HPK1 inhibitors, their preparation methods, pharmaceutical compositions and their applications

Abstract

This invention discloses an HPK1 inhibitor, its preparation method, pharmaceutical composition, and its application. Specifically, it discloses compounds as shown in Formula I or II, or pharmaceutically acceptable salts thereof. The compounds of this invention have novel structures and exhibit good activity and selectivity.

Description

Technical Field

[0001] This invention relates to an HPK1 inhibitor, its preparation method, pharmaceutical composition, and its application. Background Technology

[0002] Hematopoietic progenitor cell kinase 1 (HPK1, also known as MAP4K1) is a member of the MAP4K family and is a serine / threonine kinase. It is mainly expressed in immune cells and plays a role in regulating immune cell function.

[0003] In T cells, activation of the T cell receptor (TCR) signaling pathway leads to the recruitment of cytoplasmic HPK1 to the cell membrane, where it binds to and phosphorylates the adaptor protein SLP76. This promotes the binding of SLP76 to E3 ligase 14-3-3, resulting in the degradation of the SLP76 / LAT signaling body, thereby negatively regulating the T cell receptor (TCR) pathway and inhibiting T cell activation and effector T cell function. Compared to wild-type, HPK1 knockout (HPK1 knockout) - / - T cells with inactivated HPK1 kinase (HPK1 KD) exhibited stronger proliferative capacity and higher cytokine expression levels. The mRNA and protein expression levels of HPK1 were also significantly reduced in CD4+ T cells from patients with systemic lupus erythematosus.

[0004] HPK1 can control anti-tumor immune mechanisms in a T-cell-dependent manner. - / - In tumor-bearing mice with HPK1 KD, T cells exhibited strong tumor cell killing ability, while tumor cells expressing the immunosuppressive molecule PGE2 showed strong tumor cell killing ability in HPK1-dependent tumor cells. - / - Compared to wild-type HPK1 KD mice, they grew more slowly. Analysis of the tumor microenvironment in HPK1 KD mice revealed significantly increased expression of key immune cell biomarkers involved in anti-tumor immunity, such as CD4, CD8, IFNγ, and Granzyme B. Expression of genes related to pro-inflammatory pathways, including the chemokine CXCL14, was also significantly increased, while expression of genes related to Th2 and Treg decreased.

[0005] In 25 types of human cancers, HPK1 expression was significantly positively correlated with the T-cell exhaustion marker PD-1, and also positively correlated with other T-cell exhaustion markers such as TIGIT, CTLA-4, and LAG3 in various tumors. Decreased HPK1 expression in low-grade glioma (LGG) and clear cell renal cell carcinoma (KIRC) was associated with prolonged patient survival, while HPK1 amplification in pancreatic cancer (PAAD) and metastatic breast cancer (BRAC) was associated with poor prognosis.

[0006] Furthermore, HPK1 is also a negative regulator of B cell and dendritic cell activation and plays an important role in maintaining Treg cell function. In summary, HPK1 has multifaceted anti-tumor immunopromoting effects and is a potential therapeutic target for tumor immunotherapy and autoimmune diseases. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to address the deficiency of the relatively simple structure of existing HPK1 inhibitors. The present invention provides an HPK1 inhibitor, its preparation method, pharmaceutical composition and its application. The compound structure of the present invention is novel and has good activity and selectivity.

[0008] This invention provides compounds as shown in Formula I or II, or pharmaceutically acceptable salts thereof:

[0009]

[0010] W is either NH or O;

[0011] X 1 and X 2 Independently, it is N or CH; Y is N or CR. 4 ;

[0012] R 1 It is H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0013] R 4 R 6 and R 7 Independently, it can be H, hydroxyl, halogen, CH3, or OCH3;

[0014] R 8 and R 9 Independently, it is H, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkyl substituted with one or more OH groups; or, R 8 R 9 Together with the carbon atoms it is attached to, they form C3-C8 cycloalkyl groups;

[0015] R 2 For -CHR 2-1 R 2-2 , by one or more R 2-3 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 2-4 The substituted "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", or "substituted by one or more R..." 2-5 Replacement C6-C 10 Aryl, C6-C10 aryl, with one or more R 2-6 The substituted "5-12-membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms" or "5-12-membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0016] R 2-1 For H or -(CH2)nR 2-1-1 n can be 0, 1, 2, or 3;

[0017] R 2-1-1 For one or more R 2-7 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 2-8 The substituted "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", or "substituted by one or more R..." 2-9 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-10 The substituted "5-12-membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms" or "5-12-membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0018] R 2-3 R 2-4 R 2-5 R 2-6 R 2-7 R 2-8 R 2-9 and R 2-10 Independently halogen, hydroxyl, cyano, NR 2-11 R 2-12 , by one or more R 2-13 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-14 Substituted C1-C6 alkoxy or C1-C6 alkoxy;

[0019] R 2-11 and R 2-12 Independently H or C1-C6 alkyl;

[0020] R 2-13 and R 2-14 It can be independently a cyano, hydroxyl, amino, or halogen group;

[0021] R 2-2 For H, by one or more R2-15 Substituted C1-C6 alkyl or C1-C6 alkyl;

[0022] R 2-15 It can be independently a cyano, hydroxyl, amino, or halogen group;

[0023] R 3 for or -C(=Z) 3 )-L 1 -L 2 -L 3 -L 4 -L 5 ;

[0024] Z 1 For O, S, NH or -CR 1-1 ;

[0025] Z 2 For N or -CR 1-2 ;

[0026] Z 3 It can be NH, O, or S;

[0027] R 1-1 and R 1-2 Independently, it is H, a halogen, a C1-C4 alkyl group substituted with one or more halogens, or a C1-C4 alkyl group.

[0028] R 5 For one or more R 5-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 5-2 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 5-3 The substituted "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", or "substituted by one or more R..." 5-4 The substituted "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", or "substituted by one or more R 5-5 Replacement C6-C 10 Aryl or C6-C 10 Aryl;

[0029] R 5-1 Independently for one or more R 5-2 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 5-3 The substituted "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", or "substituted by one or more R..." 5-4 The substituted "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", or "substituted by one or more R 5-5 Replacement C6-C 10 Aryl or C6-C 10 Aryl;

[0030] R 5-2 R 5-3 R 5-4 and R 5-5 Independently halogen, cyano, hydroxyl, NR 5-2-1 R 5-2-2 C1-C6 alkyl or -C(=O)R 5 -2-3 ;R 5-2-1 and R 5-2-2 Independently H or C1-C6 alkyl; R 5-2-3 It is a C1-C6 alkyl group;

[0031] L 1 For covalent bonds, O, S, or NR 10 ;R 10 It is H or C1-C6 alkyl;

[0032] L 2 For covalent bonds, bounded by one or more R 1-3 Substituted C1-C6 alkylene or C1-C6 alkylene;

[0033] L 3 It is a covalent bond, a C3-C8 cycloalkylene group, or a 3-12 membered heteroalkylene group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms.

[0034] L 4 For covalent bonds, bounded by one or more R 1-3 Substituted C1-C6 alkylene or C1-C6 alkylene;

[0035] L 5 For one or more R 1-4 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 1-5The substituted "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", or "substituted by one or more R 1-6 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 1-7 The substituted "a heteroatom selected from one or more of N, O and S, and having 1 to 4 heteroatoms in a 3-12-membered heterocyclic alkyl group" or "a heteroatom selected from one or more of N, O and S, and having 1 to 4 heteroatoms in a 3-12-membered heterocyclic alkyl group";

[0036] R 1-3 It is independently a halogen, hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy group;

[0037] R 1-4 R 1-5 R 1-6 and R 1-7 Independently halogen, hydroxyl, cyano, NR 2-11 R 2-12 , by one or more R 2-13 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-14 Substituted C1-C6 alkoxy or C1-C6 alkoxy;

[0038] R 11 For one or more R 11-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 11-2 The substituted "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", or "substituted by one or more R 11-3 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 11-4 The substituted "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", or "substituted by one or more R..." 11-5 Substituted C1-C6 alkyl groups, C1-C6 alkyl groups;

[0039] R 11-5 Independently for one or more R 11-1 Replacement C6-C 10 Aryl, C6-C 10aryl, with one or more R 11-2 The substituted "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", "5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", or "substituted by one or more R 11-3 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 11-4 The substituted "a heteroatom selected from one or more of N, O and S, and having 1 to 4 heteroatoms in a 3-12-membered heterocyclic alkyl group" or "a heteroatom selected from one or more of N, O and S, and having 1 to 4 heteroatoms in a 3-12-membered heterocyclic alkyl group";

[0040] R 11-1 R 11-2 R 11-3 and R 11-4 Independently halogen, hydroxyl, cyano, NR 2-11 R 2-12 , by one or more R 2-13 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-14 Substituted C1-C6 alkoxy or C1-C6 alkoxy.

[0041] In a preferred embodiment of the present invention, certain groups in the compound represented by Formula I or II or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in a certain embodiment of the present invention").

[0042] When R 1 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl.

[0043] In one aspect of the present invention, when R 1 When it is a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is cyclopropyl.

[0044] In one aspect of the present invention, when R 8 and R 9 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is CH3, C2H5, iPr or n-Pr; for example, CH3.

[0045] In one aspect of the present invention, when R 8 and R 9 When independently a C1-C4 alkoxy group, the C1-C4 alkoxy group is OCH3 or OC2H5; for example, OCH3.

[0046] In one aspect of the present invention, when R 8 and R 9When independently a C1-C4 alkyl group substituted with one or more OH groups, the C1-C4 alkyl group substituted with one or more OH groups is CH2CH2OH.

[0047] In one aspect of the present invention, when R 8 R 9 When a C3-C8 cycloalkyl group is formed together with the carbon atom to which it is attached, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, such as a cyclopropyl group.

[0048] In one aspect of the present invention, when R 2 For one or more R 2-3 When the substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl is used, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl; for example, cyclohexane.

[0049] In one aspect of the present invention, when R 2 For one or more R 2-4 When replacing "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms," the phrase "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" becomes "a 3-6 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms," for example... or

[0050] In one aspect of the present invention, when R 2 For one or more R 2-5 Replacement C6-C 10 Aryl or C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl or

[0051] In one aspect of the present invention, when R 2 For one or more R 2-6 When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms"; for example, furan, thiophene, or pyridine (e.g. ).

[0052] In one aspect of the present invention, when R 2-1-1 For one or more R 2-7 When the substituted C3-C8 cycloalkyl or C3-C8 cycloalkyl is used, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl; for example, cyclohexane.

[0053] In one aspect of the present invention, when R 2-1-1 For one or more R 2-8 When replacing "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms", the "3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms" is replaced by "a 3-6 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms".

[0054] In one aspect of the present invention, when R 2-1-1 For one or more R 2-9 Replacement C6-C 10 Aryl or C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl or

[0055] In one aspect of the present invention, when R 2-1-1 When "a 5-12-membered heteroaryl group with 1-4 heteroatoms selected from one or more of N, O, and S" or "a 5-12-membered heteroaryl group with 1-4 heteroatoms selected from one or more of N, O, and S" is replaced by one or more R2-10, the "5-12-membered heteroaryl group with 1-4 heteroatoms selected from one or more of N, O, and S" is "a 5-6-membered heteroaryl group with 1-4 heteroatoms selected from one or more of N, O, and S"; for example, furan, thiophene, or pyridine (e.g. ).

[0056] In one aspect of the present invention, when R 2-3 R 2-4 R 2-5 R 2-6 R 2-7 R 2-8 R 2-9 and R 2-10 Independently for one or more R 2-13 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl, such as methyl.

[0057] In one aspect of the present invention, when R2-3 R 2-4 R 2-5 R 2-6 R 2-7 R 2-8 R 2-9 and R 2-10 Independently for one or more R 2-14 When the substituted C1-C6 alkoxy or C1-C6 alkoxy is used, the C1-C6 alkoxy is a C1-C4 alkoxy, such as a methoxy.

[0058] In one aspect of the present invention, when R 2-11 and R 2-12 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl.

[0059] In one aspect of the present invention, when R 2-2 For one or more R 2-15 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl, such as methyl.

[0060] In one aspect of the present invention, when R 1-1 and R 1-2 When independently a C1-C4 alkyl group or C1-C4 alkyl group is substituted with one or more halogens, the C1-C4 alkyl group is methyl, ethyl or isopropyl.

[0061] In one aspect of the present invention, R 5 For one or more R 5-1 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl; for example, methyl, ethyl, isopropyl or tert-butyl.

[0062] In one aspect of the present invention, R 5 For one or more R 5-2 When the substituted C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, etc. Or cyclohexyl.

[0063] In one aspect of the present invention, R 5 For one or more R 5-3When the substitution is made for "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", then the "3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" is replaced by "a 3-8 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms"; for example or

[0064] In one aspect of the present invention, when R 5 For one or more R 5-4 When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms"; for example, furan, thiophene, or pyridine (e.g. or ).

[0065] In one aspect of the present invention, when R 5 For one or more R 5-5 Replacement C6-C 10 Aryl or C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl.

[0066] In one aspect of the present invention, R 5-1 For one or more R 5-2 When the substituted C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, etc. Or cyclohexyl.

[0067] In one aspect of the present invention, R 5-1 For one or more R 5-3 When the substitution is made for "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", then the "3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" is replaced by "a 3-8 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms"; for example or

[0068] In one aspect of the present invention, when R 5-1 For one or more R 5-4 When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S, and having 1-4 heteroatoms"; for example, furan, thiophene, or pyridine (e.g. or ).

[0069] In one aspect of the present invention, when R 5-1 For one or more R 5-5 Replacement C6-C 10 Aryl or C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl.

[0070] In one aspect of the present invention, when R 5-2 R 5-3 R 5-4 and R 5-5 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl.

[0071] In one aspect of the present invention, when R 5-2-1 and R 5-2-2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl.

[0072] In one aspect of the present invention, when R 5-2-3 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl.

[0073] In one aspect of the present invention, when R 10 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl.

[0074] In one aspect of the present invention, when L 2 For one or more R 1-3 When the substituted C1-C6 alkylene or C1-C6 alkylene is used, the C1-C6 alkylene is a C1-C4 alkylene, such as methylene.

[0075] In one aspect of the present invention, when L 3When it is a C3-C8 cycloalkylene group, the C3-C8 cycloalkylene group is a C3-C6 cycloalkylene group; for example, cyclopropylene (e.g.) ).

[0076] In one aspect of the present invention, when L 3 When "a 3-12 membered heterocyclic alkylene group with heteroatoms selected from one or more of N, O, and S, and having 1-4 heteroatoms" is defined as "a 3-6 membered heterocyclic alkylene group with heteroatoms selected from one or more of N, O, and S, and having 1-2 heteroatoms", for example, a pyridine alkylene group (e.g., pyrroleyl alkylene). ).

[0077] In one aspect of the present invention, when L 4 For one or more R 1-3 When the substituted C1-C6 alkylene or C1-C6 alkylene is used, the C1-C6 alkylene is a C1-C4 alkylene; for example, methylene.

[0078] In one aspect of the present invention, when L 5 For one or more R 1-4 Replacement C6-C 10 Aryl or C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl.

[0079] In one aspect of the present invention, when L 5 For one or more R 1-5 When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms".

[0080] In one aspect of the present invention, when L 5 For one or more R 1-6 When the substituted C3-C8 cycloalkyl or C3-C8 cycloalkyl is used, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl.

[0081] In one aspect of the present invention, when L 5 For one or more R 1-7When replacing "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms", the "3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms" is replaced by "a 3-8 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms".

[0082] In one aspect of the present invention, when R 1-3 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl.

[0083] In one aspect of the present invention, when R 1-3 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group is a C1-C4 alkoxy group; for example, a methoxy group.

[0084] In one aspect of the present invention, when R 1-4 R 1-5 R 1-6 and R 1-7 Independently for one or more R 2-13 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl; for example, methyl.

[0085] In one aspect of the present invention, when R 1-4 R 1-5 R 1-6 and R 1-7 Independently for one or more R 2-14 When the substituted C1-C6 alkoxy or C1-C6 alkoxy is used, the C1-C6 alkoxy is a C1-C4 alkoxy; for example, a methoxy.

[0086] In one aspect of the present invention, when R 11 For one or more R 11-1 Replacement C6-C 10 Aryl, C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl.

[0087] In one aspect of the present invention, when R 11 For one or more R 11-2When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms".

[0088] In one aspect of the present invention, when R 11 For one or more R 11-3 When the substituted C3-C8 cycloalkyl or C3-C8 cycloalkyl is used, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl.

[0089] In one aspect of the present invention, when R 11 For one or more R 11-4 When the substitution is made for "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", then the "3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" is replaced by "a 3-8 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms"; for example

[0090] In one aspect of the present invention, when R 11 For one or more R 11-5 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl; for example, methyl.

[0091] In one aspect of the present invention, when R 11-5 For one or more R 11-1 Replacement C6-C 10 Aryl, C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl.

[0092] In one aspect of the present invention, when R 11-5 For one or more R 11-2When replacing "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" or "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms", the phrase "a 5-12-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms" is replaced by "a 5-6-membered heteroaryl group with one or more heteroatoms selected from N, O, and S and having 1-4 heteroatoms".

[0093] In one aspect of the present invention, when R 11-5 For one or more R 11-3 When the substituted C3-C8 cycloalkyl or C3-C8 cycloalkyl is used, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl.

[0094] In one aspect of the present invention, when R 11-5 For one or more R 11-4 When the substitution is made for "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms", then the "3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms" is replaced by "a 3-8 membered heterocyclic alkyl group selected from one or more of N and O, with 1-2 heteroatoms"; for example

[0095] In one aspect of the present invention, when R 11-1 R 11-2 R 11-3 and R 11-4 Independently for one or more R 2-13 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl; for example, methyl.

[0096] In one aspect of the present invention, when R 11-1 R 11-2 R 11-3 and R 11-4 Independently for one or more R 2-14 When the substituted C1-C6 alkoxy or C1-C6 alkoxy is used, the C1-C6 alkoxy is a C1-C4 alkoxy; for example, a methoxy.

[0097] In one embodiment of the present invention, W is NH.

[0098] In one aspect of the present invention, X 2 For CH.

[0099] In one aspect of the present invention, R 1It is H or C1-C6 alkyl; preferably H or methyl; more preferably H.

[0100] In one aspect of the present invention, R 4 R 6 and R 7 H stands for H independently.

[0101] In one aspect of the present invention, R 8 and R 9 Independently H or C1-C4 alkyl; or, R 8 R 9 Together with the carbon atom it is attached to, they form a C3-C8 cycloalkyl group; preferably, R 8 and R 9 Independently H or methyl, or R 8 R 9 Together with the carbon atom it is attached to, it forms a cyclopropyl group; more preferably, R 8 and R 9 Independently, it is methyl.

[0102] In one aspect of the present invention, R 2 For -CHR 2-1 R 2-2 , by one or more R 2-5 Replacement C6-C 10 aryl, with one or more R 2-3 Substituted C3-C8 cycloalkyl groups, with one or more R 2-4 The substituted "heteroatom selected from one or more of N, O, and S, and having 1-4 heteroatoms in a 3-12 membered heterocyclic alkyl group" or "heteroatom selected from one or more of N, O, and S, and having 1-4 heteroatoms in a 3-12 membered heterocyclic alkyl group"; preferably -CHR. 2-1 R 2-2 Further preferred or Carbon atoms marked with an asterisk (*) are chiral carbon atoms, and have an S configuration and / or an R configuration.

[0103] In one embodiment of the present invention, n is 0 or 1.

[0104] In one aspect of the present invention, R 2-1-1 For one or more R 2-9 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-10The substituted "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms being 1-4 of a 5-12-membered heteroaryl group" or "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms being 1-4 of a 5-12-membered heteroaryl group"; preferably phenyl, benzyl or pyridyl.

[0105] In one aspect of the present invention, R 2-3 R 2-4 R 2-5 R 2-6 R 2-7 R 2-8 R 2-9 and R 2-10 It can be halogen or hydroxyl group independently.

[0106] In one aspect of the present invention, R 2-2 For H or by one or more R 2-15 Substituted C1-C6 alkyl groups.

[0107] In one aspect of the present invention, R 2-15 It can be hydroxyl or amino on its own.

[0108] In one aspect of the present invention, R 1-1 and R 1-2 It can be methyl, ethyl, isopropyl, or chlorine on its own.

[0109] In one aspect of this invention, Z 1 It is O.

[0110] In one aspect of this invention, Z 2 Let N be the number of elements in the array.

[0111] In one aspect of this invention, Z 3 It is O.

[0112] In one aspect of the present invention, R 5 For one or more R 5-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 5-2 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, or those with one or more R 5-3 The substitutes are "3-12-membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 1-4 heteroatoms", "3-12-membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 1-4 heteroatoms", or "5-12-membered heteroaryl groups selected from one or more of N, O, and S, with 1-4 heteroatoms"; preferably methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, etc. or

[0113] In one aspect of the present invention, R 5-1 Independently for one or more R 5-3 The substitute is “a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1 to 4 heteroatoms” or “a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1 to 4 heteroatoms”.

[0114] In one aspect of the present invention, R 5-2 R 5-3 R 5-4 and R 5-5 Independent of halogen, hydroxyl, NR 5-2-1 R 5-2-2 C1-C6 alkyl or -C(=O)R 5-2-3 .

[0115] In one aspect of the present invention, L 1 It is NH.

[0116] In one aspect of the present invention, L 2 It is a covalent bond or a C1-C6 alkylene group, preferably a covalent bond or a methylene group.

[0117] In one aspect of the present invention, L 3 It is a C3-C8 cycloalkylene group or "a 3-12 membered heteroalkylene group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms"; preferably. or

[0118] In one aspect of the present invention, L 4 It is a C1-C6 alkylene group; preferably methylene.

[0119] In one aspect of the present invention, L 5 For C6-C 10 Aryl, or "a 3-12 membered heterocyclic alkyl group selected from one or more of N, O and S, with 1-4 heteroatoms"; preferably phenyl or

[0120] In one embodiment of the present invention, -C(=O)-L 1 -L 2 -L 3 -L 4 -L 5 for or

[0121] In one aspect of the present invention, R 3 for

[0122] In one aspect of the present invention, for or

[0123] In one aspect of the present invention, R 11 The heteroatom is selected from one or more of N, O, and S, and the heteroatom number is 1-4, which are 3-12 membered heterocyclic alkyl groups or C1-C6 alkyl groups; preferably methyl or

[0124] In this invention, the compound represented by Formula I can be any of the following compounds:

[0125]

[0126]

[0127]

[0128] In this invention, the compound represented by Formula II can be any of the following compounds:

[0129]

[0130] The present invention also provides a pharmaceutical composition comprising the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0131] The present invention also provides the use of the compounds shown in Formula I above, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the preparation of medicaments. Preferably, the medicaments are used for the prevention and / or treatment of HPK1-mediated diseases, including but not limited to non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, head and neck cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, liver cancer, colon cancer, rectal cancer, choriocarcinoma of the colon, breast cancer, ductal carcinoma of the breast, ovarian cancer, peritoneal cancer, endometrial cancer, uterine cancer, cervical cancer, kidney cancer, renal pelvis cancer, prostate cancer, bladder cancer, neurofibromatosis, bone cancer, brain cancer, testicular cancer, glioma, skin cancer, melanoma, sarcoma and cytokine, multiple myeloma, leukemia, non-Hodgkin's lymphoma, and myelodysplastic syndrome.

[0132] Unless otherwise specified, the terms used in this invention have the following meanings:

[0133] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0134] In this document, terms may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the bond order between the named substituent and the parent moiety; a single dash indicates a single bond, and a double dash indicates a double bond. In the absence of a single or double dash, a single bond is assumed to form between the substituent and its parent moiety. Furthermore, substituents are read "from left to right" unless otherwise indicated. For example, Indicates the left side and L 2 Connected, right side with L 4 Connected.

[0135] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0136] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0137] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0138] 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 a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, including but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentian acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0139] The terms “compound” and “pharmaceutically acceptable salt” may exist in the form of a single tautomer or a mixture thereof, preferably in the form of the more stable tautomer.

[0140] The atoms in the terms "compound" and "pharmaceutically acceptable salt" can exist in either their natural abundance or non-natural abundance form. For example, the hydrogen atom in its natural abundance form is approximately 99.985% protium and approximately 0.015% deuterium; in its non-natural abundance form, it is approximately 95% deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt" can be atoms existing in a non-natural abundance form.

[0141] The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.

[0142] 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.

[0143] The term "alkylene" refers to a subunit of a saturated straight-chain or branched alkane formed by the formal removal of two monovalent or one divalent atom or group. The two valences can be on the same carbon atom or on different carbon atoms (e.g., on the carbon atoms at opposite ends). For example, methylene can be (-CH2-), and ethylene can be -CH2CH2- or -CH(CH3)-.

[0144] The term "alkoxy group" refers to the group -OR X , where R X It is an alkyl group as defined above.

[0145] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic substituent consisting only of carbon and hydrogen atoms, which can be linked to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it can be a bridged ring system or a spirocyclic system with fused or spirocyclic linkages (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene groups). The cycloalkyl substituent can be linked to the central molecule via any suitable carbon atom. In some embodiments, a ring having 3-8 carbon atoms can be represented as a C3-C8 cycloalkyl. In some embodiments, C3-C6 cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), bicyclo[1.1.1]pentane (C5), and cyclohexyl (C6).

[0146] The term "cycloalkylene" refers to a saturated monocyclic or polycyclic cycloalkanes composed of carbon and hydrogen atoms, formed by the formal elimination of a subunit consisting of two monovalent or one divalent atom or group; when polycyclic, it can be a bridged ring system or a spirocyclic system (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene groups). The two valences can be on the same carbon atom or on different carbon atoms. For example, cyclopropylene can be... or

[0147] The term "heterocyclic alkyl" refers to a stable, saturated monocyclic or polycyclic cyclic group consisting of 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; when polycyclic, it can be a bridged ring system or a spirocyclic system with fused or spirocyclic linkages. Exemplary 3-membered heterocyclic groups include, but are not limited to, azirropropyl, ethylene oxide, and thiocyclopropane, or their stereoisomers; exemplary 4-membered heterocyclic groups include, but are not limited to, azirrobutyl, propylene oxide, thiocyclobutyl, or their isomers and stereoisomers; exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, dioxopentyl, oxathiofuranyl, dithiofuranyl, or their isomers and stereoisomers. Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfide cyclopentyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxyl, piperazine, triazinealkyl, or their isomers and stereoisomers; Exemplary 7-membered heterocyclic groups include, but are not limited to, azirheptanyl, oxeheptanyl, thioheptanyl, and diazirheptanyl, or their isomers and stereoisomers.

[0148] The term "heterocyclic alkylene" refers to a stable, 3- to 12-membered saturated monocyclic or polycyclic heterocycle composed of 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, formed by formally eliminating two monovalent or one divalent atom or group; when polycyclic, it can be a bridged ring system or a spirocyclic system with fused or spirocyclic linkages. The two valences can be on the same atom or on different atoms. For example, pyrrolidine can be... or

[0149] The term "aryl" refers to an aromatic monocyclic or polycyclic aromatic compound having 6-10 ring atoms and zero heteroatoms. When it is bicyclic, at least one ring is aromatic. Examples include phenyl, naphthyl, or...

[0150] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing one, two, or three independent aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings selected independently from nitrogen, oxygen, and sulfur. When it is a bicyclic ring, at least one ring is aromatic, such as furanyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, isozolyl, oxazolyl, diazolyl, imidazole, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, inzolyl, benzothiazolyl, benziisothiazolyl, benzozolyl, benziisozolyl, quinolinyl, isoquinolinyl, etc.

[0151] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0152] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0153] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0154] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0155] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0156] 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.

[0157] The reagents and raw materials used in this invention are all commercially available.

[0158] The positive and progressive effects of this invention are as follows: This invention provides a novel HPK1 inhibitor with better activity. Detailed Implementation

[0159] 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.

[0160] Example 1: Synthesis of Compound I-1

[0161]

[0162] Compounds SM1 (100.00 mg, 0.21 mmol, 1.00 equiv), SM2 (200 mg, 1.18 mmol, 5.6 equiv), and 400 mg of 4A molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 30 minutes. Sodium ethoxide (57 mg, 0.84 mmol, 4 equiv) was then added. The reaction mixture was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature, concentrated, and the crude product was purified by thin-layer chromatography using dichloromethane / methanol as the eluent. The obtained product was further purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD Column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: MeOH Preparative; Flow rate: 25mL / min; Gradient: 70% B to 95% B in 8min, 95% B; Wavelength: 254 / 220nm; RT1 (min): 7.32) to obtain a white solid compound I-1 (10.4mg). MS (ESI): m / z = 580; 1H NMR (400MHz, CD3OD-d4): δ8.71(s,1H),7.73(t,J=1.8Hz,1H),7.55(dt,J=8.4,0.7Hz,1H),7.48–7.36(m,3H),7.36–7.28( m,1H),7.19(dt,J=8.3,1.7Hz,1H),5.99(d,J=2.3Hz,1H),4.77–4.60(m,1H),3.99(ddd,J=11.0,4.2,2.4Hz,1H),3.81(dt, J=11.1,6.9Hz,1H),3.53–3.43(m,2H),3.40–3.35(m,1H),3.09(d,J=11.8Hz,1H),3.06–2.94(m,5H),2.95–2.86(m,1H),2 .35–2.23(m,1H),1.87(tdd,J=17.9,8.7,3.9Hz,3H),1.60(d,J=12.2Hz,1H),1.49(d,J=7.7Hz,6H),1.31(t,J=5.9Hz,1H).

[0163] Example 2 Synthesis of Compound I-2

[0164]

[0165] Compounds SM1 (100 mg, 0.33 mmol, 1.00 equiv), SM2 (60 mg, 0.33 mmol, 1.00 equiv), XantPhos (20 mg, 0.033 mmol, 0.1 equiv), Pd2(dba)3 (31 mg, 0.033 mmol, 0.1 equiv), and potassium phosphate (208 mg, 0.98 mmol, 3.0 equiv) were placed in a reaction flask, and 1,4-dioxane (5 mL) was added. The reaction mixture was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered through diatomaceous earth, and the crude product after concentration was purified by silica gel column chromatography to give compound 1 (40 mg, yield 29.2%) as a yellow solid. MS (ESI): m / z = 462.

[0166] Compound 1 (40 mg, 0.09 mmol, 1.0 equiv), SM3 (48 mg, 0.45 mmol, 5.0 equiv), and 100 mg of [unclear text - possibly a drug or treatment] were administered. Molecular sieves were placed in a reaction flask, and anhydrous ethanol (2 mL) was added. The flask was then purged with nitrogen, and the mixture was stirred at room temperature for 30 minutes. Sodium ethoxide (24.5 mg, 0.36 mmol, 4.0 equiv) was added, and the reaction mixture was stirred overnight at 90 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. This crude product was then subjected to high-pressure chromatography (Column: XBridge Shield RP18OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 62% B in 8 min, 62% B; Wavelength: 254 nm, 220 nm) to obtain a white solid compound I-2 (5.9 mg, yield 12.5%). MS (ESI): m / z = 526.

[0167] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.86(d,J=7.2Hz,1H),8.66(s,1H),7.86(d,J=8.5Hz,1H) ,7.52–7.43(m,2H),7.38-7.33(m,4H),7.28-7.25(m,1H),5.20(t,J=4.9Hz,1H),4.73(q,J=4.7H z,1H),3.93(dt,J=9.5,4.4Hz,1H),3.75(dt,J=10.5,5.1Hz,1H),2.92(s,3H),1.51(s,3H),1.4 5(s,3H),1.35(dd,J=9.3,3.4Hz,1H),1.27(d,J=3.1Hz,1H),1.24(s,3H),0.98(d,J=3.2Hz,2H).

[0168] Example 3 Synthesis of Compound I-3

[0169]

[0170] Compound 1 (100 mg, 0.223 mmol, 1.00 eq), compound SM1 (76.81 mg, 0.436 mmol, 1.95 equiv), and DIEA (112.64 mg, 0.872 mmol, 3.90 equiv) were dissolved in anhydrous DMF (2 mL). HATU (123.20 mg, 0.324 mmol, 1.45 equiv) was added to the reaction solution under ice bath conditions. The reaction solution was then transferred to room temperature and stirred overnight under nitrogen protection. After filtration, the reaction solution was purified by high-pressure purification (Column: YMC-Actus Triart C18, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 65% B in… The compound I-3 (51.4 mg) was obtained as a white solid. The reaction was carried out for 8 min at 65% B; wavelength: 254 / 220 nm; RT1 (min): 6.85. MS (ESI): m / z = 606. 1 H NMR (400MHz, CD3OD-d4): δ8.48(s,1H),7.79(s,1H),7.68–7.55(m,2H),7.53–7.30(m,8H) ,7.31–7.23(m,2H),5.40–5.34(m,1H),4.51-4.44(m,1H),3.97–3.89(m,1H),3.87(ddd,J= 11.1,6.4,1.3Hz,1H),3.77–3.62(m,2H),3.04(s,3H),2.96–2.89(m,1H),2.83(d,J=8.8H z,1H),2.68–2.55(m,2H),2.46-2.37(m,1H),1.85-1.80(m,1H),1.37(s,3H),1.35(s,3H).

[0171] Example 4 Synthesis of Compound I-4

[0172]

[0173] Compound SM1 (59.34 mg, 0.349 mmol, 1.95 equiv), compound 1 (80 mg, 0.179 mmol, 1.00 equiv), N,N-diisopropylethylamine (69.27 mg, 0.537 mmol, 3.90 equiv), and HATU (98.6 mg, 0.26 mmol, 1.45 equiv) were dissolved in DMF (2 mL). The reaction system was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and purified by high-pressure pre-treatment (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 31% B to 51% B in 8min, 51% B; Wavelength: 254; 220nm) to give a white solid compound I-4 (6.7mg). MS (ESI): m / z = 600. 1 H NMR (400MHz, CD3OD-d4): δ8.37(s,1H),7.69(s,1H),7.48-7.53(m,2H),7.25-7.32(m ,4H),7.15-7.18(m,1H),5.28(dd,J=6.0Hz,1.2Hz,1H),3.82-3.86(m,1H),3.74-3.78 (m,2H),3.62(t,J=4.8Hz,4H),3.32(d,J=4.8Jz,2H),2.92(s,3H),2.45-2.49(m,3H) ,2.30(s,2H),1.38(s,3H),1.36(s,3H),0.53(t,J=4.8Hz,2H),0.32(t,J=4.8Hz,2H).

[0174] Example 5: Synthesis of Compound I-5

[0175]

[0176] Compound 1 (100 mg, 0.210 mmol, 1.00 eq) and compound SM1 (77.95 mg, 1.050 mmol, 5.00 equiv), along with sodium ethoxide (100.00 mg), were dissolved in anhydrous ethanol (2 mL). The reaction mixture was stirred at room temperature for 20 minutes under nitrogen protection. The anhydrous ethanol solution of sodium ethoxide was then added to the reaction mixture, and the mixture was stirred overnight at 70 °C. After filtration, the reaction mixture was purified by high pressure and freeze-dried to obtain a white solid compound I-5 (13.4 mg). MS (ESI): m / z = 486; 1H NMR (400MHz, CD3OD-d4): δ8.78(s,1H),7.80(s,1H),7.69–7.61(m,2H),7.47–7.38(m,4H),7.30(t,J=7.1Hz,1H),5.76–5.29( m,1H),4.04(dd,J=11.3,4.4Hz,1H),3.95(dd,J=11.3,6.1Hz,1H),3.05(s,3H),2.49(d,J=0.7Hz,3H),1.49(d,J=9.3Hz,6H).

[0177] Example 6 Synthesis of Compound I-6

[0178]

[0179] Compound 1 (100.00 mg, 0.210 mmol), compound SM1 (167.37 mg, 1.050 mmol), and 4A molecular sieve (300.00 mg) were mixed and stirred in 3 mL of anhydrous ethanol at room temperature for 20 minutes under nitrogen protection. Sodium ethoxide (57.24 mg, 0.841 mmol) was then added, and the reaction mixture was stirred overnight at 90 °C. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography to obtain a crude product. Further purification was performed by high pressure chromatography, followed by freeze-drying to obtain a white solid compound I-6 (18.2 mg). MS (ESI): m / z = 571; 1 H NMR (400MHz, CD3OD-d4): δ8.68(s,1H),7.71(s,1H),7.50-7.56(m,2H),7.27-7.36(m,4H),7.16-7.20(m,1H),5.39(t,J=5.2 Hz,1H),3.83-3.95(m,2H),3.74(s,2H),3.63(t,J=4.8Hz,4H),2.93(s,3H),2.61(t,J=4.8Hz,4H),1.38(s,3H),1.36(s,3H).

[0180] Example 7 Synthesis of Compound I-7

[0181]

[0182] Compound 1 (100 mg, 0.36 mmol, 1.00 equiv), SM1 (60 mg, 0.36 mmol, 1.0 equiv), XantPhos (21 mg, 0.036 mmol, 0.1 equiv), Pd2(dba)3 (33 mg, 0.036 mmol, 0.1 equiv), and potassium phosphate (230 mg, 1.08 mmol, 3.0 equiv) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction system was cooled to room temperature, filtered through diatomaceous earth, and the crude product obtained by concentration was purified by silica gel column chromatography to give compound 2 (44 mg, yield 29.3%) as a yellow solid. MS (ESI): m / z = 433.

[0183] Compound 2 (44 mg, 0.102 mmol, 1.0 equiv), SM2 (86.3 mg, 0.51 mmol, 5.0 equiv), and 100 mg of 4A molecular sieve were placed in a sealed tube, and anhydrous ethanol (2 mL) was added to replace the nitrogen gas. The mixture was stirred at room temperature for 30 minutes. Then, sodium ethoxide (27.77 mg, 0.408 mmol, 4.00 equiv) was added to the sealed tube, and the nitrogen gas was replaced. The reaction flask was then placed at 90 °C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature, filtered through diatomaceous earth, and the crude product obtained by concentration of the filtrate was subjected to high pressure chromatography (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 22% B to 52% B in 8min, 52% B; Wavelength: 254 nm, 220nm) to obtain a white solid compound I-7 (2.4mg, 4.3%). MS (ESI): m / z = 552. 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.79–8.57(m,2H),8.54–8.35(m,2H),7.89(d,J=8.5Hz,1H),7.76(d,J=6.2Hz ,2H),7.52–7.31(m,2H),4.75(d,J=5.8Hz,2H),2.91(d,J=10.3Hz,9H),1.84(t,J=7.8Hz,6H),1.23(d,J=6.5Hz,6H).

[0184] Example 8 Synthesis of Compound I-8

[0185]

[0186] Under nitrogen protection, 5-bromo-2,3-dihydroisoindol-1-one SM1 (6 g, 28.3 mmol, 1.00 equiv) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and N,N-dimethylformamide (40 mL). A solution of sodium hydride (1.36 g, 56.59 mmol, 2.00 equiv) and tetrabutylammonium iodide (1.05 g, 28.3 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and then 4-methoxybenzyl chloride (4.43 g, 28.3 mmol, 1.00 equiv) was added. Stirring was continued at room temperature for another 12 hours. After the reaction was completed, the reaction solution was quenched with 100 mL of ice water, extracted with ethyl acetate (2 x 300 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to give 14.5 g of brown solid compound (yield 47.87%). MS (ESI): m / z = 333.

[0187] Under nitrogen atmosphere, sodium hydride (541.80 mg, 0.024 mmol, 3.00 equiv) was added in portions to a tetrahydrofuran / N,N-dimethylformamide (20 / 60 mL) mixed solvent of compound 1 (2.50 g, 7.526 mmol, 1.00 equiv). The reaction mixture was stirred at room temperature for 2 hours. Then, iodomethane (1.07 g, 75.3 mmol, 10.00 equiv) was added, and the reaction mixture was heated to 70 °C and stirred for 16 hours. The mixture was then cooled, quenched with 100 mL of ice water, and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to give compound 2 1.4 g, MS (ESI): m / z = 361.

[0188] In a 40 mL sealed tube, compound 2 (1.4 g, 3.886 mmol, 1.00 equiv), tert-butyl carbamate (2.28 g, 19.43 mmol, 5 equiv), cesium carbonate (3.8 g, 11.7 mmol, 3 equiv), palladium acetate (90 mg, 0.38 mmol, 0.1 equiv), and XantPhos (220 mg, 0.76 mmol, 0.2 equiv) were dissolved in 1,4-dioxane (20.00 mL). The reaction mixture was stirred at 100 °C under nitrogen protection for 18 hours, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 3 (1.1 g), MS (ESI): m / z = 397.

[0189] In a 20 mL reaction flask, a 5 mL solution of cerium ammonium nitrate (2.00 g, 3.635 mmol, 2.88 equiv) in water, compound 3 (0.50 g, 1.261 mmol, 1.00 equiv), and acetonitrile (10 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and extracted with ethyl acetate (2 x 20 mL). The combined organic phases were evaporated by rotation and purified by column chromatography to give 4100 mg of a yellow solid compound (yield 28.70%), MS (ESI): m / z = 277.

[0190] In a 100 mL reaction flask, compound 4 (260 mg, 0.94 mmol) was dissolved in 20.00 mL of ethyl acetate solution of hydrogen chloride. The reaction mixture was stirred for 12 hours under nitrogen protection at room temperature and evaporated to dryness to give 5200 mg of a yellow solid compound. MS (ESI): m / z = 177.

[0191] In a 20 mL sealed tube, compound SM2 (150.00 mg, 0.489 mmol, 1.00 equiv), compound 5 (200 mg), Pd2(dba)3 (44.78 mg, 0.05 mmol, 0.10 equiv), XantPhos (28.29 mg, 0.05 mmol, 0.10 equiv), and potassium phosphate (311.39 mg, 1.47 mmol, 3.00 equiv) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction system was concentrated and purified by column chromatography to give 6150 mg of a brown solid compound. MS (ESI): m / z = 447.

[0192] In a 20 mL reaction flask, compound 6 (150 mg, 0.336 mmol), SM3 (300 mg), 4A molecular sieve (500 mg), and anhydrous ethanol (3 mL) were stirred for 1 hour. Sodium ethoxide (160 mg) was then added, and the reaction mixture was stirred at 85 °C for 16 hours. The reaction solution was concentrated, and the crude product was purified by high-pressure reverse-phase chromatography (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40B to 62B in 10 min, 62B to B in min, B to B in min, B to B in min, B to B in min; 254 / 220 nm) to obtain a white solid compound I-8 (5.3 mg). MS (ESI): m / z = 566. 1H NMR (300MHz, CD3OD-d4): δ (ppm) 8.69 (s, 1H), 7.67 (d, J = 1.8Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 7 .27–7.48(m,5H),7.04–7.23(m,1H),5.98(d,J=1.7Hz,1H),4.69(d,J=6.1Hz,1H),3.91–4.04 (m,1H),3.80(dt,J=11.3,6.0Hz,1H),3.46(d,J=5.5Hz,1H),3.09(s,1H),2.96(q,J=15.3,11 .6Hz,3H),2.27(s,1H),1.85(d,J=18.2Hz,3H),1.52(d,J=5.6Hz,7H),1.30(d,J=3.1Hz,2H).

[0193] Example 9: Synthesis of Compound I-9

[0194]

[0195] Lithium hydroxide (28.02 mg, 1.170 mmol, 2.00 equiv) was added to a mixed solution of compound 1 (270.00 mg, 0.585 mmol, 1.00 equiv) in tetrahydrofuran (6 mL) and water (3 mL), and stirred at room temperature for two hours. After the reaction was complete, the pH of the reaction system was adjusted to 6 with 2 mol / L hydrochloric acid solution, and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to give crude compound 2 (80 mg) as a white solid. MS (ESI): m / z = 434.

[0196] Compound 2 (80.00 mg, 0.185 mmol, 1.00 equiv), compound SM1 (63.43 mg, 0.360 mmol, 1.95 equiv), N,N-diisopropylethylamine (93.03 mg, 0.720 mmol, 3.90 equiv) and HATU (101.75 mg, 0.268 mmol, 1.45 equiv) were dissolved in DMF (2 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction system was filtered and then purified by high-pressure pre-treatment (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 35% B to 47% B in 8min, 47% B; Wavelength: 254; 220nm), yielding a white solid compound I-9 (3.4mg). MS (ESI): m / z = 592; 1 H NMR (400MHz, DMSO-d6): δ9.84(s,1H),9.70-9.74(m,1H),8.64(s,1H),8.50–8.15(m,1H),7 .89(s,1H),7.63–7.48(m,1H),7.47–7.22(m,10H),5.29(p,J=4.9Hz,1H),5.11(q,J=3.3,2. 1Hz,1H),4.38(s,1H),3.87–3.69(m,3H),3.60(s,3H),2.82(t,J=8.4Hz,1H),2.70–2.58(m, 2H),2.28(d,J=7.3Hz,1H),2.21–2.07(m,1H),1.86–1.72(m,1H),1.40(s,3H),1.36(s,3H).

[0197] Example 10 Synthesis of Compound I-10

[0198]

[0199] Compound 1 (40.0 mg, 0.092 mmol, 1.00 equiv), compound SM1 (43.6 mg, 0.256 mmol, 1.95 equiv), N,N-diisopropylethylamine (46.3 mg, 0.359 mmol, 3.90 equiv), and HATU (51.5 mg, 0.136 mmol, 1.45 equiv) were dissolved in DMF (2 mL), and the reaction solution was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction system was purified by high-pressure preparative purification (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 28% B to 48% B in 8min, 48% B; Wavelength: 254 nm, 220 nm); to obtain a white solid compound I-10 (4.6mg). MS (ESI): m / z = 586; 1 H NMR (400MHz, DMSO-d6): δ9.92(s,1H),9.68(s,1H),8.58(s,1H),8.39(s 1H),7.85(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.39-7.42(m,5H),7.26(s,1H),5.28(s,1H),5.11(s,1H),3.90-3.95(m,1H),3.56- 3.59(m,5H),3.51-3.55(m,5H),3.05-3.11(m,1H),2.31-2.33(m,2H),1.52-1.55(m,1H),1.38(s,3H),1.35(s,3H),0.83-0.85(m,3H).

[0200] Example 11 Synthesis of Compound I-11

[0201]

[0202] Compound 1 (100.00 mg, 0.217 mmol, 1.00 equiv) and SM1 (65 mg, 0.878 mmol, 4.0 equiv) were added to a 20 mL sealed tube and dissolved in 6 mL of anhydrous ethanol. 400 mg of 4A molecular sieve was added, and the tube was purged with nitrogen and then sealed. After stirring at room temperature for half an hour, sodium ethoxide (74 mg, 1.083 mmol, 5.00 equiv) was added, and the tube was incubated at 90 °C for two hours. After the reaction was complete, a layer of diatomaceous earth was placed in a sand core funnel, filtered, and the filtrate was collected and evaporated to dryness. The crude product was purified by high pressure (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 26% B to 46% B in 8min, 46% B; Wavelength: 254 nm, 220nm) to obtain 12.7mg (98.5%) of white solid. MS (ESI): m / z = 472. 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),9.00(d,J=7.6Hz,1H),8.79(s,1H),8.45(s,1H),7.85(s,1H),7.62(d,J=8.0Hz,1H) ,7.46-7.31(m,5H),7.28–7.25(m,1H),5.42(s,1H),5.23(s,1H),3.92–3.78(m,2H),2.45(s,3H),1.40(s,3H),1.36(s,3H).

[0203] Example 12 Synthesis of Compound I-12

[0204]

[0205] Compound 1 (150 mg, 0.325 mmol, 1.00 equiv) and SM1 (206.95 mg, 1.3 mmol, 4.00 equiv) were added to a 20 mL sealed tube and dissolved in 6 mL of anhydrous ethanol. 400 mg of 4A molecular sieve was added, and the tube was purged with nitrogen and then sealed. After stirring at room temperature for half an hour, sodium ethoxide (110.6 mg, 1.625 mmol, 5.00 equiv) was added, and the tube was incubated at 90 °C for two hours. After the reaction was complete, a layer of diatomaceous earth was placed in a sand core funnel, filtered, and the filtrate was collected and evaporated to dryness. The crude product was purified by high pressure (Column: X Bridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30% B to 40% B in 8min, 40% B; Wavelength: 254 nm, 220nm) to obtain 10mg (98.9%) of white solid. MS (ESI): m / z = 557. 1 H NMR (400MHz, DMSO-d6): δ10.21(s,1H),9.05(d,J=7.9Hz,1H),8.81(s,1H),8.47(s ,1H),7.91(s,1H),7.63(d,J=8.0Hz,1H),7.49-7.35(m,4H),7.30-7.26(m,2H),5.4 3(dt,J=8.8,4.8Hz,1H),5.20(d,J=4.8Hz,1H),3.91(dt,J=9.4,4.4Hz,1H),3.87–3 .72(m,3H),3.59(t,J=4.5Hz,4H),2.61(t,J=4.6Hz,4H),1.42(s,3H),1.39(s,3H).

[0206] Example 13 Synthesis of Compound I-13

[0207]

[0208] Compound 1 (100 mg, 0.239 mmol), compound SM1 (202.2 mg, 1.195 mmol), and 400 mg of 4A molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The mixture was stirred at room temperature for 30 minutes under nitrogen protection. Then, sodium ethoxide (65.05 mg, 0.956 mmol) was added to the reaction flask, purging the nitrogen atmosphere, and the reaction mixture was stirred overnight at 90 °C. After cooling the reaction mixture to room temperature, the crude product was purified by column chromatography using dichloromethane / methanol eluent. The crude product was further purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15% B to 40% B in 8min, 40% B) to give a white solid compound I-13 (1mg). MS (ESI): m / z = 538; 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),8.70(s,1H),8.63(s,1H),8.51-8.52(m,1H),8.46-8.48(m,2H),7.84(d,J=8.0Hz ,1H),7.75-7.77(m,2H),7.47-7.48(m,1H),7.40-7.41(m,1H),4.73(d,J=5.2Hz,2H),2.86(t,J=8.0Hz,6H),1.80-1.82(m 6H),1.25(s,6H).

[0209] Example 14 Synthesis of Compound I-14

[0210]

[0211] Compound 1 (73.00 mg, 0.163 mmol), compound SM1 (93.1 mg, 0.815 mmol), and 300 mg of 4A molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The reaction mixture was stirred at room temperature under nitrogen protection for 30 minutes, and then sodium ethoxide (44.4 mg, 0.652 mmol) was added. The reaction was stirred overnight at 90 °C. After cooling the reaction system to room temperature, the crude product was purified by column chromatography with dichloromethane / methanol. The crude product was further purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBDC18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 60% B in 8 min, 60% B) to obtain a white solid compound I-14 (4.1 mg). MS(ESI): m / z = 512; 1 H NMR (400MHz, DMSO-d6): δ10.28(s,1H),8.83-8.84(d,J=7.2Hz,1H),8.66(s,1H),8.48(s ,1H),7.82(d,J=8.4Hz,1H),7.48-7.50(m,1H),7.37(s,1H),7.34-7.35(m,4H),7.26-7. 28(m,1H),5.18(t,J=4.8Hz,1H),4.71(d,J=6.8Hz,1H),3.90-3.94(m,1H),3.72-3.77(m ,1H),1.52(s,3H),1.45(s,3H),1.33-1.35(m,1H),1.24-1.26(m,4H),0.97-1.00(m,2H).

[0212] Example 15 Synthesis of Compound I-15

[0213]

[0214] Compound 1 (100.00 mg, 0.217 mmol, 1.00 equiv) and SM1 (146.67 mg, 0.867 mmol, 4.0 equiv) were added to a 20 mL sealed tube and dissolved in 6 mL of anhydrous ethanol. 400 mg of 4A molecular sieve was added, nitrogen was purged, and the tube was sealed. After stirring at room temperature for half an hour, sodium ethoxide (73.72 mg, 1.083 mmol, 5.00 equiv) was added, and the tube was incubated at 90 °C for two hours. After the reaction was complete, a layer of diatomaceous earth was placed in a sand core funnel, filtered, and the filtrate was collected and evaporated to dryness. The crude product was purified by high pressure (Column: X Bridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30% B to 50% B in 8min, 50% B; Wavelength: 254 nm, 220nm) to obtain 25.7mg (92.3%) of white solid. MS (ESI): m / z = 567. 1 H NMR (400MHz, DMSO-d6): δ10.19(s,1H),9.29(d,J=7.7Hz,1H),8.76(s,1H),8 .45(s,1H),7.92(s,1H),7.62(d,J=8.4Hz,1H),7.54–7.32(m,5H),7.28(t,J =7.0Hz,1H),5.37(dt,J=8.4,4.7Hz,1H),5.23(s,1H),4.01–3.77(m,2H),2. 91(t,J=7.6Hz,6H),1.85(dd,J=10.3,5.8Hz,6H),1.40(s,3H),1.36(s,3H).

[0215] Example 16 Synthesis of Compound I-16

[0216]

[0217] Compound 1 (300 mg, 0.651 mmol, 1.00 equiv) and SM1 (792.0 mg, 3.25 mmol, 5.00 equiv) were added to a 20 mL sealed tube and dissolved in 10 mL of anhydrous ethanol. 1.5 g of 4A molecular sieve was added, and the tube was purged with nitrogen and then sealed. After stirring at room temperature for half an hour, sodium ethoxide (178.5 mg, 2.604 mmol, 4.00 equiv) was added, and the mixture was reacted at 90 °C for two hours. After the reaction was complete, the reaction system was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was evaporated to dryness. Thin-layer chromatography (dichloromethane:methanol = 3:1) was used to obtain a white solid compound 2 (212 mg, 51.0%). MS (ESI): m / z = 640.

[0218] Compound 2 (200 mg, 0.313 mmol, 1.00 equiv) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2 mL) was added to the reaction mixture at room temperature under nitrogen protection. After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure at low temperature. The crude product was purified by high-pressure purification (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 7 min, 40% B; Wavelength: 220 nm) to obtain a yellow solid compound I-16 (110.4 mg, yield 65.3%). MS (ESI): m / z = 540. 1 H NMR (400MHz, DMSO-d6): δ9.52(s,1H),8.83(d,J=5.7Hz,1H),8.66(s,1H),8.39(s,1H),7.68(d,J=1.8H z,1H),7.46(dd,J=8.3,1.8Hz,1H),7.41(d,J=8.3Hz,1H),7.36(d,J=4.6Hz,5H),7.28(q,J=5.1,4.5Hz, 1H),5.92(s,1H),4.62(d,J=5.6Hz,1H),3.89(d,J=8.0Hz,1H),3.71(d,J=7.9Hz,2H),3.34-3.31(m,1H) ,3.24-2.95(m,3H),2.36-2.34(m,1H),2.17-2.15(m,2H),2.06-2.04(m,2H),1.40(s,3H),1.39(s,3H).

[0219] Example 17 Synthesis of Compound I-17

[0220]

[0221] Compound 1 (300 mg, 0.65 mmol, 1 equiv) and SM1 (170 mg, 1.08 mmol, 1.6 equiv) were added to a 20 mL sealed tube and dissolved in 8 mL of anhydrous ethanol. 1.5 g of 4A molecular sieve was added, and the tube was purged with nitrogen before sealing. After stirring at room temperature for half an hour, sodium ethoxide (200 mg, 5 equiv) was added to the reaction system. The reaction was then carried out at 90 °C for 12 hours. After the reaction was completed, a layer of diatomaceous earth was spread in a sand core funnel, filtered, the filtrate was collected, evaporated to dryness, and the crude product was prepared by high pressure (Column: XBridgePrep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 25%B to 40%B in 8min, 40%B; Wavelength: 220nm) to obtain a white solid product (21.2mg, 92.2%).

[0222] MS(ESI): m / z = 554. 1 H NMR (400MHz, CD3OD-d4): δ10.26 (s, 1H), 9.54 (d, J = 6.4Hz, 1H), 9.46 (s, 1H) ),9.16(s,1H),8.51(s,1H),8.26-8.10(m,6H),6.77(s,1H),6.02(s,1H),5 .44-5.43(m,1H),4.67-4.64(m,1H),4.51-4.43(m,1H),3.66-3.61(m,3H) ,3.01(s,3H),2.89-2.82(m,4H),2.67-2.64(m,2H),2.21(d,J=5.1Hz,6H).

[0223] Example 18 Synthesis of Compound I-18

[0224]

[0225] Compounds 1 (240 mg, 0.519 mmol, 1.00 equiv), 2 (631 mg, 2.595 mmol, 5.00 equiv), and 300 mg were administered. Molecular sieves were placed in a reaction flask, and ethanol (3 mL) was added. The flask was then purged with nitrogen, and the mixture was stirred at room temperature for 30 minutes. Sodium ethoxide (178.5 mg, 2.604 mmol, 4.00 equiv) was then added, and the nitrogen was purged again. The reaction flask was placed at 90 °C for 16 h. After the reaction was complete, the reaction system was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was evaporated to dryness. Thin-layer chromatography (dichloromethane:methanol = 3:1) was used to obtain a white solid compound 3 (210 mg, 63.1%). (ESI), [M+H) + =641.

[0226] Compound 3 (200.00 mg, 0.312 mmol, 1.00 equiv) was dissolved in dichloromethane (4 mL), and nitrogen was purged at room temperature. Trifluoroacetic acid (2 mL) was added and the reaction proceeded for 30 minutes. The reaction mixture was then concentrated to obtain a crude product (110.4 mg). This crude product was then prepared under high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 35% B in 9 min, 35% B; Wavelength: 220 nm) to obtain a yellow solid (28.5 mg, 16.9%). (ESI), [M+H) + =541; 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.12(d,J=7.6Hz,1H),8.81(s,1H),8.46(s,1H),7.86 (s,1H),7.63(d,J=8.6Hz,1H),7.46(d,J=8.3Hz,1H),7.45–7.34(m,4H),7.28(t,J=7.0Hz,1H ),5.40(d,J=7.2Hz,1H),5.24(s,1H),3.93(dd,J=10.7,4.3Hz,1H),3.83(dd,J=10.9,5.2Hz ,1H),3.11(t,J=12.0Hz,2H),2.24(d,J=13.6Hz,2H),1.97(s,3H),1.40(s,3H),1.36(s,3H).

[0227] Example 19 Synthesis of Compound I-19

[0228]

[0229] Compound 1 (400 mg, 8.05 mmol) and hydroxylamine aqueous solution (2.66 g, 80.520 mmol) were placed in a reaction flask, and anhydrous ethanol (10.0 mL) was added. The reaction flask was purged with nitrogen, and the flask was placed at 90 °C and reacted overnight. After the reaction was completed, the reaction system was cooled to room temperature, washed once with water, and extracted with isopropanol / chloroform (1:1) (5 x 10 mL). The crude product was evaporated to dryness at low temperature to give compound 2 (1.1 g, 79.16%) as a white solid. MS (ESI): m / z = 158.

[0230] Compound 2 (408 mg, 2.600 mmol), substrate SM2 (400 mg, 0.867 mmol), and 800 mg of molecular sieve were placed in a reaction flask, and anhydrous ethanol (10 mL) was added. The reaction flask was then purged with nitrogen. The mixture was stirred at room temperature for 30 minutes. Then, sodium ethoxide (235.92 mg, 3.467 mmol) was added to the reaction flask, and the nitrogen was purged again. The reaction was then incubated at 90 °C overnight. After cooling the reaction system to room temperature, the crude product was obtained by CH2Cl2 / MeOH 10:1 platelet analysis. The crude product was subjected to Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 38% B to 52% B in 7min, 52% B) to give a white solid compound (16.8mg, 3.48%). MS (ESI): m / z = 555; 1 H NMR (400MHz, DMSO-d6): δ9.32–9.30(d,1H),8.78(s,1H),7.71–7.66(m,1H),7.65 –7.64(m,1H),7.60–7.58(m,1H),7.47–7.38(m,4H),7.31–7.28(m,1H),5.47(s,1H ),4.08–4.04(m,1H),3.99–3.95(m,1H),3.24(s,1H),3.10(s,1H),2.78(s,1H),2 .56–2.53(m,3H),2.28–2.26(m,2H),2.16–2.13(m,2H),1.53(s,3H),1.50(s,3H).

[0231] Example 20 Synthesis of Compound I-20

[0232]

[0233] Compound 1 (1 g, 1 equiv) was dissolved in anhydrous ethanol (10 mL). Under nitrogen protection, a 50% aqueous solution of hydroxylamine (4.34 g, 10 equiv) was added to the reaction system, and the mixture was stirred at 90 °C for 12 hours. The organic solvent was removed by rotary evaporation at low temperature to give a white solid (800 mg, 93%). (ESI), [M+H) + =186.

[0234] A mixture of compound 2 (480 mg, 3 equiv), compound 3 (300 mg, 1 equiv), and 4A molecular sieve (1 g) was dissolved in anhydrous ethanol (30 mL) and stirred at room temperature under nitrogen protection for 30 minutes. Then, sodium ethoxide (200.00 mg, 4.00 equiv) was added to the reaction system. The mixture was stirred at 90 °C under nitrogen for 12 hours. The solvent was evaporated, and the mixture was prepared by high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 45% B in 7 min, 45% B; Wavelength: 220 nm) to obtain a white solid compound (16 mg), (ESI), [M+H). + =583. 1 H NMR(400MHz,Methanol-d4)δ9.34(s,1H),8.78(s,1H),7.79(s,1H),7.72–7.56(m ,2H),7.43(dt,J=15.0,7.6Hz,4H),7.31(t,J=7.2Hz,1H),5.46(s,1H),4.48(d,J =13.5Hz,1H),4.07–3.95(m,3H),3.42–3.34(m,1H),3.32–3.27(m,1H),3.02(t,J =11.5Hz,1H),2.16(d,J=2.1Hz,5H),1.98–1.80(m,2H),1.53(s,3H),1.51(s,3H).

[0235] Example 21 Synthesis of Compound I-21

[0236]

[0237] Compound 1 (1 g, 0.008 mol, 1.00 equiv) was dissolved in ethanol (10 mL). Hydroxylamine aqueous solution (5.28 g, 0.080 mol, 10.0 equiv) was added to the reaction solution, and the mixture was stirred overnight at 90°C under nitrogen protection. The reaction solution was first extracted with dichloromethane to remove impurities, and then extracted again with a mixture of chloroform and acetone (1:1). The extract was concentrated under reduced pressure to obtain the crude compound 2 (800 mg) as a white solid. m / z (ESI), [M+H] + =173;

[0238] Compound 2 (546 mg, 3.170 mmol, 5.00 equiv), compound 3 (300 mg, 0.650 mmol, 1.00 equiv), and 4A molecular sieve (1.5 g) were dissolved in ethanol (5 mL) and stirred at room temperature for 30 min under nitrogen protection. Sodium ethoxide (177 mg, 2.601 mmol, 4.00 equiv) was added to the reaction solution and stirred at 90°C for 2 h under nitrogen protection. The reaction solution was purified by high-pressure purification (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 37% B in 8 min, 37% B; Wavelength: 220 nm) to obtain a white solid compound (13.8 mg). m / z (ESI), [M+H) + =570; 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.05(d,J=7.7Hz,1H),8.81(s,1H),8.46(s,1H),7.91(s,1H),7.63(d,J=8.5Hz,1H),7.48–7.28(m,6H),5.4 2(d,J=6.8Hz,1H),5.23(s,1H),3.89(s,1H),3.81(d,J=7.1Hz,2H),3.31 (s,2H),2.64(s,3H),2.40(s,3H),2.20(s,3H),1.42(s,3H),1.39(s,3H).

[0239] Example 22 Synthesis of Compound I-22

[0240]

[0241] A mixture of compounds 1 (100 mg, 1 equiv) and 2 (90.7 mg, 5 equiv), and 4A molecular sieve (1 g) was dissolved in anhydrous ethanol (8 mL) and stirred at room temperature under nitrogen protection for 30 minutes. Then, sodium ethoxide (59 mg, 4 equiv) was added to the reaction system. The mixture was stirred at 90 °C under nitrogen for 12 hours. The solution was filtered and evaporated to dryness, then purified by high-pressure purification (Column: XBridge Prep OBDC18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B in 8 min, 60% B; Wavelength: 220 nm) to give a white solid product (19.2%, 99.2%). [M+H] + =548. 1 H NMR (400MHz, DMSO-d6) δ10.21 (s, 1H), 9.12 (d, J = 7.9Hz, 1H), 8.81 (s, 1H), 8.44 (s,1H),7.93(d,J=1.8Hz,1H),7.66–7.56(m,1H),7.51–7.18(m,6H),5.41(d,J =6.0Hz,1H),5.19(s,1H),3.91(d,J=6.6Hz,1H),3.81(d,J=6.0Hz,1H),3.71(t ,J=8.5Hz,1H),3.31–3.05(m,2H),3.07–2.79(m,2H),1.42(s,3H),1.39(s,3H).

[0242] Example 23 Synthesis of Compound I-23

[0243]

[0244] A mixture of compounds 1 (100 mg, 1 equiv), 2 (95 mg, 5 equiv), and 4A molecular sieve (1.5 g) was dissolved in anhydrous ethanol (8 mL) and stirred at room temperature under nitrogen protection for 30 min. Then, sodium ethoxide (59 mg, 4 equiv) was added to the reaction mixture. The mixture was stirred at 90 °C for 12 h under nitrogen protection. The solution was filtered and evaporated to dryness. The product was then prepared by high pressure (Column: XBridge PrepOBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 8 min, 55% B; Wavelength: 220 nm) to give a white solid product (21.2 mg, 92.2%). MS (ESI): [M+H]+ =486. 1 HNMR (400MHz, DMSO-d6) δ10.16(s,1H),9.13(d,J=7.8Hz,1H),8.79(s,1H),8.43(s,1H),7.88(d,J=1.8Hz,1H),7.72–7.59(m, 1H),7.50–7.18(m,6H),5.43–5.39(m,1H),5.20(t,J=4.9Hz,1H),3.94–3.80(m,2H),2.82(q,J=7.6Hz,2H),1.41–1.31(m,9H).

[0245] Example 24 Synthesis of Compound I-24

[0246]

[0247] A mixture of compounds 1 (100 mg, 1 equiv) and 2 (110 mg, 5 equiv), and 4A molecular sieve (1 g) was dissolved in anhydrous ethanol (8 mL) and stirred at room temperature under nitrogen protection for 30 min. Then, sodium ethoxide (59 mg, 4 equiv) was added to the reaction mixture. The mixture was stirred at 90 °C for 12 h under nitrogen protection. The mixture was filtered and evaporated to dryness, and then prepared by high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B in 8 min, 60% B; Wavelength: 220 nm) to give a white solid product (17.4 mg, 95%). MS (ESI): [M+H) + =500. 1 HNMR (400MHz, DMSO-d6) δ10.15(s,1H),9.23(d,J=7.8Hz,1H),8.78(s,1H),8.42(s,1H),7.90(d,J=1.8Hz,1H),7.63(dd,J=8.3,1 .8Hz,1H),7.47–7.26(m,6H),5.42–5.38(m,1H),5.18(t,J=4.9Hz,1H),3.94–3.82(m,2H),3.19–3.13(m,1H),1.42–1.35(m,12H).

[0248] Example 25 Synthesis of Compound I-25

[0249]

[0250] A mixture of compounds 1 (100 mg, 1 equiv) and 2 (125 mg, 5 equiv), and 4A molecular sieve (1 g) was dissolved in anhydrous ethanol (8 mL) and stirred at room temperature under nitrogen protection for 30 min. Then, sodium ethoxide (59 mg, 4 equiv) was added to the reaction mixture. The mixture was stirred at 90 °C for 12 h under nitrogen protection. The solvent was removed by filtration and the product was prepared by high pressure (Column: XBridge Prep OBDC18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B in 8 min, 65% B; Wavelength: 220 nm) to give a white solid product (16.9, 99.6%). MS (ESI): [M+H) + =514. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.32(d,J=7.8Hz,1H),8.77(s,1H),8.43(s,1H),7.92(d,J=1.8Hz,1H),7.63(d,J=8. 4Hz,1H),7.48–7.35(m,5H),7.27(t,J=7.2Hz,1H),5.40–5.38(m,1H),5.19(s,1H),3.94–3.82(m,2H),1.42–1.39(m,15H).

[0251] Example 26 Synthesis of Compound I-26

[0252]

[0253] A mixture of compound 1 (150 mg, 1 equiv), compound 2 (185 mg, 5 equiv), and 4A molecular sieve (1.5 g) was dissolved in anhydrous ethanol (8 mL) and stirred under nitrogen at room temperature for 30 minutes. Then, sodium ethoxide (89 mg, 4 equiv) was added to the reaction system. The mixture was stirred under nitrogen at 90 °C for 12 hours. The solvent was removed by filtration and the product was prepared by high pressure (Column: XBridge PrepOBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 8 min, 55% B; Wavelength: 220 nm) to give a white solid product (16 mg). (ESI), [M+H) + =498. 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.12(d,J=7.8Hz,1H),8.75(s,1H),8.43(s,1H),7.88(d,J=1.8Hz,1H),7.63–7.61(m,1H),7.46–7.26(m,6H ), 5.37–5.35(m,1H),5.19(t,J=4.9Hz,1H),3.92–3.80(m,2H),2.24–2.2 0(m,1H),1.41(s,3H),1.37(s,3H),1.14–1.11(m,3H),1.02–0.99(m,1H).

[0254] Example 27 Synthesis of Compound I-27

[0255]

[0256] Compound 1 (1 g, 1 equiv) and 50% hydroxylamine aqueous solution (6.3 g, 10 equiv) were dissolved in anhydrous ethanol (20 mL), and stirred overnight at 90 °C under nitrogen protection. The solvent was removed by rotary evaporation to give a white solid (1.1 g, 98%). (ESI), [M+H) + =138.

[0257] Compounds 3 (100 mg, 1 equiv), 2 (148.00 mg, 5.00 equiv), and 1 g of 4A molecular sieve were dissolved in ethanol (5 mL). The mixture was stirred under nitrogen at room temperature for 30 minutes. Sodium ethoxide (58.00 mg, 5.00 equiv) was added to the reaction system, and the reaction was carried out overnight at 90 °C. The solvent was evaporated by filtration, and the mixture was prepared under high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 50% B in 7 min, 50% B; Wavelength: 220 nm) to give a white solid product (10.2 mg, 96%). (ESI), [M+H) + =535. 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),9.46–9.25(m,2H),8.95–8.78(m,2H),8.54–8.40(m,2H),7.85(s,1H),7.68–7. 63(m,2H),7.47–7.32(m,5H),7.27(t,J=7.2Hz,1H),5.43–5.40(m,2H),4.01–3.93(m,2H),1.41(s,3H),1.36(s,3H).

[0258] Example 28 Synthesis of Compound I-28

[0259]

[0260] Compound 1 (100.00 mg, 0.216 mmol, 1.00 equiv), compound 2 (147.93 mg, 1.079 mmol, 5.00 equiv), and 400 mg of 4A molecular sieve were added to a 20 ml sealed tube and dissolved in 8 ml of anhydrous ethanol. After stirring under nitrogen at room temperature for half an hour, sodium ethoxide (51.38 mg, 0.755 mmol, 3.50 equiv) was added, and the mixture was reacted at 90 °C under nitrogen for two hours. After the reaction was complete, the mixture was filtered and evaporated to dryness. The solution was then prepared under high pressure (Column: X Bridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 25% B to 48% B in 8min, 48% B; Wavelength: 220nm) to obtain 10mg (92.9%) of a white solid. MS (ESI): [M+H] + =535. 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.35(d,J=7.7Hz,1H),8.90(s,1H),8.87–8 .80(m,1H),8.44(s,1H),8.25(d,J=7.8Hz,1H),8.08(td,J=7.7,1.8Hz,1H),7.88 (d,J=1.8Hz,1H),7.69–7.60(m,2H),7.50–7.35(m,5H),7.32–7.25(m,1H),5.45– 5.41(m,1H),5.34(t,J=5.2Hz,1H),4.07–3.89(m,2H),1.42(s,3H),1.37(s,3H).

[0261] Example 29 Synthesis of Compound I-29

[0262]

[0263] Compound 1 (260 mg), compound 2 (150 mg), Pd2(dba)3 (78 mg), Xantphos (50 mg), potassium phosphate (543 mg), and 10 mL of 1,4-dioxane were added to a 20 mL sealed tube. The mixture was reacted at 100 °C under nitrogen for 2 h. After the reaction was complete, the crude product was purified by silica gel column chromatography to obtain a brown solid product 3 (250 mg, 97.1%). MS (ESI): [M+H] + =418.

[0264] Compound 3 (100 mg), compound 4 (210 mg), and 4A molecular sieve (400 mg) were added to a 20 mL sealed tube. 6 mL of ethanol was added, and the mixture was stirred under nitrogen at room temperature for 0.5 h. Sodium ethoxide (200 mg) was then added, and the reaction was carried out overnight at 90 °C. After the reaction was complete, the mixture was filtered and evaporated to dryness. Purification was performed using a XBridge Prep OBD C18 column (30*150 mm, 5 μm); mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B in 7 min, 40% B; wavelength: 220 nm) to obtain a white solid (13.2 mg, 99.4%). MS (ESI): [M+H] + =537. 1 HNMR (400MHz, DMSO-d6) δ9.64 (s, 2H), 8.70 (d, J = 3.4Hz, 2H), 8.62 (d, J = 4.9Hz, 1H),8.41(s,1H),8.34(d,J=6.2Hz,1H),7.96(d,J=7.7Hz,1H),7.76(s,1H),7.5 9(t,J=6.5Hz,1H),7.53(d,J=8.4Hz,1H),7.47(d,J=8.3Hz,1H),6.10(s,1H),4 .71(d,J=5.8Hz,2H),3.43(t,J=8.0Hz,6H),2.23(t,J=8.0Hz,6H),1.40(s,6H).

[0265] Example 30 Synthesis of Compound I-30

[0266]

[0267] Compound 1 (100.00 mg, 0.231 mmol), compound 2 (195.65 mg, 1.156 mmol), and 500 mg of molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The reaction flask was then purged with nitrogen. The mixture was stirred at room temperature for 30 minutes. Then, sodium ethoxide (62.94 mg, 0.925 mmol) was added to the reaction flask, and the nitrogen was purged again. The reaction was carried out overnight at 90 °C. After cooling the reaction system to room temperature, the crude product was obtained by chromatography using CH2Cl2 / MeOH 5:1. The crude product was then subjected to Prep-HPLC (Column: Sunfire prep C18 column, 30*150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 23% B in 8 min, 23% B) to obtain a white solid compound (5.3 mg). MS (ESI): [M+H) + =538; 1 H NMR (400MHz, DMSO-d6): δ8.78(s,1H),8.69(s,1H),8.56–8.55(m,1H),8.15–8.13(m,1H),7.85–7.80(m,1H),7.69–7.6 7(m,1H),7.57–7.55(m,1H),7.49–7.47(m,1H),4.96(s,2H),3.37(t,J=8.0Hz,6H),2.22(t,J=8.0Hz,6H),1.26(s,6H).

[0268] Example 31 Synthesis of Compound I-31

[0269]

[0270] Compound 1 (500.00 mg, 2.26 mmol, 1.00 equiv), SM1 (1.56 g, 11.31 mmol, 5.00 equiv), and N,N-diisopropylethylamine (1.46 g, 5.0 eq) were dissolved in acetonitrile (20 mL) and stirred at room temperature under nitrogen atmosphere for 4 hours. After the reaction was completed, the reaction mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound 2 (270 mg) as a brown solid. MS (ESI): m / z = 323.

[0271] Compound 2 (100 mg, 0.31 mmol, 1.00 equiv), compound SM2 (109.99 mg, 0.62 mmol, 2 equiv), Xantphos (27 mg, 0.1 equiv), Pd2(dba)3 (44.86 mg, 0.1 equiv), and potassium phosphate (450 mg, 3.0 eq) were dissolved in dioxane (5 mL) and stirred overnight at 90 °C under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 3 (130 mg) as a brown solid. MS (ESI): m / z = 463.

[0272] Compound 3 (100 mg, 0.216 mmol, 1.00 equiv) and SM3 (109.77 mg, 0.649 mmol, 3.00 equiv) were dissolved in ethanol (5 mL). 500 mg of 4A molecular sieve was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. Then, sodium ethoxide (59 mg, 0.865 mmol, 4.00 eq) was added, and the mixture was stirred overnight at 90 °C under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated by rotary evaporation. The crude product was then subjected to high pressure (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5% B to 35% B in 8min, 35% B; Wavelength: 220nm; RT1 (min): 7.77) to give a white solid compound I-31 (2.2mg). MS (ESI): m / z = 568 1 H NMR (400MHz, DMSO-d6): δ10.11(s,1H),9.31(s,1H),8.67-8.80(m,1H),8.55 -8.60(m,1H),8.48–8.41(m,1H),7.88–7.70(m,1H),7.66–7.54(m,1H),7.30 –7.47(m,1H),5.46–5.19(m,2H),4.01–3.81(m,1H),3.70-4.02(m,2H),3.01 (s,6H),1.93(s,3H),1.91(s,3H),1.38(d,J=13.3Hz,4H),1.26–1.10(m,2H).

[0273] Example 32 Synthesis of Compound I-32

[0274]

[0275] Compound 1 (75 mg), compound 2 (125 mg), and 4A molecular sieve (300 mg) were added to a 20 mL sealed tube. 8 mL of ethanol was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 0.5 h. Sodium ethoxide (100 mg) was then added, and the reaction was carried out at 90 °C for 3 h. After the reaction was complete, the mixture was filtered and evaporated to dryness. Purification was performed under high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 45% B in 7 min, 45% B; Wavelength: 220 nm) to obtain a white solid product (2.6 mg, 99.4%). MS (ESI): [M+H) + =556. 1 HNMR(400MHz,DMSO-d6)δ9.49(s,1H),8.74–8.56(m,2H),8.38(s,1H),7.69(d,J=1.8Hz,1H),7.51–7.24(m,7H),5.97(s,1H),5.2 0(t,J=5.0Hz,1H),4.64(q,J=5.6Hz,1H),3.93–3.74(m,3H),3.68–3.47(m,5H),2.63(t,J=4.7Hz,4H),1.41(s,3H),1.40(s,3H).

[0276] Example 33 Synthesis of Compound I-33

[0277]

[0278] Compound 1 (100 mg, 1 equiv) and compound 2 (186 mg, 5 equiv) were dissolved in ethanol (10 mL), and 1 g of 4A molecular sieve was added. The mixture was stirred for 30 minutes under nitrogen atmosphere at room temperature. Then, sodium ethoxide (58.00 mg, 5.00 equiv) was added to the reaction system, and the reaction was carried out overnight at 90 °C under nitrogen atmosphere. The reaction mixture was evaporated to dryness and prepared under high pressure (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 7 min, 40% B; Wavelength: 220 nm) to obtain a white solid (14 mg, 99%). (ES+), [M+H) + =569. 1H NMR(400MHz, DMSO-d6)δ9.47(s,1H),8.68(s,1H),8.60(d,J=6.1Hz,1H),8.36(s,1H),7.68(d,J=1.7Hz,1H),7.54–7.06(m,7H),5.97(s,1H),4.6 4(t,J=5.7Hz,1H),3.84(d,J=12.8Hz,3H),3.66(dd,J=10.8,6.2Hz,1H) ,2.68(s,4H),2.50–2.42(m,3H),2.22(s,3H),1.41(s,3H),1.40(s,3H).

[0279] Example 34 Synthesis of Compound I-34

[0280]

[0281] In a 100 mL reaction flask, 1 g of compound 1, 1.1 g of compound 2, and 1.2 g of N,N-diisopropylethylamine were dissolved in 40 mL of acetonitrile. The mixture was stirred overnight at room temperature under nitrogen atmosphere. After the reaction was complete, the crude product was purified by rapid column chromatography to give 21.18 g (94%) of a white solid. MS (ESI): [M+H] + =386.

[0282] Compound 3 (300 mg, 0.777 mmol, 1.00 equiv), compound 4 (143.85 mg, 0.816 mmol, 1.05 equiv), Pd2(dba)3 (71.19 mg, 0.078 mmol, 0.1 equiv), XantPhos (44.98 mg, 0.078 mmol, 0.1 equiv), and potassium phosphate (495.06 mg, 2.332 mmol, 3 equiv) were added to a 40 mL sealed tube and dissolved in 16 mL of 1,4-dioxane. The reaction was carried out at 100 °C under nitrogen for 2 hours. After the reaction was complete, the solution was evaporated to dryness and analyzed by TLC using DCM:MeOH / 15:1 to give 260 mg (89.3%) of a yellow solid, compound 5. MS (ESI): [M+H] + =526.

[0283] In a 20 mL sealed tube, compound 5 (260.00 mg, 0.495 mmol, 1.00 equiv), compound 6 (418.52 mg, 2.473 mmol, 5.00 equiv), and 500 mg of 4A molecular sieve were added, followed by 6 mL of anhydrous ethanol. Nitrogen gas was introduced, and the mixture was stirred at room temperature for half an hour. Then, sodium ethoxide (168.30 mg, 2.473 mmol, 5.00 equiv) was added, and the reaction was carried out under nitrogen at 90 °C for 3 hours. After the reaction was complete, the mixture was filtered and evaporated to dryness. A DCM:MeOH / 3:1 plate test yielded 80 mg (90.2%) of a grayish-white solid, compound 7. MS (ESI): [M+H] + =631.

[0284] Compound 7 (80.00 mg, 0.127 mmol, 1.00 equiv) was added to a 20 mL sealed tube and dissolved in 4 mL of dichloromethane. Then, 1.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was evaporated to dryness and then subjected to high-pressure chromatography (Column: Xselect CSH OBD Column 30*150 mm 5 μm, n; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 15% B in 8 min, 15% B; Wavelength: 254 nm) to obtain 11.7 mg of a white solid compound. MS (ESI): [M+H] + =531. 1 H NMR(400MHz,Methanol-d4)δ8.67(s,1H),7.80–7.78(m,1H),7.69–7.67(m,1H),7.55–7.53(m,1H),6.42(s,1H ),3.58(t,J=8.0Hz,6H),3.39(s,2H),3.02(s,2H),2.39(t,J=8.0Hz,6H),1.58(d,J=4.1Hz,6H),1.24(s,6H).

[0285] Example 35 Synthesis of Compound I-35

[0286]

[0287] Compound 1 (500 mg, 1.0 eq), compound SM1 (941.8 mg, 3.0 eq), and N,N-diisopropylethylamine (1.46 g, 5.0 eq) were dissolved in acetonitrile (20 mL). The reaction mixture was stirred overnight at 50 °C under nitrogen atmosphere. After the reaction was complete, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 2 (270 mg) as a brown solid. MS (ESI): m / z = 322.

[0288] Compound 2 (100.0 mg, 0.31 mmol, 1.0 equiv), compound SM2 (164.3 mg, 0.93 mmol, 3.0 equiv), Xantphos (17.9 mg, 0.031 mmol, 0.1 equiv), Pd2(dba)3 (28.5 mg, 0.031 mmol, 0.1 equiv), and potassium phosphate (251 mg, 3.0 eq) were dissolved in dioxane (8 mL). The reaction mixture was stirred overnight at 90 °C under nitrogen atmosphere. After the reaction was complete, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 3 (60 mg) as a yellow solid. MS (ESI): m / z = 434.

[0289] Compound 3 (60 mg, 1 eq), SM2 (117.12 mg, 0.692 mmol, 5 equiv), and 500 mg of 4A molecular sieve were dissolved in ethanol (5 mL). The mixture was stirred at room temperature under nitrogen for 30 minutes. Sodium ethoxide (47.10 mg, 0.692 mmol, 5 equiv) was added to the reaction system, and the reaction was carried out overnight at 90 °C. The mixture was filtered and evaporated to dryness. Compound I-35 (2.9 mg) was obtained by high-pressure preparation (XBridge Prep C18 OBD Column, 30*50 mm, 5 μm 13 nm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B in 8 min, 40% B; RT1 (min): 7.23). MS (ESI): m / z = 567. 1H NMR (400MHz, DMSO-d6): δ9.50(s,1H),8.91(s,1H),8.71–8.56(m,1H),8.51(dd ,J=4.8,1.6Hz,1H),8.38(s,1H),7.83–7.65(m,2H),7.60–7.19(m,2H),5.94(s, 1H),5.32(d,J=16.5Hz,1H),4.72(d,J=5.5Hz,1H),4.13–3.61(m,2H),3.01(d, J=11.5Hz,6H),1.93(s,3H),1.91(s,3H),1.36–1.31(m,6H),1.24–1.10(m,2H).

[0290] Example 36 Synthesis of Compound I-36

[0291]

[0292] SM1 (154.1 mg, 1.09 mmol, 5.00 equiv), compound 1 (100.0 mg, 0.217 mmol, 1.0 equiv), and 500 mg of 4A molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The reaction flask was purged with nitrogen and stirred at room temperature for 30 minutes. Then, sodium ethoxide (59.0 mg, 0.868 mmol, 4.0 equiv) was added, and the reaction system was stirred overnight at 90 °C. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting mixture was then subjected to column chromatography (dichloromethane / methanol: 10:1) to obtain the crude product. The crude product was then subjected to reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30*150 mm). Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 70% B in 7 min, 70% B) purification yielded a white solid compound I-36 (10.3 mg). MS (ESI): m / z = 540. 1HNMR (400MHz, DMSO-d6): δ1.27-1.43(m,9H),1.56-1.59(d,3H),1.76-1.80( m,2H),2.01-2.15(m,2H),2.87-2.90(m,1H),3.81-3.93(m,2H),5.19-5.21(m ,1H),5.38-5.40(m,1H),7.26-7.29(m,1H),7.35-7.47(m,5H),7.60-7.62(m, 1H),7.91(s,1H),8.44(s,1H),8.77(s,1H),9.22-9.24(m,1H),10.18(s,1H).

[0293] Example 37 Synthesis of Compound I-37

[0294]

[0295] Compound 1 (50.0 mg, 0.112 mmol, 1.00 eq), compound SM1 (57.7 mg, 0.335 mmol, 3 eq) and 500 mg of 4A molecular sieve were dissolved in ethanol (4 mL), stirred at room temperature under nitrogen atmosphere for 30 minutes, and then sodium ethoxide (30.4 mg, 0.447 mmol, 4 eq) was added. The reaction mixture was stirred overnight at 90 °C. After the reaction was completed, the reaction system was filtered and evaporated to dryness. The crude product was subjected to high-pressure treatment (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15% B to 40% B in 8min, 40% B; Wavelength: 220nm; RT1 (min): 7.70) to obtain a white solid compound I-37 (7.8mg). MS (ESI): m / z = 570. 1H NMR (400MHz, DMSO-d6): δ10.31(s,1H),8.78–8.69(m,2H),8.49(s,1H),7.83(d,J=8. 5Hz,1H),7.52(d,J=8.5Hz,1H),7.45(s,1H),7.40–7.32(m,4H),7.28(td,J=5.9,2.7 Hz,1H),4.74(q,J=5.8Hz,1H),3.92(dd,J=10.8,4.3Hz,1H),3.81(s,2H),3.73(dd,J =10.9,5.7Hz,1H),2.65(s,4H),2.37(s,4H),2.17(s,3H),1.46(s,3H),1.29(s,3H).

[0296] Example 38 Synthesis of Compound I-38

[0297]

[0298] Compound 1 (2.00 g, 9.09 mmol, 1.00 equiv) and SM1 (1.51 g, 9.99 mmol, 1.1 equiv) were placed in a reaction flask, and acetonitrile (20.0 mL) and N,N-diisopropylethylamine (3.52 g, 27.27 mmol, 3 equiv) were added. The reaction mixture was stirred overnight at 50 °C under nitrogen atmosphere. After the reaction was completed, the reaction system was cooled to room temperature and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5:1) to give compound 2 (600 mg) as a white solid, MS (ESI): m / z = 335.

[0299] Compound 2 (200 mg, 0.597 mmol, 1.00 equiv), substrate SM2 (116.44 mg, 0.657 mmol, 1.1 equiv), XantPhos (34.57 mg, 0.06 mmol, 0.1 equiv), potassium phosphate (634 mg, 2.985 mmol, 5 equiv), and Pd2(dba)3 (34.35 mg, 0.06 mmol, 0.1 equiv) were dissolved in anhydrous 1,4-dioxane (20 mL). The reaction mixture was stirred overnight at 90 °C under nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The crude product was purified by dichloromethane / methanol to give a brown solid product 3. MS (ESI): m / z = 476.

[0300] Compound 3 (100 mg, 0.21 mmol, 1.00 equiv), SM3 (72.01 mg, 0.63 mmol, 3 equiv), and 1 g of 4A molecular sieve were placed in a reaction flask, and anhydrous ethanol (5 mL) was added. The reaction flask was then purged with nitrogen. The mixture was stirred at room temperature for 30 minutes, and then sodium ethoxide (57.24 mg, 0.84 mmol, 4 equiv) was added. The reaction system was stirred overnight at 90 °C under nitrogen atmosphere. After the reaction was completed, the crude product obtained by concentration of the reaction mixture was purified by high-pressure preparation (Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 35% B to 65% B in 8min, 65% B; Wave Length: 220nm; RT1 (min): 7.50;) to give a white solid compound I-38 (24.6mg, yield 22%). MS (ESI): m / z = 526. 1 H NMR (400MHz, DMSO-d6): δ10.44(s,1H),8.65(s,1H),8.51(s,1H),8.10(s,1H),7.88(d,J=8.5Hz,1H) ,7.68(s,1H),7.53(d,J=8.5Hz,1H),7.27(d,J=4.4Hz,4H),7.25–7.08(m,1H),5.09(s,1H),3.85(s, 1H),3.58(dd,J=10.6,4.5Hz,1H),3.53–3.47(m,1H),3.08(dd,J=13.7,6.4Hz,1H),2.87(dd,J=13.7 ,6.8Hz,1H),1.50(s,3H),1.45(s,6H),1.34–1.21(m,1H),1.18–1.06(m,1H),0.99(d,J=3.4Hz,2H).

[0301] Example a: Synthesis of Compound II-1

[0302]

[0303] Compound 1 (1 g, 3 mmol), compound SM1 (453 mg, 3 mmol), XantPhos (89.7 mg, 9.75 mol), Pd2(dba)3 (173.6 mg, 0.3 mmol), and potassium phosphate (1.9 g, 9 mmol) were placed in a reaction flask, and 1,4-dioxane (10 mL) was added. The reaction system was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography to give compound 2 (300 mg, 0.689 mmol, 23%) as a yellow solid. MS (ESI): m / z = 436.

[0304] Compound 2 (300 mg, 0.689 mmol), SM2 (256.5 mg, 3.46 mmol), and 600 mg of [unclear text - possibly a drug or treatment] were administered. Molecular sieves were placed in a reaction flask and anhydrous ethanol (0.5 mL) was added. The reaction system was stirred at room temperature under nitrogen protection for 30 minutes. Then, sodium ethoxide (187.7 mg, 2.756 mmol) was added to the reaction flask, and the reaction system was stirred overnight at 90 °C. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered with diatomaceous earth. The filtrate was concentrated to obtain a crude product, which was purified by reverse-phase preparation (Column: YMC-ActusTriart C18, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 57% B in 8 min, 57% B; Wavelength: 254 / 220 nm) to give a white solid compound II-1 (47.6 mg, 0.107 mmol, 16%). MS (ESI): m / z = 446; 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),9.26(s,1H),9.06(d,J=7.2Hz,1H) ,8.78(s,1H),8.52–8.40(m,1H),7.94(d,J=8.9Hz,1H),7.59(d,J=9.0Hz,1 H),7.46–7.32(m,4H),7.30–7.21(m,1H),5.37(s,1H),5.23(t,J=5.0Hz,1H ),3.90(dt,J=11.0,4.5Hz,1H),3.76(dt,J=10.7,5.3Hz,1H),2.46(s,3H).

[0305] Example b: Synthesis of compound II-2

[0306]

[0307] Compound 1 (300 mg, 0.97 mmol), compound SM1 (147.7 mg, 0.97 mmol), XantPhos (56.61 mg, 0.097 mmol), Pd2(dba)3 (89.6 mg, 0.097 mmol), and potassium phosphate (623.1 mg, 2.93 mmol) were placed in a reaction flask, and 1,4-dioxane (0.5 mL) was added. The reaction system was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature, filtered with diatomaceous earth, and the crude product obtained by concentration was purified by column chromatography to give compound 2 (150 mg, yield 36.5%) as a yellow solid. MS (ESI): m / z = 421.

[0308] Compound 2 (150 mg, 0.36 mmol), SM2 (303.6 mg, 1.79 mmol), and 300 mg of [unclear text - possibly a drug or treatment] were administered. Molecular sieves were placed in a reaction flask and anhydrous ethanol (0.5 mL) was added. The reaction system was stirred at room temperature under nitrogen protection for 30 minutes, and then sodium ethoxide (97.2 mg, 1.43 mmol) was added. The mixture was stirred overnight at 90 °C. After the reaction was completed, the reaction system was cooled to room temperature and filtered with diatomaceous earth. The crude product obtained by concentrating the filtrate was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40B to 60B in 8 min, 60B to B in min, B to B in min, B to B in min, B to B in min; 254; 220 nm) to obtain a white solid compound II-2 (85.5 mg, yield 46%). MS (ESI): m / z = 540; 1H NMR (400MHz, DMSO-d6): δ9.42(s,1H),9.19(s,1H),8.84(d,J=6.1Hz,1H),8.64(s,1H) ,8.38(d,J=2.2Hz,1H),7.91(d,J=8.9Hz,1H),7.46–7.34(m,5H),7.34–7.26(m,1H),5. 94(s,1H),5.25(t,J=4.8Hz,1H),4.63(q,J=5.6Hz,1H),3.87(dt,J=10.6,4.3Hz,1H), 3.68(dt,J=10.7,5.5Hz,1H), 2.88(dd,J=9.4,6.1Hz,6H), 1.85(dd,J=9.4,6.2Hz,6H).

[0309] Example c: Synthesis of Compound II-3

[0310]

[0311] Compound 1 (145 mg, 0.33 mmol), SM1 (283.3 mg, 1.67 mmol), and 290 mg were administered. Molecular sieves were placed in a reaction flask, and anhydrous ethanol (0.5 mL) was added. After purging with nitrogen, the mixture was stirred at room temperature for 30 minutes. Then, sodium ethoxide (90.7 mg, 1.33 mmol) was added, and the reaction system was stirred overnight at 90 °C under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and filtered with diatomaceous earth. The crude product obtained by concentrating the filtrate was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in 8 min, 55% B; Wavelength: 254; 220 nm) to obtain a white solid compound II-3 (85.5 mg, yield 46%). MS (ESI): m / z = 541; 1H NMR (400MHz, DMSO-d6): δ10.17(s,1H),9.36(d,J=7.0Hz,1H),9.25(s,1H),8.75( s,1H),8.50(s,1H),7.94(d,J=8.9Hz,1H),7.60(d,J=9.0Hz,1H),7.48–7.41(m,2H ),7.38(t,J=7.7Hz,2H),7.28–7.21(m,1H),5.42–5.16(m,2H),3.93(dt,J=10.7,4 .4Hz,1H),3.78(dt,J=10.5,4.7Hz,1H),2.89(t,J=7.7Hz,6H),1.97–1.73(m,6H).

[0312] Example of effect: Biological experimental method

[0313] The test compound was dissolved in 100% DMSO, with a stock solution concentration of 10 mM. The initial test concentration was 10 μM, with three-fold serial dilutions, and ten data points, each repeated twice.

[0314] The experiment on the inhibition of HPK1 kinase activity by the compound was conducted using ADP-Glo TM Platform. The reaction was carried out in 384-well plates, each well containing 0.3 nM HPK1, 5 μM ATP, 0.05 mg / ml MBP, 0-10 μM of the compound, and 1% DMSO. The reaction buffer consisted of 50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, and 0.01% Brij 35, pH 7.5. The compound and kinase were incubated at 25°C for 15 min, and the substrate and ATP were added to initiate the reaction. After reacting at 25°C for 1 hour, ADP-Glo ​​was added. TM The reagent was added to terminate the reaction, and the mixture was incubated at 25°C for 1 hour. The kinase detection reagent was then added, and after incubation at 25°C for 1 hour, the chemiluminescent signal was detected. Based on this reading, the inhibition percentage was calculated, and the IC50 of the compound was calculated using a four-parameter fitting method. 50 The results are shown in Table 1:

[0315] Table 1

[0316] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> I-1 A I-2 A I-3 C I-4 C I-5 C I-6 A I-7 A I-8 A I-9 A I-10 C I-11 A I-12 A I-13 A I-14 A I-15 A I-16 A I-17 A I-18 A I-19 A I-20 A I-21 A I-22 A I-23 A I-24 A I-25 A I-26 A I-27 A I-28 A I-29 C I-30 B I-31 A I-32 A I-33 A I-34 A I-35 B I-36 A I-37 A I-38 C II-1 C II-2 A II-3 A

[0317] Where A represents IC 50 It is 0.01-5nM; B indicates IC 50 5-10 nM; C represents IC 50 It is 10-100 nM.

Claims

1. A compound as shown in Formula II or a pharmaceutically acceptable salt thereof: ； W is NH; X 1 is N or CH; X 2 is CH; R 2 is -CHR 2-1 R 2-2 ; R 2-1 is H or -(CH2)n-R 2-1-1 ; n is 0 or 1 ; R 2-1-1 is C6-C 10 aryl, furan, thiophene or pyridine; R 2-2 H or Ci-C6alkyl substituted by one or more R 2-15 Ci-C6alkyl substituted by one or more R R 2-15 independently hydroxyl or amino; R 11 For or C1-C6 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula II, ###0002### Formula II When R 2 -1-1 For C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl; when R is C1-C6alkyl substituted by one or more R 2-2 2-15 when R is C1-C6alkyl substituted by one or more R 2-15 C1-C4alkyl; when R 11 is Ci-C6alkyl, said Ci-C6alkyl is C1-C4 alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula II, ###0002### Formula II when R is C1-C6alkyl, said C1-C6alkyl is methyl; 2 -2 when R is C1-C6alkyl, said C1-C6alkyl is methyl; 2-15 when R is C1-C6alkyl, said C1-C6alkyl is methyl; when R 11 is C1-C6alkyl, said C1-C6alkyl is methyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula II, ###0002### Formula II R 2-1-1 is phenyl or pyridyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula II, ###0002### Formula II R 11 is methyl or .

6. The compound as shown in II or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 For , , , , or , the carbon atom marked with an "*" is a chiral carbon atom, in the S configuration and / or the R configuration.

7. The compound as shown in II or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound as shown in Formula II is any one of the following compounds: 。 8. A pharmaceutical composition comprising the compound as shown in Formula II or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, and a pharmaceutically acceptable excipient.

9. Use of a compound of Formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament, wherein The drug is used for preventing and / or treating diseases related to HPK1.

10. Use according to claim 9, wherein The diseases related to HPK1 are non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, head and neck cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, liver cancer, colon cancer, rectal cancer, large intestinal villous adenoma, breast cancer, breast ductal carcinoma, ovarian cancer, peritoneal cancer, endometrial cancer, corpus uteri cancer, cervical cancer, kidney cancer, renal pelvis cancer, prostate cancer, bladder cancer, neurofibromatosis, bone cancer, brain cancer, testicular cancer, glioma, skin cancer, melanoma, cell tumor and sarcoma, multiple myeloma, leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome.

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