,d,J=8.4Hz),7.62(1H,d,J=8.8Hz),7.32(1H,d,J=2.0Hz),7.31–7. 25(2H,m),7.05–7.00(2H,m),6.98(1H,dd,J=8.4Hz,2.0Hz),6.66(1H,d,J=0.4Hz),4 .73(2H,q,J=9.2Hz),3.68(3H,s),3.67–3.60(4H,m),3.48(2H,s),2.46–2.36(4H,m).

[0841] Synthetic route of compound 111

[0842]

[0843] Synthesis of compound 111-g

[0844] Sodium hydroxide (341 mg, 8.51 mmol) was added to a solution of 6-hydroxybenzo[d]thiazolyl-2-carboxynitrile (300 mg, 1.70 mmol) in anhydrous ethanol (15 mL) and water (3 mL). The mixture was heated to 100 °C and stirred overnight. The solution was evaporated to dryness, water was added, and the pH was adjusted to 5-6 with dilute hydrochloric acid. A large amount of white solid precipitated. The solid was filtered and evaporated to dryness to give compound 111-g (330 mg, 99%). LC-MS (ESI): m / z 195.9 (M+H) + .

[0845] Synthesis of compound 111-f

[0846] At room temperature, concentrated sulfuric acid (98%) (0.5 mL) was slowly added to a methanol (15 mL) solution of compound 111-g (330 mg, 1.69 mmol), and the mixture was heated to 70°C and stirred overnight. The solution was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate (40 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 111-f (261 mg, 74%). LC-MS (ESI): m / z 209.9 (M+H) + .

[0847] Synthesis of compound 111-e

[0848] To a DMSO (15 mL) solution of compound 111-f (220 mg, 1.05 mmol), 5-fluoro-2-nitropyridine (149 mg, 1.05 mmol) and potassium carbonate (291 mg, 2.103 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 111-e (330 mg, 95%). LC-MS (ESI): m / z 331.9 (M+H) + .

[0849] Synthesis of compound 111-d

[0850] Palladium on carbon 10% (300 mg) was added to a 20 mL solution of compound 111-e (330 mg, 1.00 mmol) in ethyl acetate at room temperature. The mixture was purged with hydrogen several times and stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated to dryness to give compound 111-d (264 mg, 88%). LC-MS (ESI): m / z 302.0 (M+H) + .

[0851] Synthesis of compound 111-c

[0852] 4-(trifluoromethyl)benzoyl chloride (274 mg, 1.31 mmol) was slowly added dropwise to a pyridine (6 mL) solution of compound 111-d (264 mg, 0.88 mmol) at room temperature, and the mixture was reacted overnight at room temperature. The solution was evaporated to dryness, extracted with 30 mL of saturated ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 111-c (410 mg, 99%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 474.0 (M+H) + .

[0853] Synthesis of compound 111-b

[0854] Diphenylphosphonyl hydroxylamine (202 mg, 0.87 mmol) was added to a 1,4-dioxane (10 mL) solution of compound 111-c (410 mg, 0.87 mmol). The reaction mixture was heated to 80 °C and stirred overnight. LCMS monitoring showed that nearly half of the starting material remained unreacted. The reaction mixture was cooled to room temperature, and diphenylphosphonyl hydroxylamine (202 mg, 0.87 mmol) was added. The mixture was stirred at 80 °C for another 2 hours. LCMS monitoring showed that the starting material was almost completely reacted. The mixture was evaporated to dryness, and saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (40 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by rapid separation column chromatography (mobile phase: EA / PE: 0% to 100%) to give compound 111-b (218 mg, 54%). LC-MS (ESI): m / z 471.0 (M+H) + .

[0855] Synthesis of compound 111-a

[0856] Lithium hydroxide monohydrate (97 mg, 2.32 mmol) was added to a tetrahydrofuran (15 mL) and water (2 mL) solution of compound 111-b (218 mg, 0.46 mmol) at room temperature, and the mixture was reacted at this temperature for 3 hours. Ice was added, and the pH was slowly adjusted to 5-6 with dilute hydrochloric acid. Ethyl acetate (30 mL) was added, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 111-a (210 mg, 99%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 457.0 (M+H) + .

[0857] Synthesis of Compound 111

[0858] HATU (350 mg, 0.920 mmol) was added to a solution of compounds 111-a (210 mg, 0.460 mmol) and 1-c (176 mg, 0.51 mmol) in dichloromethane (10 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (297 mg, 2.30 mmol). The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative HPLC to give compound 111 (3 mg, 0.91%). LC-MS (ESI): m / z 713.1 (M+H) + .

[0859] Synthetic route of compound 112

[0860]

[0861] Synthesis of compound 112-h

[0862] 4-Aminoresorcinol hydrochloride (500 mg, 3.09 mmol), sodium bicarbonate (26 mg, 0.31 mmol), and ethyl triethoxylate (1.5 mL, 6.93 mmol) were added to a 10 mL microwave-safe tube at room temperature. The tube was sealed, purged with nitrogen several times, and heated to 100 °C overnight. Water was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (mobile phase: EA / PE, 0-50%) to give compound 112-h (499 mg, 78%). LC-MS (ESI): m / z 208.0 (M+H) + .

[0863] Synthesis of compound 112-g

[0864] To a DMSO (20 mL) solution of compound 112-h (480 mg, 2.32 mmol), 5-fluoro-2-nitropyridine (329 mg, 2.32 mmol) and potassium carbonate (352 mg, 2.55 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 112-g (760 mg, 100%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 330.0 (M+H) + .

[0865] Synthesis of compound 112-f

[0866] Palladium on carbon 10% (300 mg) was added to a 20 mL solution of compound 112-g (760 mg, 2.31 mmol) in ethyl acetate at room temperature. The mixture was purged with hydrogen several times and stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated to dryness to give compound 112-f (248 mg, 36%). LC-MS (ESI): m / z 300.0 (M+H) + .

[0867] Synthesis of compound 112-e

[0868] Lithium hydroxide, monohydrate (174 mg, 4.14 mmol), was added to a tetrahydrofuran (10 mL) and water (2 mL) solution of compound 112-f (248 mg, 0.83 mmol) at room temperature. The mixture was reacted overnight at this temperature. Ice was added, and the pH was slowly adjusted to 5-6 with dilute hydrochloric acid. The solution was evaporated to dryness and dissolved in a mixture of dichloromethane and methanol. The mixture was stirred for 1 hour, filtered, and the organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation, compound 112-e (224 mg, 100%) was obtained. The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 271.9 (M+H) + .

[0869] Synthesis of compound 112-d

[0870] HATU (628 mg, 1.65 mmol) was added to a solution of compound 112-e (224 mg, 0.83 mmol) and N-Boc-piperazine (154 mg, 0.83 mmol) in N,N-dimethylformamide (15 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (534 mg, 4.13 mmol). The mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 112-d (360 mg, 99%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 440.1 (M + H) + .

[0871] Synthesis of compound 112-c

[0872] 4-(trifluoromethyl)benzoyl chloride (256 mg, 1.23 mmol) was slowly added dropwise to a pyridine (10 mL) solution of compound 112-d (360 mg, 0.82 mmol) at room temperature, and the mixture was reacted overnight at room temperature. The mixture was evaporated to dryness, extracted with saturated ammonium chloride solution (30 mL x 2) and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 112-c (501 mg, 100.00%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 612.1 (M+H) + .

[0873] Synthesis of compound 112-b

[0874] Diphenylphosphonyl hydroxylamine (286 mg, 1.23 mmol) was added to a 20 mL solution of 1,4-dioxane (20 mL) of compound 112-c (501 mg, 0.82 mmol), and the reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and diphenylphosphonyl hydroxylamine (286 mg, 1.23 mmol) was added again, followed by stirring overnight at 80 °C. LC-MS monitoring showed that the reaction proceeds were almost completely reacted. The mixture was evaporated to dryness, and extracted with 40 mL of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid separation column chromatography (mobile phase: EA / PE: 0% to 100%) to give compound 112-b (167 mg, 34%). LC-MS (ESI): m / z 609.1 (M+H) + .

[0875] Synthesis of compound 112-a

[0876] Trifluoroacetic acid (1 mL) was added to a solution of compound 112-b (167 mg, 0.27 mmol) in dichloromethane (10 mL) at room temperature, and the mixture was reacted overnight at this temperature. The reaction solution was evaporated to dryness to give compound 112-a (140 mg, 100%). LC-MS (ESI): m / z 509.1 (M+H) + .

[0877] Synthesis of Compound 112

[0878] At room temperature, 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene (111 mg, 0.41 mmol) and triethylamine (139 mg, 0.28 mmol) were added to a tetrahydrofuran (10 mL) solution of compound 112-a (140 mg, 0.28 mmol) at room temperature.

[0879] The mixture was reacted overnight at this temperature (1.38 mmol). The reaction solution was evaporated to dryness, and the crude product was purified by preparative HPLC to give compound 112 (51.2 mg, 27%). LC-MS (ESI): m / z 697.1 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ9.12(1H,dd,J=2.4,0.8Hz),8.40(2H,d,J=8.4Hz),7.98(1H,dd ,J=9.6Hz,0.8Hz),7.96–7.91(3H,m),7.71(1H,d,J=2.0Hz),7.67(1H,dd,J=9.6Hz,2.4 Hz),7.33(1H,dd,J=8.8Hz,2.4Hz),7.28(2H,d,J=8.8Hz),7.02(2H,d,J=8.8Hz),4.74( 2H,q,J=8.8Hz),3.96–3.90(2H,m),3.72–3.65(2H,m),3.50(2H,s),2.48–2.42(4H,m).

[0880] Bioactivity test

[0881] Experiment 1: Cellular luciferase reporter gene experiment

[0882] Experimental procedure:

[0883] LNCaP cells were cultured in 1640 medium supplemented with 10% FBS, then transferred to 6-well plates and incubated overnight (5% CO2 incubator, 37°C). STAT3-Luc reporter gene plasmid (from YEASEN) was added and transfected for 24 h. Cells were harvested, plated, and after cell adhesion, different concentrations of the compound were added, pre-incubated for 30 min, followed by the addition of human IL-6 (final concentration 4 ng / mL), and incubated for 24 h in a 5% CO2 incubator, 37°C. Bright Lite reagent was added, and the luminescence value was read using a multi-mode microplate reader. Inhibition rate (Inhibition (%) = (Max mean – value) / (Max mean – Min mean) × 100%) was calculated, a dose-response curve was fitted, and the IC50 was calculated. 50 Values. The activity results of representative compounds of this invention are shown in the table below. Wherein, "IC value" is... 50 ">10μM" is indicated by "*", and "10μM≥IC" indicates that the value of IC is greater than 10μM. 50 ">1μM" is represented by "**", and "1μM≥IC" is represented by "**". 50 ">100nM" is represented by "***", "IC" 50 ≤100nM is represented by “****”.

[0884] Table 1

[0885]

[0886] Experiment 2: CTG method for detecting cell proliferation inhibition

[0887] The experiments were conducted on 384-well or 96-well plates. The specific procedure is as follows:

[0888] Add the cell suspension to be tested (MDA-MB-468 cells, 50 μL for 384-well plate; 100 μL for 96-well plate) to 384 or 96-well plates. Incubate the plates overnight in a 0% CO2 incubator at 37°C. Add the corresponding concentration of the compound to each well using an HPD300 micro-dosing instrument (obtain 9-10 concentration gradients of the compound through 3-fold dilution). Incubate the cell plates in a 0% CO2 incubator at 37°C for 4 days. On the day of assay, equilibrate the 384 or 96-well plates to room temperature for 10-30 minutes, then add CellTiter Glo reagent (25 μL for 384-well plate; 100 μL for 96-well plate), shake for 10 minutes in the dark, and incubate for 10 minutes. Place the plates in an ENVIDION reader, plot the drug efficacy inhibition rate curve using XLFit, and calculate the IC50. 50 Values. The activity results for representative compounds are shown in the table below. Among them, "IC50" is... 50 ">10μM" is indicated by "*", and "10μM≥IC" indicates that the value of IC is greater than 10μM. 50 ">1μM" is represented by "**", and "1μM≥IC" is represented by "**". 50 ">100nM" is represented by "***", and "100nM≥IC" is used for other purposes. 50 >10nM is represented by "****-", "IC 50 ≤10nM is represented by “****+”.

[0889] Table 2

[0890]

[0891]

[0892]

[0893] It should be understood that the embodiments and implementations described in this invention are for illustrative purposes only, and various modifications or variations therein will be suggested to those skilled in the art, and these are included within the spirit and scope of this application and the appended claims. All publications, patents and patent applications referenced in this invention are incorporated herein by reference and used for all purposes.

Claims

1. A heterocyclic compound as shown in Formula I, its stereoisomer, its pharmaceutically acceptable salt, a stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule: in, X 1 For NR 4 , O or S; R 4 For hydrogen, C 1-6 Alkyl, with one or more R 4-1 Replacement C 1-6 Alkyl, -C(=O)R 4a -C(=O)OR 4b -C(=O)NR 4c1 R 4c2 C 6-20 aryl, with one or more R 4-2 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 4-3 Substituted "5-12-membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 3-12 cycloalkyl, with one or more R 4-4 Replacement C 3-12 Cycloalkyl, "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4-12 membered heterocycloalkyl group", and bound by one or more R 4-5 Substituted "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4-12 membered heterocyclic alkyl groups", C 5-7 Cycloalkenyl, with one or more R 4-6 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 4-7 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 4-1 For deuterium, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 41a -NR 41b1 R 41b2 -C(=O)OR 41c -C(=O)NR 41d1 R 41d2 -S(O)2NR 41e1 R 41e2 -S(O)2R 41f C 6-20 aryl, with one or more R 41-1 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 41-2 Substituted "5-12-membered heteroaryl groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, S, and N", C 3-12 cycloalkyl, with one or more R 41-3 Replacement C 3-12 Cycloalkyl, "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4-12 membered heterocycloalkyl group", and bound by one or more R 41-4 Substituted "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4-12 membered heterocyclic alkyl groups", C 5-7 Cycloalkenyl, with one or more R 41-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 41-6 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 4-2 R 4-3 R 4-4 R 4-5 R 4-6 R 4-7 R 41-1 R 41-2 R 41-3 R 41-4 R 41-5 and R 41-6 Independently for C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -C(=O)R 42a -NR 42b1 R 42b2 -C(=O)OR 42c -C(=O)NR 42d1 R 42d2 -S(O)2NR 42e1 R 42e2 -S(O)2R 42f -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, C 6-20 Aryl, "5-12 membered heteroaryl groups containing 1-4 heteroatoms independently selected from O, S, and N", C 3-12 Cycloalkyl, "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4-12 membered heterocycloalkyl", C 5-7 Cycloalkenyl, or "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N in 5-7 membered heterocyclic alkenyl groups"; when there are multiple substituents, they may be the same or different; R 4a R 4b R 4c1 R 4c2 R 41a R 41b1 R 41b2 R 41c R 41d1 R 41d2 R 41e1 R 41e2 R 41f R 42a R 42b1 R 42b2 R 42c R 42d1 R 42d2 R 42e1 R 42e2 and R 42f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; X 2 For CR 5 Or N; R 5 For hydrogen, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, hydroxyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R 5a -NR 5b1 R 5b2 -C(=O)OR 5c -C(=O)NR 5d1 R 5d2 -S(O)2NR 5e1 R 5e2 , or, -S(O)2R 5f When there are multiple substituents, they may be the same or different. R 5a R 5b1 R 5b2 R 5c R 5d1 R 5d2 R 5e1 R 5e2 and R 5f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; Y 1 and Y 4 Independent for CR 6 Or N; Y 2 For CR 8 Y 3 For CR 7 Or N; or Y 3 For CR 8 Y 2 For CR 7 Or N; R 6 and R 7 Independently hydrogen, C 1-6 Alkyl groups, halogens, and C atoms substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 8 for n2 is 0, 1, 2 or 3; It is a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N; or a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N; R 9 It is cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, with one or more R 9-1 Replacement C 1-6 Alkyl, halogen, hydroxyl, -OC 1-6 Alkyl, with one or more R 9-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 9-3 Replacement -SC 1-6 Alkyl, -C(=O)R 9a -NR 9b1 R 9b2 -C(=O)OR 9c -C(=O)NR 9d1 R 9d2 -S(O)2NR 9e1 R 9e2 -S(O)2R 9f C 3-12 cycloalkyl, with one or more R 9-4 Replacement C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4 to 12-membered heterocycloalkyl group", and being bound by one or more R 9-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 9-6 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, a 5 to 12-membered heteroaryl", and bonded by one or more R 9-7 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 9-1 R 9-2 R 9-3 R 9-4 R 9-5 R 9-6 R 9-7 R 9-8 and R 9-9 Independently deuterium, azide, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 9-1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 91a -NR 91b1 R 91b2 -C(=O)OR 91c -C(=O)NR 91d1 R 91d2 -S(O)2NR 91e1 R 91e2 -S(O)2R 91f , C 3-12 cycloalkyl, with one or more R 9-1-4 Replacement C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4 to 12-membered heterocycloalkyl group", and being bound by one or more R 9-1-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 9-1-6 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, a 5 to 12-membered heteroaryl", and bonded by one or more R 9-1-7 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 9-1-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-1-9 The substituent is "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; or, when R 9-4 R 9-5 R 9-8 and R 9-9 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-4 Two Rs 9-5 Two Rs 9-8 Or two Rs 9-9 They connect to each other, forming C atoms with the atoms they are connected to. 3-12 Cycloalkanes, or, "containing 1-3 heteroatoms, the heteroatoms being independently selected from 5-7 membered heterocycles selected from O, S, and N"; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N"; R 9-1-1 R 9-1-2 R 9-1-3 R 9-1-4 R 9-1-5 R 9-1-6 R 9-1-7 R 9-1-8 and R 9-1-9 Independently deuterium, azide, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 911a -NR 911b1 R 911b2 -C(=O)OR 911c -C(=O)NR 911d1 R 911d2 -S(O)2NR 911e1 R 911e2 or -S(O)2R 911f ; R 9a R 9b1 R 9b2 R 9c R 9d1 R 9d2 R 9e1 R 9e2 R 9f R 91a R 91b1 R 91b2 R 91c R 91d1 R 91d2 R 91e1 R 91e2 R 91f R 911a R 911b1 R 911b2 R 911c R 911d1 R 911d2 R 911e1 R 911e2 and R 911f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; n3 can be 0, 1, 2, or 3; R 10 It is an azide group, halogen, hydroxyl group, cyano group, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R 10a -NR 10b1 R 10b2 -C(=O)OR 10c -C(=O)NR 10d1 R 10d2 -S(O)2NR 10e1 R 10e2 -S(O)2R 10f C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl, or "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N in 5-7 membered heterocyclic alkenyl groups"; when there are multiple substituents, they may be the same or different; R 10a R 10b1 R 10b2 R 10c R 10d1 R 10d2 R 10e1 R 10e2 and R 10f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; L2 is the connection key. C 1-6 Alkylene, by one or more R 11 Replacement C 1-6 Alkylene, O, S or NR 12 ; R 11 For deuterium, halogen, cyano, hydroxyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR 11d1 R 11d2 -S(O)2NR 11e1 R 11e2 -S(O)2R 11f =O, -OC 1-6 Alkyl or -SC 1-6 alkyl; R 12 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -C(=O)R 12a -NR 12b1 R 12b2 -C(=O)OR 12c -C(=O)NR 12d1 R 12d2 -S(O)2NR 12e1 R 12e2 or -S(O)2R 12f When there are multiple substituents, they may be the same or different. R 11a R 11b1 R 11b2 R 11c R 11d1 R 11d2 R 11e1 R 11e2 R 11f R 12a R 12b1 R 12b2 R 12c R 12d1 R 12d2 R 12e1 R 12e2 and R 12f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; L1 is End b is connected to ring A, and Z is either O or S; R 3 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; L 11 C 1-6 Alkylene, by one or more R 13 Replacement C 1-6 Alkylene, C 2-6 alkynyl group, with one or more R 14 Replacement C 2-6 alkynyl group, C 2-6 alkenyl or with one or more R 15 Replacement C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different; R 13 R 14 and R 15 Independently deuterium, halogen, cyano, hydroxyl, -C(=O)R 13a -NR 13b1 R 13b2 -C(=O)OR 13c -C(=O)NR 13d1 R 13d2 -S(O)2NR 13e1 R 13e2 -S(O)2R 13f -OC 1-6 Alkyl or -SC 1-6 alkyl; R 13a R 13b1 R 13b2 R 13c R 13d1 R 13d2 R 13e1 R 13e2 and R 13f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; Ring A is C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N"; n1 is 0, 1, 2, 3, 4 or 5; R 1 For deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl, with one or more R 1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 1a -NR 1b1 R 1b2 -C(=O)OR 1c -C(=O)NR 1d1 R 1d2 -S(O)2NR 1e1 R 1e2 or -S(O)2R 1f When there are multiple substituents, they may be the same or different. R 1-1 R 1-2 and R 1-3 Independently halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR 11d1 R 11d2 -S(O)2NR 11e1 R 11e2 or -S(O)2R 11f ; R 1a R 1b1 R 1b2 R 1c R 1d1 R 1d2 R 1e1 R 1e2 R 1f R 11a R 11b1 R 11b2 R 11c R 11d1 R 11d2 R 11e1 R 11e2 and R 1f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl, -SR 2e , by one or more R 2f Replacement -SC 1-6 Alkyl, -NR 2g1 R 2g2 , or, by one or more R 2h Replacement -NR 2i C 1-6 Alkyl; R 2b OR 2b1 SR 2b2 or -NR 2b31 R 2b32 When there are multiple substituents, they may be the same or different. R 2g2 R 2i and R 2b32 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 2a R 2b1 R 2b2 R 2b31 R 2c R 2d R 2e R 2f R 2g1 and R 2h Independently for C 3-12 cycloalkyl, with one or more R 2-1 Replacement C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4 to 12-membered heterocycloalkyl group", and being bound by one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, a 5 to 12-membered heteroaryl", and bonded by one or more R 2-4 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 2-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-6 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 2-1 R 2-2 R 2-3 R 2-4 R 2-5 and R 2-6 Independently, it is an azide group, halogen, hydroxyl group, cyano group, C 1-6 Alkyl, with one or more R 2-1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 2-1-3 Replacement -SC 1-6 Alkyl, -C(=O)R 21a -NR 21b1 R 21b2 -C(=O)OR 21c -C(=O)NR 21d1 R 21d2 -S(O)2NR 21e1 R 21e2 -S(O)2R 21f C 3-12 cycloalkyl, -OC 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 2-1-1 R 2-1-2 and R 2-1-3 Independently, it is an azide group, halogen, hydroxyl group, cyano group, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 22a -NR 22b1 R 22b2 -C(=O)OR 22c -C(=O)NR 22d1 R 22d2 -S(O)2NR 22e1 R 22e2 -S(O)2R 22f C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl or "5-7 membered heterocyclic alkenyl containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 21a R 21b1 R 21b2 R 21c R 21d1 R 21d2 R 21e1 R 21e2 R 21f R 22a R 22b1 R 22b2 R 22c R 22d1 R 22d2 R 22e1 R 22e2 and R 22f Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 4c1 and R 4c2 R 41b1 and R 41b2 R 41d1 and R 41d2 R 41e1 and R 41e2 R 42b1 and R 42b2 R 42d1 and R 42d2 R 42e1 and R 42e2 R 5b1 and R 5b2 R 5d1 and R 5d2 R 5e1 and R 5e2 R 9b1 and R 9b2 R 9d1 and R 9d2 R 9e1 and R 9e2 R 91b1 and R 91b2 R 91d1 and R 91d2 R 91e1 and R 91e2 R 911b1 and R 911b2 R 911d1 and R 911d2 R 911e1 and R 911e2 R 10b1 and R 10b2 R 10d1 and R 10d2 R 10e1 and R 10e2 R 11b1 and R 11b2 R 11d1 and R 11d2 R 11e1 and R 11e2 R 12b1 and R 12b2 R 12d1 and R 12d2 R 12e1 and R 12e2 R 13b1 and R 13b2 R 13d1 and R 13d2 R 13e1 and R 13e2 R 1b1 and R 1b2 R 1d1 and R 1d2 R 1e1 and R 1e2 R 11b1 and R 11b2 R 11d1 and R 11d2 R 11e1 and R 11e2 R 21b1 and R 21b2 R 21d1 and R 21d2 R 21e1 and R 21e2 R 22b1 and R 22b2 R 22d1 and R 22d2 R 22e1 and R 22e2 Independently, each of them, together with the attached N, forms a 3- to 8-membered heterocycle containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N, or is formed by one or more R... a The substituted ring "contains 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from 3 to 8-membered heterocycles of O, S, and N"; R a Independently, it can be O, hydroxyl, halogen, cyano, or C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl groups, -OC groups substituted with one or more deuterium atoms 1-6 Alkyl, -SC 1-6 Alkyl groups, -SC groups substituted with one or more halogens 1-6 Alkyl groups, -SC groups substituted with one or more deuterium groups 1-6 Alkyl, -C(=O)R a1 -NR a21 R a22 -C(=O)OR a3 -C(=O)NR a41 R a42 -S(O)2NR a51 R a52 or -S(O)2R a6 ;R a1 R a21 R a22 R a3 R a41 R a42 R a51 R a52 and R a6 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl group; when there are multiple substituents, they may be the same or different.

2. The heterocyclic compound of Formula I as claimed in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, The structure of the heterocyclic compound shown in Formula I is shown in Formula II: in, It can be a single bond or a double bond; B is C, CH, or N; Y 3 For CR 7 Or N; The definitions of other groups are as described in claim 1.

3. The heterocyclic compound, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule as described in claim 1 or 2, characterized in that, Its structure is shown in Equation III: in, It has aromatic properties; It can be a single bond or a double bond; B is C, CH, or N; Y 3 For CR 7 Or N; G1 and G2 are independently C or N; G3, G4 and G5 are independently C, CH, NH, N, O or S; The definitions of other groups are as described in claim 1 or 2.

4. The heterocyclic compound, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule as described in any one of claims 1-3, characterized in that, Its structure is shown in Equation IV: in, It has aromatic properties; It can be a single bond or a double bond; B is C, CH, or N; G1 and G2 are independently C or N; G3 and G4 are independently C, CH, NH, N, O or S; L3 represents O and C. 1-6 Alkylene or NR 2g2 ;R 2g2 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; Ar is C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 aryl, "a 5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-4 The substituted form is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, which are independently selected from O, S, and N"; The definitions of other groups are as described in any one of claims 1-3.

5. The heterocyclic compound of Formula I as claimed in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, In heterocyclic compounds as shown in Formula I X 1 For NR 4 O or S, R 4 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, or, C 3-12 cycloalkyl; X 2 For CR 5 Or N, R 5 It is hydrogen; Y 1 and Y 4 Independent for CR 6 ; Y 2 For CR 8 Y 3 For CR 7 Or N; or Y 3 For CR 8 Y 2 For CR 7 Or N; R 6 and R 7 Independently hydrogen; R 8 for n2 is 0 or 1; n3 is 0; The terms are: "a 5-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S and N", "a 5-membered or 5-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S and N", or "a 6-membered or 6-membered heterocycle containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S and N". R 9 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, halogen, or with one or more R 9-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4 to 12-membered heterocyclic alkyl groups", and being substituted by one or more R 9-6 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 They connect to each other, forming C atoms with the atoms they are connected to. 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N"; R 9-1-1 and R 9-1-2 Halogens are independent of each other; R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C 1-6 alkyl; L2 is the connection key. C 1-6 Alkylene, O, S or NR 12 ;R 12 It is hydrogen or C 1-6 alkyl; L1 is End b is connected to ring A, and Z is O; R 3 It is hydrogen or C 1-6 alkyl; L 11 C 1-6 Alkylene or C 2-6 alkynyl group; Ring A is C 3-12 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, 4 to 12 membered heterocycloalkyl", C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S and N, 5 to 12-membered heteroaryl" or "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S and N, 5 to 7-membered heterocyclic alkenyl"; n1 is either 0 or 1; R 1 C 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl or with one or more R 1-2 Replacement -OC 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 1-1 and R 1-2 Halogens are independent of each other; R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl, or, -NR 2g1 R 2g2 When there are multiple substituents, they may be the same or different. R 2g2 It is hydrogen or C 1-6 alkyl; R 2a R 2c R 2d and R 2g1 Independently halogenated, by one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4 to 12-membered heterocyclic alkyl groups", and being substituted by one or more R 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 Substitutions are defined as "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different; R 2-2 R 2-3 and R 2-4 Independently halogenated, by one or more R 2-1-1 Replacement C 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl or -OC 3-12 Cycloalkyl; when there are multiple substituents, they may be the same or different; R 2-1-1 and R 2-1-2 Halogens are independent of each other.

6. The heterocyclic compound of formula IV as claimed in claim 4, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, In the heterocyclic compounds shown in Formula IV It can be a single bond or a double bond; G1 and G2 are independently C or N; G3 and G4 are independently C, O, CH, NH or N; n2 is 0 or 1; R 9 Halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, halogen, C 3-12 cycloalkyl, with one or more R 9-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4 to 12-membered heterocyclic alkyl groups", and being substituted by one or more R 9-6 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 Formation C 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N"; R 9-1-1 and R 9-1-2 Halogens are independent of each other; R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C 1-6 alkyl; X 1 For NR 4 O or S; R 4 For hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl or C substituted with one or more halogens 1-6 alkyl; B is CH, C, or N; n1 is either 0 or 1; R 1 C 1-6 alkyl; L3 represents O and C. 1-6 Alkylene or NR 2g2 ;R 2g2 It is hydrogen or C 1-6 alkyl; Ar is a variable that is controlled by one or more R. 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 The substituted form is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, which are independently selected from O, S, and N"; R 2-3 and R 2-4 C that is independently a halogen, or a C substituted with one or more halogens. 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl or -OC 3-12 Cycloalkyl.

7. The heterocyclic compound of Formula I as claimed in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, X 1 For NR 4 O or S, R 4 For hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, or, C 3-12 cycloalkyl; And / or, Y 1 and Y 4 Independent for CR 6 Y 2 For CR 8 Y 3 For CR 7 ;R 6 and R 7 Independently hydrogen; And / or, R 9 Independent of halogen, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, -NR 9b1 R 9b2 , by one or more R 9-1 Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, with one or more R 9-5 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4 to 12-membered heterocyclic alkyl groups", and being substituted by one or more R 9-6 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, 5 to 12 membered heteroaryl", C 5-7 Cycloalkenyl, with one or more R 9-8 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 9-9 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 9-1 R 9-5 R 9-6 R 9-8 and R 9-9 Independently halogen, cyano, C 1-6 Alkyl, with one or more R 9-1-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 9-1-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NR 91b1 R 91b2 , or -C(=O)NR 91d1 R 91d2 Or, when there are multiple substituents, they may be the same or different; when R 9-8 When the number of substitutions is greater than 1 and they are substitutions on the same atom, any two Rs 9-8 Formation C 3-12 Cycloalkanes; when R 9-6 The number of R is greater than 1, and the two R 9-6 They are connected to each other, forming "5-7 membered heterocycles containing 1-3 heteroatoms, each heteroatom being independently selected from O, S and N"; R 9-1-1 and R 9-1-2 Halogens are independent of each other; R 9b1 R 9b2 R 91d1 R 91d2 R 91b1 and R 91b2 Independently hydrogen or C 1-6 alkyl; And / or, L2 is the connection key, C 1-6 Alkylene, O, S or NR 12 ;R 12 It is hydrogen or C 1-6 alkyl; And / or, L1 is End b is connected to ring A, and Z is O; R 3 It is hydrogen or C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; L 11 C 1-6 Alkylene, C 2-6 alkynyl or C 2-6 alkenyl; And / or, R 2 For hydrogen, by one or more R 2a Replacement C 1-6 Alkyl, -OR 2c , by one or more R 2d Replacement -OC 1-6 Alkyl, -NR 2g1 R 2g2 When there are multiple substituents, they may be the same or different. R 2g2 It is hydrogen or C 1-6 alkyl; R 2a R 2c R 2d and R 2g1 and independently for one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4 to 12-membered heterocyclic alkyl groups", and being substituted by one or more R 2-3 Replacement C 6-20 aryl or aryl with one or more R 2-4 Substitutions are defined as "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different; R 2-2 R 2-3 and R 2-4 Independently halogenated, by one or more R 2-1-1 Replacement C 1-6 Alkyl, with one or more R 2-1-2 Replacement -OC 1-6 Alkyl, or, -OC 3-12 Cycloalkyl; when there are multiple substituents, they may be the same or different; R 2-1-1 and R 2-1-2 Halogens are independent of each other.

8. The heterocyclic compound of Formula I as claimed in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, for And / or, for And / or, n2 is 0 or 1; And / or, n3 is 0; And / or, R 9 for Cl, -CN, methyl, Ethyl, And / or, L1 is End b is connected to ring A, and Z is O; And / or, for And / or, L2 is -O-, connector, -CH2-、 -S- or And / or, R 2 For hydrogen, 9. The heterocyclic compound of Formula I as claimed in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules, characterized in that, The heterocyclic compound shown in Formula I has any of the following structures:

10. A pharmaceutical composition comprising substance A and a pharmaceutical excipient; wherein substance A is a therapeutically effective amount of a heterocyclic compound of formula I as claimed in claim 1, its stereoisomer, its pharmaceutically acceptable salt, a stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule.

11. The use of a substance A in the preparation of a STAT3 inhibitor, wherein the substance A is a heterocyclic compound as described in Formula I as claimed in claim 1, its stereoisomer, its pharmaceutically acceptable salt, its stereoisomer, its prodrug, its deuterated compound, or its PROTAC molecule.

12. The use of a substance A in the preparation of a medicament for inhibiting phosphorylation of STAT3 protein; wherein the substance A is a heterocyclic compound as shown in Formula I as claimed in claim 1, its stereoisomer, its pharmaceutically acceptable salt, a stereoisomer of its pharmaceutically acceptable salt, its prodrug, its deuterated compound, or its PROTAC molecule.

13. The use of substance A in the preparation of a medicament for the treatment or prevention of cancer; wherein substance A is a heterocyclic compound of formula I as described in claim 1, its stereoisomers, its pharmaceutically acceptable salts, stereoisomers of its pharmaceutically acceptable salts, its prodrugs, its deuterated compounds, or its PROTAC molecules; wherein the cancer is selected from one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, hematologic malignancies, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

Images