Heterocyclic compounds, processes for their preparation, pharmaceutical compositions and uses thereof

Abstract

The application discloses a heterocyclic compound, a preparation method, a pharmaceutical composition and application thereof. Specifically disclosed is a heterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound has novel structure, and has good activity and selectivity.

Description

Technical Field

[0001] This invention relates to a heterocyclic compound, 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 a heterocyclic compound, its preparation method, pharmaceutical composition and its application. The compound of the present invention has a novel structure and good activity and selectivity.

[0008] The present invention solves the above-mentioned technical problems through the following technical solution:

[0009] This invention provides heterocyclic compounds as shown in Formula I, or pharmaceutically acceptable salts thereof:

[0010]

[0011] in,

[0012] R 1 For OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C3-C6 cycloalkyl or C3-C6 cycloalkyl;

[0013] Each R 3-1 Independently oxo, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, or C2-C6 alkenyl or NR 3-1-1 R 3 -1-2 ;R 3-1-1 and R 3-1-2 Independently H or C1-C6 alkyl;

[0014] R 2 -C (=Z) 5 )-R 2-1 or R 2-2 ;

[0015] Z 5 For O, S, or NH;

[0016] R 2-1 For one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 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 2-1-1 The substitution is for "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", and -OR. 2-1-2 -NHR 2-1-3 or -(CH2)mR 2-1-11 ;

[0017] R 2-1-2 and R 2-1-3 Independently for one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0018] m is 1 or 2;

[0019] R 2-1-11 For one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1 Replacement C3-C12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0020] R 2-2 For H, by one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or with one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 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..." 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 Substituted with 5-6-membered heteroaryl, 5-10-membered heterocyclic alkyl, C6-C 10 "Aryl, or C3-C8 cycloalkyl ring fused 5-10 membered heteroaryl", "with 5-6 membered heteroaryl, 5-10 membered heterocycloalkyl, C6-C 10 "aryl, or C3-C8 cycloalkyl ring-fused 5-10 membered heteroaryl" or

[0021]

[0022] Each R 2-1-1 Independently NH2, halogen, OH, CN, and reacted with one or more R 2-1-1-1Substituted C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy or -C(=O)R 2-1-1-2 Each R 2-1-1-1 Independently halogen or OH; R 2-1-1-2 It is a C1-C6 alkyl group;

[0023] n is 0 or 1;

[0024] Z 1 For O, S or NR 2-1-4 ;

[0025] Z 2 For CR 2-1-5 R 2-1-6 ;

[0026] Z 3 For NR 2-1-4 or CR 2-1-7 R 2-1-8 ;

[0027] Z 4 For NR 2-1-4 or CR 2-1-9 R 2-1-10 ;

[0028] Each R 2-1-4 Independently H or C1-C4 alkyl;

[0029] R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently, it is H, NH2, halogen, OH, CN, C1-C6 alkyl, or is bound by one or more R 2-1-1-3 Substituted C1-C6 alkyl groups, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl; each R 2-1-1-3 It can be a halogen or OH on its own;

[0030] Or, “R” 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form carbonyl groups, thiocarbonyl groups, and are influenced by one or more R groups." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0031] Or, “R” 2-1-5 and R 2-1-7 "or "R 2-1-7 and R 2-1-9 "Together with the carbon atoms they are attached, they form a structure consisting of one or more R atoms." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0032] Each R 2-1-5-1 It is NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0033] Each R 2-1-5-2 Independently NH2, halogen, OH, CN, and reacted with one or more R 2-1-1-3 Substituted C1-C6 alkyl, C1-C6 alkyl, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl;

[0034] R 3 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C1-C6 heteroalkyl, C1-C6 heteroalkyl, or substituted with one or more R 3-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0035] R 4 For (a), (b), or (c):

[0036] (a) by one or more R 4-1Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 4-1 The substitute is "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4" or "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4".

[0037] (b) by one or more R 4-1 Substituted with 5-6-membered heteroaryl, 5-10-membered heterocyclic alkyl, C6-C 10 "aryl, or C3-C8 cycloalkyl ring fused with 5-10 heteroaryl" or "with 5-6 heteroaryl, 5-10 heterocycloalkyl, C6-C 10 "Aryl, or C3-C8 cycloalkyl ring-fused 5-10 membered heteroaryl";

[0038] (c) H, OH, halogens, CN, and one or more R 4-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 4-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 4-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 4-1 Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 4-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 4-1 The substituted terms are "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", and -O-C3-C. 12 cycloalkyl, with one or more R 4-1 Replacement -O-C3-C 12 Cycloalkyl, -C(O)C1-C6 alkyl, NH2, -C(O)NR 4-2 R 4-3 -SR 4-2 -S(O)R 4-2 -S(O)2-R 4-2 -S(O)2NR 4-2 R 4-3 -NR 4-3 C(O)NR 4-2 R 4-3 or -NR 4-3 C(O)OR 4-2 ;

[0039] R 4-2 and R 4-3 Independently H, C1-C6 alkyl or -C0-C6 alkylene-R 4-2-1 Or, R 4-2 and R 4-3 Together with the N atoms attached to them, they form "5-12-membered heteroaryl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4" or "3-12-membered heterocyclic alkyl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4".

[0040] R 4-2-1 For C6-C 10 Aryl, "5-12-membered heteroaryl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms" or "3-12-membered heterocyclic alkyl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms";

[0041] Each R 4-1 Independently oxidized, halogenated, NR 4-1-1 R 4-1-2 , OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, with one or more R 3-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 3-1 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 3-1 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..." 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkyl, -S(O)2NR 4-1-1 R 4-1-2 -C(O)NR 4-1-1 R 4-1-2 -OC(O)NR 4-1-1 R 4-1-2 -C(O)R 4-1-3 -OC(O)R 4-1-3 -C(O)OR 4-1-4 -OR 4-1-4 -SR4-1-4 -S(O)R 4-1-5 -S(O)2R 4-1-5 or -S(O)(=NH)R 4-1-5 ;

[0042] R 4-1-1 and R 4-1-2 Independently H, C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0043] R 4-1-3 H, C1-C6 alkyl, C2-C6 alkenyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0044] R 4-1-4 H, C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0045] R 4-1-5 C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0046] X is N or CR 6 ;

[0047] R 6 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 3-1Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 3-1 Replacement C3-C 12 cycloalkyl or C3-C 12 cycloalkyl;

[0048] R 5 H, NH2, halogen, CN, OH, C1-C6 alkyl group substituted with one or more halogens, C3-C alkyl group substituted with one or more halogens 12 cycloalkyl, C3-C 12 Cycloalkyl, C1-C6 alkoxy or C1-C6 alkoxy substituted with one or more halogens.

[0049] This invention provides heterocyclic compounds as shown in Formula I, or pharmaceutically acceptable salts thereof:

[0050]

[0051] in,

[0052] R 1 For OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C3-C6 cycloalkyl or C3-C6 cycloalkyl;

[0053] Each R 3-1 Independently oxo, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, or C2-C6 alkenyl or NR 3-1-1 R 3 -1-2 ;R 3-1-1 and R 3-1-2 Independently H or C1-C6 alkyl;

[0054] R 2 -C (=Z) 5 )-R 2-1 or R 2-2 ;

[0055] Z 5 For O, S, or NH;

[0056] R 2-1 For one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 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 2-1-1 The substitution is for "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", and -OR. 2-1-2 or -NHR 2-1-3 ;

[0057] R 2-1-2 and R 2-1-3 Independently for one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0058] R 2-2 For H, by one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or with one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1The 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..." 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 Substituted with 5-6-membered heteroaryl, 5-10-membered heterocyclic alkyl, C6-C 10 "Aryl, or C3-C8 cycloalkyl ring fused 5-10 membered heteroaryl", "with 5-6 membered heteroaryl, 5-10 membered heterocycloalkyl, C6-C 10 "aryl, or C3-C8 cycloalkyl ring-fused 5-10 membered heteroaryl" or

[0059]

[0060] Each R 2-1-1 Independently NH2, halogen, OH, CN, and reacted with one or more R 2-1-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy or -C(=O)R 2-1-1-2 Each R 2-1-1-1 Independently halogen or OH; R 2-1-1-2 It is a C1-C6 alkyl group;

[0061] n is 0 or 1;

[0062] Z 1 For O, S or NR 2-1-4 ;

[0063] Z 2 For CR 2-1-5 R 2-1-6 ;

[0064] Z 3 For NR 2-1-4 or CR 2-1-7 R 2-1-8 ;

[0065] Z 4 For NR 2-1-4 or CR 2-1-9 R 2-1-10 ;

[0066] Each R 2-1-4Independently H or C1-C4 alkyl;

[0067] R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently, it is H, NH2, halogen, OH, CN, C1-C6 alkyl, or is bound by one or more R 2-1-1-3 Substituted C1-C6 alkyl groups, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl; each R 2-1-1-3 It can be a halogen or OH on its own;

[0068] Or, “R” 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form carbonyl groups, thiocarbonyl groups, and are influenced by one or more R groups." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0069] Or, “R” 2-1-5 and R 2-1-7 "or "R 2-1-7 and R 2-1-9 "Together with the carbon atoms they are attached, they form a structure consisting of one or more R atoms." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0070] Each R 2-1-5-1 It is NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0071] Each R 2-1-5-2 Independently NH2, halogen, OH, CN, and reacted with one or more R 2-1-1-3Substituted C1-C6 alkyl, C1-C6 alkyl, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl;

[0072] R 3 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C1-C6 heteroalkyl, C1-C6 heteroalkyl, or substituted with one or more R 3-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0073] R 4 For (a), (b), or (c):

[0074] (a) by one or more R 4-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 4-1 The substitute is "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4" or "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4".

[0075] (b) by one or more R 4-1 Substituted with 5-6-membered heteroaryl, 5-10-membered heterocyclic alkyl, C6-C 10 "aryl, or C3-C8 cycloalkyl ring fused with 5-10 heteroaryl" or "with 5-6 heteroaryl, 5-10 heterocycloalkyl, C6-C 10 "Aryl, or C3-C8 cycloalkyl ring-fused 5-10 membered heteroaryl";

[0076] (c) H, OH, halogens, CN, and one or more R 4-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 4-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 4-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R4-1 Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 4-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 4-1 The substituted terms are "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", and -O-C3-C. 12 cycloalkyl, with one or more R 4-1 Replacement -O-C3-C 12 Cycloalkyl, -C(O)C1-C6 alkyl, NH2, -C(O)NR 4-2 R 4-3 -SR 4-2 -S(O)R 4-2 -S(O)2-R 4-2 -S(O)2NR 4-2 R 4-3 -NR 4-3 C(O)NR 4-2 R 4-3 or -NR 4-3 C(O)OR 4-2 ;

[0077] R 4-2 and R 4-3 Independently H, C1-C6 alkyl or -C0-C6 alkylene-R 4-2-1 Or, R 4-2 and R 4-3 Together with the N atoms attached to them, they form "5-12-membered heteroaryl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4" or "3-12-membered heterocyclic alkyl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4".

[0078] R 4-2-1 For C6-C 10 Aryl, "5-12-membered heteroaryl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms" or "3-12-membered heterocyclic alkyl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms";

[0079] Each R 4-1 Independently oxidized, halogenated, NR 4-1-1 R 4-1-2 , OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, with one or more R 3-1Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 3-1 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 3-1 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..." 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkyl, -S(O)2NR 4-1-1 R 4-1-2 -C(O)NR 4-1-1 R 4-1-2 -OC(O)NR 4-1-1 R 4-1-2 -C(O)R 4-1-3 -OC(O)R 4-1-3 -C(O)OR 4-1-4 -OR 4-1-4 -SR 4-1-4 -S(O)R 4-1-5 -S(O)2R 4-1-5 or -S(O)(=NH)R 4-1-5 ;

[0080] R 4-1-1 and R 4-1-2 Independently H, C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0081] R 4-1-3 H, C1-C6 alkyl, C2-C6 alkenyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0082] R 4-1-4H, C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0083] R 4-1-5 C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0084] X is N or CR 6 ;

[0085] R 6 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 3-1 Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 3-1 Replacement C3-C 12 cycloalkyl or C3-C 12 cycloalkyl;

[0086] R 5 H, NH2, halogen, CN, OH, C1-C6 alkyl group substituted with one or more halogens, C3-C alkyl group substituted with one or more halogens 12 cycloalkyl, C3-C 12 Cycloalkyl, C1-C6 alkoxy or C1-C6 alkoxy substituted with one or more halogens.

[0087] In a preferred embodiment of the present invention, certain groups in the heterocyclic compound of Formula I or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention, R 2-1 -(CH2)mR 2 -1-11 m is 1 or 2;

[0088] R 2-1-11 For one or more R 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 2-1-1Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 2-1-1 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 2-1-1 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".

[0089] The present invention also provides heterocyclic compounds as shown in Formula II or pharmaceutically acceptable salts thereof:

[0090]

[0091] in,

[0092] Y is N or CR 1-1 ;

[0093] R 1-1 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C3-C6 cycloalkyl or C3-C6 cycloalkyl;

[0094] Each R 3-1 Independently oxo, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, or C2-C6 alkenyl or NR 3-1-1 R 3 -1-2 ;R 3-1-1 and R 3-1-2 Independently H or C1-C6 alkyl;

[0095] n is 0 or 1;

[0096] Z 1 For O, S or NR 2-1-4 ;

[0097] Z 2 For CR2-1-5 R 2-1-6 ;

[0098] Z 3 For NR 2-1-4 or CR 2-1-7 R 2-1-8 ;

[0099] Z 4 For NR 2-1-4 or CR 2-1-9 R 2-1-10 ;

[0100] Each R 2-1-4 Independently H or C1-C4 alkyl;

[0101] R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently, it is H, NH2, halogen, OH, CN, C1-C6 alkyl, or is bound by one or more R 2-1-1-3 Substituted C1-C6 alkyl groups, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl; each R 2-1-1-3 It can be a halogen or OH on its own;

[0102] Or, “R” 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form carbonyl groups, thiocarbonyl groups, and are influenced by one or more R groups." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0103] Or, “R” 2-1-5 and R 2-1-7 "or "R 2-1-7 and R 2-1-9 "Together with the carbon atoms they are attached, they form a structure consisting of one or more R atoms." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0104] Each R 2-1-5-1 It is NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0105] Each R 2-1-5-2 Independently NH2, halogen, OH, CN, and reacted with one or more R 2-1-1-3 Substituted C1-C6 alkyl, C1-C6 alkyl, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl;

[0106] R 3 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 3-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 3-1 Substituted C1-C6 heteroalkyl, C1-C6 heteroalkyl, or substituted with one or more R 3-1 The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0107] R 4 For (a), (b), or (c):

[0108] (a) by one or more R 4-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 4-1 The substitute is "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4" or "a 5-10 membered monocyclic heteroaryl group whose heteroatoms are selected from one or more of N, O and S and whose heteroatoms number 1-4".

[0109] (b) by one or more R 4-1 Substituted with 5-6-membered heteroaryl, 5-10-membered heterocyclic alkyl, C6-C 10"aryl, or C3-C8 cycloalkyl ring fused with 5-10 heteroaryl" or "with 5-6 heteroaryl, 5-10 heterocycloalkyl, C6-C 10 "Aryl, or C3-C8 cycloalkyl ring-fused 5-10 membered heteroaryl";

[0110] (c) H, OH, halogens, CN, and one or more R 4-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 4-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy, or substituted with one or more R 4-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 4-1 Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 4-1 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 4-1 The substituted terms are "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", and -O-C3-C. 12 cycloalkyl, with one or more R 4-1 Replacement -O-C3-C 12 Cycloalkyl, -C(O)C1-C6 alkyl, NH2, -C(O)NR 4-2 R 4-3 -SR 4-2 -S(O)R 4-2 -S(O)2R 4-2 -S(O)2NR 4-2 R 4-3 -NR 4-3 C(O)NR 4-2 R 4-3 or -NR 4-3 C(O)OR 4-2 ;

[0111] R 4-2 and R 4-3 Independently H, C1-C6 alkyl or -C0-C6 alkylene-R 4-2-1 Or, R 4-2 and R 4-3 Together with the N atoms attached to them, they form "5-12-membered heteroaryl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4" or "3-12-membered heterocyclic alkyl groups with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4".

[0112] R 4-2-1 For C6-C 10 Aryl, "5-12-membered heteroaryl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms" or "3-12-membered heterocyclic alkyl with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms";

[0113] Each R 4-1 Independently oxidized, halogenated, NR 4-1-1 R 4-1-2 , OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, with one or more R 3-1 Replacement C6-C 10 Aryl, C6-C 10 aryl, with one or more R 3-1 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 3-1 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..." 3-1 Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkyl, -S(O)2NR 4-1-1 R 4-1-2 -C(O)NR 4-1-1 R 4-1-2 -OC(O)NR 4-1-1 R 4-1-2 -C(O)R 4-1-3 -OC(O)R 4-1-3 -C(O)OR 4-1-4 -OR 4-1-4 -SR 4-1-4 -S(O)R 4-1-5 -S(O)2R 4-1-5 or -S(O)(=NH)R 4-1-5 ;

[0114] R 4-1-1 and R 4-1-2 Independently H, C1-C4 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0115] R 4-1-3 H, C1-C6 alkyl, C2-C6 alkenyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0116] R 4-1-4 H, C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0117] R 4-1-5 C1-C6 alkyl, C3-C 12 Cycloalkyl, "a 3-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and having 1-4 heteroatoms", C6-C 10 Aryl or "a 5-12 membered heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms";

[0118] X is N or CR 6 ;

[0119] R 6 H, OH, halogen, CN, or one or more R 3-1 Substituted C1-C6 alkyl, C1-C6 alkyl, or substituted with one or more R 3-1 Substituted C2-C6 alkenyl, C2-C6 alkenyl, or those with one or more R 3-1 Substituted C2-C6 ynyl group, C2-C6 ynyl group, or group with one or more R groups 3-1 Replacement C3-C 12 cycloalkyl or C3-C 12 cycloalkyl;

[0120] R 5 H, NH2, halogen, CN, OH, C1-C6 alkyl group substituted with one or more halogens, C3-C alkyl group substituted with one or more halogens 12 cycloalkyl, C3-C 12Cycloalkyl, C1-C6 alkoxy or C1-C6 alkoxy substituted with one or more halogens.

[0121] In a preferred embodiment of the present invention, certain groups in the heterocyclic compound of formula I or II or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0122] Y is CR 1-1 .

[0123] In one aspect of the present invention, R 1-1 For H.

[0124] In one aspect of the present invention, R 1 It is a halogen, a C1-C6 alkyl, or a C3-C6 cycloalkyl.

[0125] In one aspect of this invention, Z 5 It is O.

[0126] In one aspect of the present invention, R 2-1 For -OR 2-1-2 -NHR 2-1-3 or -(CH2)mR 2-1-11 .

[0127] In one aspect of the present invention, R 2-1 For -OR 2-1-2 or -NHR 2-1-3 .

[0128] In one aspect of the present invention, R 2-1-2 For one or more R 2-1-1 Replacement C3-C 12 cycloalkyl, with one or more R 2-1-1 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".

[0129] In one aspect of the present invention, R 2-1-3 "A 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1-4."

[0130] In one embodiment of the present invention, m is 1.

[0131] In one aspect of the present invention, R 2-1-11 For one or more R 2-1-1The 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".

[0132] In one aspect of the present invention, R 2-2 For H, by one or more R 2-1-1 The substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4, which are 5-12-membered heteroaryl groups" or

[0133] In one embodiment of the present invention, each R 2-1-1 It is independently NH2, CN, C1-C6 alkyl, or composed of one or more R 2-1-1-1 Substituted C1-C6 alkyl groups.

[0134] In one aspect of this invention, Z 2 For CR 2-1-5 R 2-1-6 .

[0135] In one aspect of this invention, Z 3 For CR 2-1-7 R 2-1-8 .

[0136] In one aspect of this invention, Z 4 For CR 2-1-9 R 2-1-10 .

[0137] In one aspect of the present invention, R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently H, halogen, OH, CN, C1-C6 alkyl, or by one or more R 2-1-1-3 Substituted C1-C6 alkyl groups, -C(O)R 2-1-5-1 Or C3-C 12 cycloalkyl;

[0138] Or, “R” 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form a carbonyl group, which is then bonded by one or more R groups." 2-1-5-2 Replacement C3-C 12 cycloalkyl, C3-C 12 cycloalkyl, with one or more R 2-1-5-2The substituted "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms";

[0139] Or, “R” 2-1-5 and R 2-1-7 "Together with the carbon atoms they are attached, they form C3-C" 12 Cycloalkyl or “a 3-12 membered heterocycloalkyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms number 1-4”.

[0140] In one embodiment of the present invention, each R 2-1-5-1 It is NH2.

[0141] In one embodiment of the present invention, each R 2-1-5-2 Independently for one or more R 2-1-1-3 Substituted C1-C6 alkyl or C1-C6 alkyl.

[0142] In one aspect of the present invention, R 3 For H.

[0143] In one aspect of the present invention, R 4 For one or more R 4-1 The substituted heteroatom is selected from one or more of N, O, and S, and is a 5-10 membered monocyclic heteroaryl group with 1-4 heteroatoms, or is replaced by one or more R 4-1 The substitute is "5-10-membered heteroaryl ring fused with 5-10-membered heterocyclic alkyl ring".

[0144] In one embodiment of the present invention, each R 4-1 Independent for NR 4-1-1 R 4-1-2 Or C1-C6 alkyl.

[0145] In one aspect of the present invention, R 4-1-1 and R 4-1-2 H stands for H independently.

[0146] In one embodiment of the present invention, X is CR 6 .

[0147] In one aspect of the present invention, R 5 It is NH2.

[0148] In one aspect of the present invention, R 6 It is a halogen.

[0149] In one aspect of the present invention, when R 1 When the halogen is halogen, the halogen is F or Cl, preferably F.

[0150] In one aspect of the present invention, 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.

[0151] In one aspect of the present invention, when R 1 When it is a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a C3-C4 cycloalkyl group, such as cyclopropyl.

[0152] In one aspect of the present invention, when R 2-1-2 For one or more R 2-1-1 Replacement C3-C 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group is either cyclobutane or adamantane.

[0153] In one aspect of the present invention, when R 2-1-2 For one or more R 2-1-1 When the substituted "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" is a tetrahydrofuranyl group (e.g., 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 a tetrahydrofuranyl group (e.g., 3-12 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms). ), tetrahydropyranyl (e.g.) ), morpholino (e.g.) ),

[0154]

[0155] In one aspect of the present invention, when R 2-1-3 When the term is "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", then "a 3-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4" is "a 3-6 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", for example, morpholino (e.g., ).

[0156] In one aspect of the present invention, when R 2-1-11 For one or more R 2-1-1 When the substituted "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" is a morpholinoyl group (e.g., )or

[0157] In one aspect of the present invention, when R 2-2 For one or more R 2-1-1 When the substituted "heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1-4, it is a 5-12 membered heteroaryl group", and the substituted "heteroatoms are selected from one or more of N, O, and S", it is a 5-12 membered heteroaryl group. 2-1-1 The phrase "a 5-12-membered heteroaryl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4" is replaced with "a 5-6-membered heteroaryl group whose heteroatoms are selected from one or more of N, O, and S, and whose heteroatoms number 1-4", for example, pyrazolyl (e.g.) ).

[0158] In one aspect of the present invention, when each R 2-1-1 Independently for one or more R 2-1-1-1 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl, such as methyl, ethyl or isopropyl.

[0159] In one aspect of the present invention, when each R 2-1-1-1 When it is a halogen on its own, the halogen is F.

[0160] In one aspect of the present invention, when R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 When it is a halogen on its own, the halogen is F.

[0161] In one aspect of the present invention, when R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently for one or more R 2-1-1-3 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl, such as methyl, ethyl or isopropyl.

[0162] In one aspect of the present invention, when R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently for C3-C 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group is adamantane.

[0163] In one aspect of this invention, "R" 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form a structure consisting of one or more R atoms." 2-1-5-2 Replacement C3-C 12 cycloalkyl or C3-C 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl.

[0164] In one aspect of this invention, "R" 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2-1-10 "Together with the carbon atoms they are attached, they form a structure consisting of one or more R atoms." 2-1-5-2 When the substitution of "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" or "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms" is replaced by "a heteroatom selected from one or more of N, O and S, and a 3-12 membered heterocyclic alkyl group having 1-4 heteroatoms", such as oxadiidine, tetrahydrofuranyl or tetrahydropyranyl.

[0165] In one aspect of this invention, "R" 2-1-5 and R 2-1-7 "or "R 2-1-7 and R 2-1-9 "Together with the carbon atoms they are attached, they form C3-C" 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group is a C3-C6 cycloalkyl group, such as cyclopentyl.

[0166] In one aspect of this invention, "R" 2-1-5 and R 2-1-7 "or "R 2-1-7 and R 2-1-9 When the carbon atoms attached to them form a "3-12 membered heterocyclic alkyl group with heteroatoms selected from one or more of N, O and S and having 1-4 heteroatoms", the "3-12 membered heterocyclic alkyl group with heteroatoms selected from one or more of N, O and S and having 1-4 heteroatoms" is "3-6 membered heterocyclic alkyl group with heteroatoms selected from one or more of N, O and S and having 1-4 heteroatoms", such as tetrahydrofuranyl or tetrahydropyranyl.

[0167] In one embodiment of the present invention, each R 2-1-5-2 Independently for one or more R 2-1-1-3 When the substituted C1-C6 alkyl or C1-C6 alkyl is used, the C1-C6 alkyl is a C1-C4 alkyl, such as methyl.

[0168] In one aspect of the present invention, when R 4 For one or more R 4-1 When the substituted "heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1-4, it is a 5-10 membered monocyclic heteroaryl group", and the substituted "heteroatoms are selected from one or more of N, O, and S", it is a 5-10 membered monocyclic heteroaryl group. 4-1 The substituted "5-10 membered monocyclic heteroaryl group selected from one or more of N, O and S, with 1-4 heteroatoms" is replaced by one or more R 4 -1 The substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4, which are 5-6 membered monocyclic heteroaryl groups", such as pyridyl (e.g. ).

[0169] In one aspect of the present invention, when R 4 For one or more R 4-1 When replacing "5-10-membered heteroaryl group fused with a 5-10-membered heterocyclic alkyl ring", the "5-10-membered heteroaryl group fused with a 5-10-membered heterocyclic alkyl ring" is...

[0170] In one embodiment of the present invention, Y is CH.

[0171] In one aspect of the present invention, R 1 It can be F, Cl, methyl, or cyclopropyl.

[0172] In one aspect of the present invention, R 2-1-5 R 2-1-6 R 2-1-7 R 2-1-8 R 2-1-9 and R 2-1-10 Independently H, halogen, or by one or more R 2-1-1-3 Substituted C1-C6 alkyl; or, "R 2-1-5 and R 2-1-6 “R” 2-1-7 and R 2-1-8 "or "R 2-1-9 and R 2 -1-10 "Together with the carbon atoms they are attached, they form carbonyl groups."

[0173] In one embodiment of the present invention, each R 2-1-1-3 It is OH on its own.

[0174] In one aspect of this invention, Z 1 It can be O or S.

[0175] In one aspect of the present invention, in the heterocyclic compound represented by Formula I, R 2 For H,

[0176] In one aspect of the present invention, in the heterocyclic compound represented by Formula II, for

[0177]

[0178] In one aspect of the present invention, R 4 For one or more R 4-1 The substitute is "5-10-membered heteroaryl ring fused with 5-10-membered heterocyclic alkyl ring".

[0179] In one aspect of the present invention, R 4 for

[0180] In one embodiment of the present invention, X is CF.

[0181] In one embodiment of the present invention, the heterocyclic compound represented by I is R 4 for Among them, R 1 and R 2 The definition is as stated in the previous item.

[0182] In one embodiment of the present invention, the heterocyclic compound represented by II is R 4 for Wherein, n, Z 1 Z 2 Z 3 and Z 4 The definition is as stated in the previous item.

[0183] In one aspect of the present invention, the heterocyclic compound represented by Formula I is selected from any of the following compounds:

[0184]

[0185]

[0186]

[0187] In one aspect of the present invention, the heterocyclic compound represented by Formula II is selected from any of the following compounds:

[0188]

[0189]

[0190]

[0191] The present invention also provides a pharmaceutical composition comprising the heterocyclic compound as shown in Formula I or II above, or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0192] The present invention also provides the use of the heterocyclic compounds of formula I or II or their pharmaceutically acceptable salts, or the pharmaceutical compositions thereof, in the preparation of a medicament. Preferably, the medicament is used for the prevention and / or treatment of HPK1-mediated diseases. These HPK1-mediated diseases include, but are 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.

[0193] Unless otherwise specified, the terms used in this invention have the following meanings:

[0194] 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.

[0195] 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.

[0196] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0197] 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.

[0198] 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.

[0199] 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).

[0200] 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.

[0201] 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.

[0202] The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.

[0203] 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.

[0204] The term "alkoxy group" refers to the group -OR X , where R X It is an alkyl group as defined above.

[0205] The term "cycloalkyl" refers to a 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).

[0206] The term "heterocyclic alkyl" refers to a stable 3- to 12-membered monocyclic or polycyclic cyclic group composed 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.

[0207] The term "aryl" refers to an aromatic monocyclic or polycyclic aromatic compound having 6-10 ring atoms and zero heteroatoms. When it is a bicyclic compound, at least one ring is aromatic. Examples include phenyl, naphthyl, etc.

[0208] 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.

[0209] 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).

[0210] 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.

[0211] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] The reagents and raw materials used in this invention are all commercially available.

[0216] The positive and progressive effects of this invention are as follows: This invention provides a novel HPK1 inhibitor with better activity. Detailed Implementation

[0217] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0218] Example 1: Synthesis of compounds I-1, I-1-A and I-1-B

[0219]

[0220] Compound 1 (2.1 g, 3.99 mmol, 1.00 equiv) and a selective fluoride reagent (2.1 g, 5.98 mmol, 1.5 equiv) were dissolved in chloroform / water (20 mL / 20 mL) in a 100 mL glass vial under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 36 hours. The reaction mixture was extracted with dichloromethane (2 x 100 mL), the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography to give compound 2 (640 mg) as a yellow solid. MS (ESI): [M+H] + =544.

[0221] In a 20 mL glass vial, solid phosgene (218.37 mg, 0.736 mmol, 1.00 equiv) was dissolved in dichloromethane (2 mL). Under nitrogen atmosphere at 0 °C, this solution was added dropwise to a solution of N,N-diisopropylethylamine (380.43 mg, 2.943 mmol, 4.00 equiv), compound 2 (400 mg, 0.736 mmol, 1.00 equiv), and trans-alcohol (600 mg crude) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by column chromatography to give a yellow solid compound 3 (300 mg). MS (ESI): [M+H] + =672.

[0222] In a 20 mL sealed tube under nitrogen atmosphere, trifluoroacetic acid (3 mL) was added dropwise to a 10 mL solution of dichloromethane (300 mg) of compound 3. The reaction mixture was stirred at room temperature for 60 min, the reaction solution was concentrated, and the solution was prepared by 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: 15 B to 35 B in 8 min, 35 B to B in min, B to B in min, B to B in min, B to B in min; 254; 220 nm; RT1: 7.35) to give a white solid compound I-1 (70 mg). MS (ESI): [M+H) + =472. 1H NMR (400MHz, CD3OD): δ (ppm) 9.05 (s, 1H), 7.28 (s, 1H), 7.03 (d, J = 6.4Hz, 1H), 4.84–4.82 (m, 1H), 4.30 (t, J = 4.4Hz, 2 H),3.99–3.93(m,2H),3.80–3.76(m,1H),3.40–3.35(m,3H),2.37–2.32(m,1H),1.91(s,3H),1.02(d,J=7.2Hz,3H).

[0223] 19 F NMR (376MHz, CD3OD): δ-140.48,-141.85.

[0224] Compound I-1 (60 mg) was separated by chiral separation (PREP_CHIRAL_HPLC (Column: CHIRAL ARTCellulose-SB, 2*25 cm, 5 μm; Mobile phase A: MTBE (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 10 B to 10 B in 19 min; 220 / 254 nm; RT1: 10.372; RT2: 13.198) to obtain compounds I-1-A (14.1 mg) and I-1-B (12.8 mg).

[0225] I-1-A: Retention time was 10.372 min, MS (ESI): [M+H] + =472. 1 H NMR (400MHz, CD3OD): δ (ppm) 9.05 (s, 1H), 7.27 (s, 1H), 7.02 (d, J = 6.0Hz, 1H), 4.84–4.82 (m, 1H), 4.30 (t, J = 4.4Hz, 2 H),3.98–3.93(m,2H),3.79–3.76(m,1H),3.39–3.34(m,3H),2.38–2.33(m,1H),1.91(s,3H),1.03(d,J=7.2Hz,3H).

[0226] 19 F NMR (376MHz, CD3OD): δ-140.45,-141.81.

[0227] I-1-B: Retention time was 13.198 min, MS (ESI): [M+H] + =472. 1H NMR (400MHz, CD3OD): δ (ppm) 9.05 (s, 1H), 7.27 (s, 1H), 7.02 (d, J = 6.0Hz, 1H), 4.84–4.82 (m, 1H), 4.30 (t, J = 4.4Hz, 2 H),3.98–3.93(m,2H),3.79–3.76(m,1H),3.40–3.35(m,3H),2.37–2.32(m,1H),1.91(s,3H),1.02(d,J=7.2Hz,3H).

[0228] 19 F NMR (376MHz, CD3OD): δ-140.46,-141.83.

[0229] Example 2 Synthesis of Compound I-2

[0230]

[0231] In a 50 mL sealed tube, compound 1 (300 mg, 0.53 mmol) was dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (157 mg, 1.2 mmol) and a mixture of trans-alcohols (415 mg, 4.0 mmol) were added at room temperature, purging with nitrogen. Solid phosgene (84 mg, 0.28 mmol) was then dissolved in a suitable amount of dichloromethane and added dropwise at 0 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 0.5 h. The reaction was then purified by thin-layer chromatography to give a yellow solid compound 2 (200 mg). MS (ESI): m / z, [M+H] + =689.

[0232] Compound 2 (80 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (HPLC) (Column: XBridgePrep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 25% B in 8 min, 25% B; Wavelength: 254 nm) to obtain an orange-yellow solid compound I-2 (6 mg). MS (ESI): m / z, [M+H) + =488. 1H NMR (300MHz, DMSO-d6) δ9.85(s,1H),9.43(s,1H),7.41(s,1H),7.06(d,J=6.5Hz,1H),4.81(d,J=4.0Hz,1H),4. 34(s,3H),3.94(q,J=7.6,7.0Hz,6H),3.72(d,J=10.7Hz,2H),3.31(s,1H),1.95(s,3H),1.18(d,J=7.2Hz,3H).

[0233] 19 F NMR (376MHz, DMSO-d6): δ-138.65.

[0234] Example 3: Synthesis of compounds I-3, I-3-A and I-3-B

[0235]

[0236] In a 100 mL single-necked flask under nitrogen atmosphere, N-bromosuccinimide (600 mg, 3.2 mmol) was added to a 20 mL solution of compound 1 (1.4 g, 2.66 mmol, 1.0 equiv) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was quenched with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by column chromatography to give compound 2 (1.5 g, 47.8% yield), a brown solid. m / z (ES+), [M+H] + =606.

[0237] In a 40 mL sealed tube, compound 2 (1.4 g, 2.32 mmol, 1.0 equiv), methylboric acid (1 g, 16.66 mmol), palladium acetate (54 mg, 0.23 mmol), RuPhos (214 mg, 0.46 mmol), and cesium carbonate (2.268 g, 6.96 mmol) were dissolved in toluene / water (20 / 2 mL). The reaction mixture was stirred at 95 °C for 6 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by column chromatography to give compound 3 (800 mg). m / z (ES+), [M+H) + =540.

[0238] In a 40 mL sealed tube, solid phosgene (304.1 mg, 1.03 mmol, 0.7 equiv) was dissolved in dichloromethane (1 mL) and added dropwise at 0 °C under nitrogen atmosphere to a dichloromethane solution of compound 3 (790 mg, 1.464 mmol, 1.0 equiv), trans-alcohol (1.5 g, 14.64 mmol, 10.0 equiv), and N,N-diisopropylethylamine (567.6 mg, 4.392 mmol, 3.0 equiv) in 10 mL. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by column chromatography to give a mixture of yellow solid compounds 4 and I-3 (580 mg, yield 59.33%). m / z (ES+), [M+H) + =668.

[0239] In a 40 mL sealed tube, trifluoroacetic acid (5 mL) was added dropwise to a solution of compound 4 / I-3 mixture (580 mg, 0.87 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated, and the crude product was purified by preparative liquid chromatography (HPLC) (Column: XBridge Prep C18 OBD Column, 19 × 150 mm 5 μm; Mobile phase A: undefined, Mobile phase B: undefined; Flow rate: 20 mL / min; Gradient: 15 B to 40 B in 7 min, 40 B to B in min, B to B in min, B to B in min, B to B in min; 254 nm;) to give a white solid compound (+ / -) 5 425 mg. (ES+), [M+H) + =468.

[0240] 250 mg of compound I-3 was purified by chiral column chromatography (Column: CHIRAL ART Cellulose-SB, 5*25cm, 5µm; Mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 20 B to 20 B in 23 min; 254 / 220 nm; RT1 (min): 18.119; RT2 (min): 20.955) to obtain isomers I-3-A and I-3-B.

[0241] Isomer I-3-A:

[0242] The retention time is 18.119 minutes.

[0243] (ES+),[M+H]+=468. 1H NMR (CD3OD-d4, 400MHz): δ (ppm) 1.13 (d, J = 7.2Hz, 3H), 2.05 (s, 3H), 2.43-2.48 (m, 1H), 2.52 (s, 3H), 3.44–3.48 (m, 1H), 3.53-3.55 (m, 2H) 3 ...

[0244] 19 F NMR (376MHz, CD3OD-d4): δ-141.56.

[0245] Isomer I-3-B:

[0246] The retention time is 20.955 minutes.

[0247] (ES+),[M+H]+=468. 1 H NMR (CD3OD-d4, 400MHz): δ (ppm) 1.13 (d, J = 7.2Hz, 3H), 2.05 (s, 3H), 2.43-2.48 (m, 1H), 2.52 (s, 3H), 3.44–3.48 (m, 1H), 3.53-3.55 (m, 2H), 3.90(dd,J=10.5,1.9Hz,1H),4.02–4.09(m,2H),4.48(t,J=4.4Hz,2H),4.92-4.93(m,1H),7.18(d,J=6.0Hz,1H),7.45(s,1H),9.32(s,1H).

[0248] 19 F NMR (376MHz, CD3OD-d4): δ-141.56.

[0249] Example 4 Synthesis of Compound I-4

[0250]

[0251] In a 50 mL reaction flask, compound 1 (500 mg, 0.82 mmol), boric acid (142 mg, 1.65 mmol), potassium phosphate (526 mg, 2.47 mmol), palladium acetate (37 mg, 0.16 mmol), and Ruphos (154 mg, 0.33 mmol) were dissolved in a mixed solvent of toluene (5 mL) and water (1 mL). Nitrogen gas was purged, and the reaction mixture was stirred at 95 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography to give compound 2 (230 mg, 97%) as a brown solid. MS (ESI): m / z, [M+H] + =566.

[0252] In a 50 mL reaction flask, compound 2 (230 mg, 0.4 mmol) was dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (157 mg, 1.2 mmol) and a mixture of trans-alcohols (415 mg, 4.0 mmol) were added at room temperature, purging with nitrogen. Solid phosgene (84 mg, 0.28 mmol) was dissolved in a suitable amount of dichloromethane and added dropwise to the reaction mixture at 0 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 0.5 h. The reaction was then purified by thin-layer chromatography to give a yellow solid compound 3 (220 mg, 80% yield). MS (ESI): m / z, [M+H] + =694.

[0253] Compound 3 (80 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added at room temperature and stirred for 1 h. After the reaction was complete, the reaction system was concentrated, and the crude product was purified by preparative liquid chromatography (HPLC) (Column: XBridge PrepOBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 50% B in 8 min, 50% B; Wavelength: 254 nm) to obtain an orange-yellow solid compound (+ / -)I-4 (16.9 mg). MS (ESI): m / z, [M+H) + =494. 1H (300MHz, DMSO-d6): δ9.31 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 4.82 (d, J = 2.1Hz, 1H), 4.81-4.82 (m, 2H), 3.94-3.99 (m, 2H), 3. 74-3.76 (m, 1H), 3.33-3.40 (m, 3H), 2.32-2.39 (m, 2H), 1.97 (s, 3H), 1.93-1.96 (m, 1H), 1.03-1.06 (m, 4H), 0.46-0.48 (m, 2H).

[0254] 19 F NMR (282MHz, DMSO-d6): δ-140.49.

[0255] Example 5: Synthesis of Compound I-5

[0256]

[0257] In a 10 mL sealed tube, triethylamine (77.14 mg, 0.762 mmol, 3.50 equiv) and EDCI were added to a solution of compound 1 (140.00 mg, 0.218 mmol, 1.00 equiv) in acetonitrile (4.00 mL). The reaction mixture was stirred overnight at 40 °C, and the solution was evaporated to dryness and column-secured to give compound 2 (60 mg) as a brown solid. MS (ESI): [M+H) + =609.

[0258] In an 8 mL sealed tube, compound 2 (160 mg) was dissolved in dichloromethane (4 mL), nitrogen gas was introduced, and trifluoroacetic acid (1.2 mL) was added under stirring at room temperature for two hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by high-performance liquid chromatography (HPLC) (Column: X Bridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 23% B to 43% B in 8 min, 43% B; Wavelength: 254 nm; 220 nm; RT1 (min): 8.48) to obtain a pale yellow solid compound I-5 (33.3 mg). MS (ESI): [M+H) + =409. 1H NMR(400MHz,CD3OD)δ9.29(s,1H),7.37(s,1H),7.15(d,J=6.0Hz,1H),4.41–4.39(m,2H) ,4.06(t,J=8.4Hz,2H),3.71–3.54(m,2H),3.49–3.47(m,2H),2.55(s,3H),2.00(s,3H).

[0259] 19 F NMR (376MHz, CD3OD): δ-141.49.

[0260] Example 6 Synthesis of Compound I-6

[0261]

[0262] Compound 1 (110 mg, 0.202 mmol, 1.0 equiv), compound SM1 (147.44 mg, 0.606 mmol, 3.0 equiv), and DIPEA (104.43 mg, 0.808 mmol, 4.0 equiv) were dissolved in dichloromethane (5 mL). Solid phosgene (89.99 mg, 0.303 mmol, 1.5 equiv) was added to the reaction solution in an ice bath. The mixture was then stirred at room temperature for 4 hours under nitrogen protection. The reaction solution was purified by high pressure and freeze-dried to obtain compound 2 (191 mg) as a yellow solid. MS (ESI): [M+H] + =813.

[0263] Compound 2 (196 mg, 0.233 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for two hours under nitrogen protection. The reaction solution was purified by high pressure and freeze-dried to obtain a yellow solid compound I-6 (12.8 mg). MS (ESI): [M+H] + =513; 1 H NMR(400MHz,CD3OD)δ9.05(s,1H),7.26(s,1H),7.00(d,J=6.0Hz,1H),5.29–5.25(m,1H),4.29(t,J=4.4Hz,2H),4.03–3.88 (m,2H),3.38–3.28(m,3H),3.25–3.13(m,2H),2.96–2.92(m,1H),2.36–2.31(m,1H),2.19–2.10(m,1H),2.02–1.85(m,5H).

[0264] 19F NMR (376MHz, CD3OD): δ-140.20,-141.61.

[0265] Example 7 Synthesis of Compound I-7

[0266]

[0267] Solid phosgene (82 mg, 0.416 mmol, 1.50 equiv) was dissolved in dichloromethane (1 mL) in a 40 mL sealed tube. This solution was then added dropwise to a dichloromethane (2 mL) solution of compound 1 (150 mg, 0.277 mmol, 1.00 equiv), SM1 (202 mg, 0.831 mmol, 3.00 equiv), and DIEA (143 mg, 1.108 mmol, 4.00 equiv). The mixture was stirred at room temperature for 3 hours, then concentrated by rotary evaporation. The resulting solution was separated by preparative thin-layer chromatography to obtain a yellow solid compound 2 (80 mg). MS (ESI): [M+H] + =813.

[0268] Compound 1 (70.00 mg, 0.086 mmol, 1.00 equiv) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for two hours under nitrogen protection. The reaction solution was then evaporated to dryness, and purified by high-performance liquid chromatography (HPLC) (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH:DCM=1:1--HPLC; Flow rate: 20 mL / min; Gradient: 80% B to 80% B in 15 min; Wavelength: 220 / 254 nm; RT1 (min): 5.54; RT2 (min): 11.69) to give a white solid compound I-7 (15.0 mg). MS (ESI): [M+H) + =513; 1 H NMR (400MHz, CD3OD) δ9.08(s,1H),7.28(s,1H),7.05–7.03(m,1H),5.05–4.94(m,1H),4.30(t,J=4.4Hz,2H),4.09(t,J=10.8 Hz,2H),3.81(d,J=10.8Hz,2H),3.39(t,J=4.4Hz,2H),3.28–3.20(m,2H),3.04–2.98(m,2H),1.91(s,3H),1.85–1.74(m,2H).

[0269] 19F NMR (376MHz, CD3OD): δ-140.33,-141.59.

[0270] Example 8 Synthesis of Compounds I-8

[0271]

[0272] Compound 1 (10 g, 40.118 mmol, 1.00 equiv) was dissolved in THF (200 mL), and nitrogen was purged. The reaction system was kept at -78 °C. LIHMDS (60.42 mL, 361.062 mmol, 9 equiv) was slowly added to the system. After stirring at 0 °C for 15 minutes, the system was cooled to -78 °C, and then SM1 (10.49 g, 60.177 mmol, 1.5 equiv) was slowly (dropwise over 5 minutes) added to the reaction system. The system was stirred at room temperature for two hours. After the reaction was complete, the system was quenched with water (400 mL). The mixture was extracted with ethyl acetate (2 x 200 mL), the organic phases were combined, washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to silica gel normal phase chromatography (PE / EA = 4:1) to obtain a yellow oily compound 2 (6 g, yield 35.31%). m / z(ES+)[M+H) + =424.

[0273] Compound 2 (5.5 g, 12.985 mmol, 1.00 equiv) and LiBH4 (565.71 mg, 25.97 mmol, 2 equiv) were dissolved in tetrahydrofuran (30 mL), purged with nitrogen, and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched at 0 °C with 1 N sodium hydroxide solution, extracted with ethyl acetate (2 x 200 mL), the organic phases were combined, washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude yellow oily compound 3 (3 g, yield 58.41%). m / z(ES+), [M+H] + =396.

[0274] Compound 3 (2.5 g, 6.320 mmol, 1.00 equiv) and tetrabutylammonium fluoride (20 mL, 76.493 mmol, 12.10 equiv) were dissolved in THF (20 mL), and nitrogen was purged. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction system was quenched with water (200 mL). The mixture was extracted with ethyl acetate (2 x 200 mL), the organic phases were combined, washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to silica gel normal-phase chromatography (CHCl3 / MeOH = 5:1) to give a yellow oily compound 4 (1.1 g, yield 61.87%). m / z (ES+), [M+H) + =282.

[0275] Compound 4 (1.1 g, 3.910 mmol, 1.00 equiv) and SM2 (22 mg, 0.088 mmol, 0.02 equiv) were dissolved in THF (10 mL), and nitrogen was purged. TSCl (792 mg, 4.154 mmol, 1.06 equiv) was slowly added at 0 °C. Then, triethylamine (0.5 mL, 4.941 mmol, 1.26 equiv) was slowly added at the same temperature over a period exceeding 30 seconds. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (200 mL), extracted with ethyl acetate (2 x 200 mL), and the organic phases were combined. The mixture was washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to silica gel normal-phase chromatography (PE / EA = 1:2) to obtain a yellow solid compound 5 (578 mg, yield 56.14%). m / z (ES+), [M+H) + =264.

[0276] Compound 5 (55 mg, 0.209 mmol, 1.00 equiv), triphosgene (124.90 mg, 0.230 mmol, 1.1 equiv), and DIEA (81.00 mg, 0.627 mmol, 3 equiv) were dissolved in dichloromethane (1 mL), and nitrogen was purged. Triphosgene (92.98 mg, 0.314 mmol, 1.5 equiv) was slowly added at 0 °C. The reaction system was reacted at room temperature for 4 hours. After the reaction was completed, the reaction system was concentrated to obtain a crude product. The crude product was subjected to silica gel normal-phase chromatography (PE / EA = 2:1) to obtain a bright yellow solid compound 6 (50 mg, yield 28.74%). m / z (ES+), [M+H) + =833.

[0277] Compound 6 (47 mg, 0.056 mmol, 1.00 equiv) was dissolved in trifluoroacetic acid (2 mL), and nitrogen was purged. The reaction system was then reacted at 55 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (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: 5% B to 30% B in 8 min, 30% B; Wavelength: 220 nm) to give a yellow-green solid compound I-8 (3.8 mg, yield 11.81%). (ES+), [M+H) + =499. 1 H NMR (400MHz, CD3OD-d4) δ9.21(s,1H),7.39(s,1H),7.15(d,J=6.0Hz,1H),5.48–5.42(m,1H),4.42(t,J=4.4 Hz,2H),4.29(d,J=10.9Hz,1H),4.13(td,J=11.2,5.5Hz,3H),4.04–3.87(m,4H),3.51(s,2H),2.03(s,3H). 19 F NMR (376MHz, CD3OD-d4): δ-140.11,-141.92.

[0278] Example 9: Synthesis of Compounds I-9

[0279]

[0280] Compound 1 (200 mg, 0.368 mmol, 1.00 equiv), SM1 (409.03 mg, 1.104 mmol, 3 equiv), and N,N-diisopropylethylamine (142.66 mg, 1.104 mmol, 3 equiv) were dissolved in dichloromethane (10 mL). A solution of solid phosgene (76.42 mg, 0.258 mmol, 0.7 equiv) in dichloromethane (1 mL) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by thin-layer chromatography to obtain a yellow solid compound 2 (180 mg, yield 43.71%). MS (ESI): m / z, [M+H] + =941.

[0281] Compound 2 (170 mg, 0.181 mmol, 1.00 equiv) was dissolved in 4 mol / L methanol hydrochloride (10 mL) solution and stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and the crude product obtained by thin-layer chromatography was further purified by high-performance liquid chromatography (HPLC) (Column: Xselect CSH OBD Column 30*150 mm 5 μm, n; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 28% B in 7 min; Wavelength: 254 nm) to obtain a yellow solid compound I-9 (4.8 mg, yield 5.05%). MS (ESI): m / z, [M+H) + =502. 1 H NMR(400MHz,CD3OD-d4)δ9.20(d,J=0.8Hz,1H),7.53(s,1H),7.20(dd,J=6.1,0.8Hz,1H ),4.69(td,J=9.6,4.8Hz,1H),4.58(t,J=4.5Hz,2H),4.13(dd,J=10.6,4.8Hz,1H),3.9 8–3.90(m,1H),3.74(dd,J=11.1,3.4Hz,1H),3.67–3.58(m,3H),3.45(td,J=11.6,2.2H z,1H),3.27(dd,J=10.7,9.5Hz,1H),2.12(s,3H),1.97–1.83(m,2H),1.70–1.56(m,1H). 19 F NMR (400MHz, CD3OD-d4): δ-141.18, -141.47.

[0282] Example 10 Synthesis of Compound I-10

[0283]

[0284] Compound 1 (70 mg, 0.129 mmol, 1.00 equiv) was dissolved in dichloromethane (3 mL, 0.035 mmol, 0.27 equiv), and trifluoroacetic acid (3 mL, 0.026 mmol, 0.20 equiv) was added to the reaction system. The reaction was carried out under nitrogen protection at room temperature for 2 hours. The reaction mixture was evaporated to dryness and purified by high-pressure purification (Column: Xselect CSH OBD Column 30*150 mm 5 μm, n; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 8 min, 40% B; Wavelength: 254 nm; RT1 (min): 6) to give an orange solid product I-10 (22.3 mg). MS (ESI): [M+H) + =344, 1 H NMR (400MHz, CD3OD) δ 8.89 (s, 1H), 7.41 (s, 1H), 6.90 (d, J = 6.0Hz, 1H), 4.45 (t, J = 4.4Hz, 2H), 3.52 (t, J = 4.4Hz, 2H), 2.05 (s, 3H).

[0285] 19 F NMR (376MHz, CD3OD): δ-146.94,-157.95.

[0286] Example 11 Synthesis of Compound I-11

[0287]

[0288] In a 40 mL sealed tube, compound 1 (100 mg, 0.184 mmol, 1.00 equiv) and SM1 (187.90 mg, 1.840 mmol, 10 equiv) were dissolved in 8 mL of tetrahydrofuran. Solid phosgene (56.0 mg, 0.368 mmol, 2 equiv) and pyridine (21.83 mg, 0.276 mmol, 1.5 equiv) were added to the reaction system. The reaction was carried out under nitrogen protection for 3 hours. The reaction system was purified by thin-layer chromatography (TLC) (dichloromethane / methanol: 10:1). Compound 2 (85 mg, yield 68.78%) was obtained as a yellow solid. m / z (ES+), [M+H) + =672.

[0289] In a 40 mL sealed tube, trifluoroacetic acid (3 mL) was added dropwise to a solution of compound 2 (85.00 mg, 0.126 mmol, 1.00 equiv) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated, and the crude product was subjected to preparative liquid chromatography (PLC) at high pressure (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: 8% B to 25% B in 8 min, 25% B in 1 min; Wavelength: 254 nm) to give a yellow solid compound I-11 (8.6 mg, yield 14.41%). m / z (ES+), [M+H) + =472. 1 H NMR(400MHz,CD3OD-d4)δ9.18(s,1H),7.40(s,1H),7.15(d,J=6.0Hz,1H),4.50–4.3 5(m,2H),3.73-3.98(m,4H),3.51(t,J=4.4Hz,2H),3.20-2.70(m,4H),2.03(s,3H). 19 F NMR (376MHz, CD3OD-d4): δ-140.57, -158.28.

[0290] Example 12 Synthesis of Compound I-12

[0291]

[0292] In a 40 mL sealed tube, 100 mg of compound 1, 148 mg of SM1, 68 mg of t-BubrettPhos Pd G3 (0.075 mmol, 0.41 equiv), 44.58 mg of t-BubrettPhos (0.092 mmol, 0.5 equiv), and 180 mg of cesium carbonate were weighed and dissolved in 4 mL of 1,4-dioxane. Nitrogen gas was introduced, and the mixture was allowed to react overnight at 110 °C. After the reaction was complete, the mixture was purified by preparative thin-layer chromatography using dichloromethane:methanol (10:1) to give a yellow solid compound 2 (130 mg). MS (ESI): [M+H] + =624.

[0293] In an 8 mL sealed tube, compound 2 (130 mg) was dissolved in dichloromethane (3 mL), nitrogen gas was introduced, and trifluoroacetic acid (1 mL) was added under stirring at room temperature for two hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by high-pressure purification (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: 15% B to 50% B in 8 min, 50% B; Wavelength: 254 nm; RT1 (min): 7.55) to obtain a yellow solid compound I-12 (10.9 mg). MS (ESI): [M+H) + =424. 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.62(s,1H),7.94(s,1H),7.55(s,1H),7.36(s,1H),6.74( d,J=5.6Hz,1H),6.25(s,2H),5.68(s,1H),4.30(s,2H),3.83(s,3H),3.38(s,2H),1.94(s,3H).

[0294] 19 F NMR (376MHz, DMSO-d6): δ-145.08,-155.35.

[0295] Example 13 Synthesis of Compound I-13

[0296]

[0297] In a sealed 40 mL tube under nitrogen atmosphere, solid phosgene (150 mg, 0.250 mmol, 1.0 equiv) was added to a dichloromethane (2 mL) solution of compound 1 (150 mg, 0.250 mmol, 1.0 equiv), compound SM1 (150 mg, 0.250 mmol, 1.0 equiv), and DIPEA (150 mg, 0.250 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 3 hours, concentrated by rotary evaporation, and then subjected to preparative thin-layer chromatography to obtain solid compound 2 (80 mg). MS (ESI): [M+H] + =630.

[0298] In a 20 mL sealed tube, 1 mL of trifluoroacetic acid was added dropwise to a 2 mL solution of compound 2 (80 mg, 0.127 mmol, 1.0 equiv) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The mixture was then subjected to high-performance liquid chromatography (HPLC) (Column: YMC-Actus Triart C18 ExRS, 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 32% B in 7 min, 32% B; Wavelength: 254 / 220 nm; RT1 (min): 7.72) to give a white solid compound I-13 (1.6 mg). MS (ESI): [M+H) + =430; 1 H NMR (400MHz, CD3OD) δ9.19 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.17 (d, J = 6.0Hz, 1H), 4.11–4.05 (m, 2H ), 3.90 (d, J = 10.8Hz, 1H), 3.50–3.47 (m, 1H), 2.47–2.44 (m, 1H), 2.06 (s, 3H), 1.14 (d, J = 7.2Hz, 3H).

[0299] 19 F NMR (376MHz, CD3OD): δ-140.86,-141.77.

[0300] Example 14 Synthesis of Compound I-14

[0301]

[0302] Compound 1 (140 mg, 0.258 mmol, 1.00 equiv), compound SM1 (210 mg, 0.774 mmol, 3.00 equiv), and DIEA (135 mg, 1.04 mmol, 4 equiv) were dissolved in dichloromethane (5 mL). Solid phosgene (115 mg, 0.387 mmol, 1.5 equiv) was added to the reaction solution in an ice bath, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. The reaction solution was purified by high pressure and freeze-dried to obtain compound 2 (196 mg) as a yellow solid. MS (ESI): [M+H] + =841.

[0303] Compound 2 (196 mg, 0.233 mmol, 1.00 equiv) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for two hours under nitrogen protection. The reaction solution was purified by high pressure and freeze-dried to obtain compound I-14 (12.8 mg) as a yellow solid. MS (ESI): [M+H] + =541; 1 H NMR (400MHz, CD3OD) δ9.07(s,1H),7.27(s,1H),7.03(d,J=6.0Hz,1H),4.55(d,J=4.8Hz,1H),4.30(t,J=4.4Hz,2H),3.85–3.80 (m,2H),3.52(d,J=8.8Hz,1H),3.39(t,J=4.4Hz,2H),2.92–2.72(m,4H),1.91(s,3H),1.79–1.50(m,4H),1.30(d,J=6.8Hz,3H).

[0304] 19 F NMR (376MHz, CD3OD): δ-140.24,-141.52.

[0305] Example 15 Synthesis of Compound I-15

[0306]

[0307] Compound 1 (200 mg) and triethylamine (118 mg) were dissolved in dichloromethane (8 mL) and cooled in an ice-water bath under nitrogen atmosphere. After the temperature stabilized, bromoacetyl chloride (100 mg) was slowly added dropwise to the reaction solution. The mixture was then stirred at room temperature for 2 hours. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a light brown solid compound 2 (114 mg). m / z (ES+), [M+H] + =648.

[0308] Compound 2 (144 mg) and compound SM2 (90 mg) were dissolved together in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (86.4 mg) was added to the reaction system, and the reaction was carried out overnight at 60 °C under nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give a light brown solid compound 3 (110 mg). m / z(ES+), [M+H] + =794.

[0309] Compound 3 (110 mg) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and the mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After the reaction was complete, the pH of the reaction system was adjusted to 8 with triethylamine, and then extracted with ethyl acetate. The organic phase was concentrated to give compound 4 (49 mg). m / z(ES+), [M+H] + =494.

[0310] Compound 4 (29 mg) was dissolved in methanol (5 mL), and 40% formaldehyde aqueous solution (8.9 mg) was added. The mixture was stirred at room temperature under nitrogen for two hours. Sodium cyanoborohydride (8.8 mg) was then added to the reaction system, and the mixture was stirred at room temperature under nitrogen for another hour. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by reversed-phase liquid chromatography to give a pale yellow solid compound I-15 (2.4 mg). m / z (ES+), [M+H) + =508. 1 H NMR (400MHz, CD3OD-d4): δ9.20(s,1H),8.32(s,1H),7.26(s,1H),6.87(d,J=6.4Hz,1H),4.30(t,J=4.4Hz,2H),4.08(d,J=4.5Hz,2H),3.82( d,J=4.5Hz,2H),3.72(s,2H),3.41(t,J=4.4Hz,2H),2.94(d,J=4.5Hz,2H),2.75-2.79(m,2H),2.27(s,3H),1.97(s,3H),1.49-1.52(m,2H). 19 F NMR (376MHz, CD3OD-d4): δ-142.50.

[0311] Example 16 Synthesis of Compound I-16

[0312]

[0313] Compound 1 (200 mg, 1.00 equiv) and compound SM 1 (54 mg, 2.00 equiv) were dissolved in 8 mL of DMF. DIEA (120 mg, 3.00 equiv) was added to the reaction mixture, and the reaction was carried out under nitrogen protection at room temperature for 4 hours. After the reaction was complete, the product was purified by preparative thin-layer chromatography (CH₂Cl₂ / MeOH = 10:1) to obtain a brown solid product 2 (102 mg). MS (ESI): [M+H] + =653.

[0314] Compound 2 (100 mg, 1.00 equiv) was dissolved in 8 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added to the reaction system. The reaction was carried out under nitrogen protection at room temperature for 1 hour. The solution was evaporated to dryness and purified by 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: 24% B to 34% B in 8 min, 34% B; Wave Length: 254 nm; 220 nm; RT1 (min): 7.3) to give a white solid product I-16 (47.5 mg). MS (ESI): [M+H) + =453, 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.39(s,1H),8.29(s,1H),7.33(s,1H),6.89(d,J=6.0Hz,1H),6.27(s,2H) ,5.69(s,1H),4.29(s,2H),3.65(t,J=4.4Hz,4H),3.37(s,2H),3.23(s,2H),2.56(t,J=4.4Hz,4H),1.92(s,3H).

[0315] 19 F NMR (376MHz, DMSO-d6): δ-141.25.

[0316] Example II-1 Synthesis of Compound II-1

[0317]

[0318] The intermediate synthesis procedure was the same as that for compound II-9. Compound 1 (80 mg) was dissolved in dichloromethane (3 mL) in an 8 mL sealed tube, purged with nitrogen, and trifluoroacetic acid (1 mL) was added at room temperature with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH – HPLC; Flow rate: 60 mL / min; Gradient: 25% B to 50% B in 10 min, 50% B; Wavelength: 254 nm) to give a yellow solid compound II-1 (14.5 mg). MS (ESI): m / z [M+H]+ =409. 1 H NMR (400MHz, DMSO-d6): δ9.25(s,1H),7.32(s,1H),7.24(s,1H),6.71(d,J=6.2Hz,1 H),6.08(s,2H),5.66(s,1H),4.23-4.29(m,4H),3.42(t,J=6.0Hz,3H),1.90(s,3H).

[0319] 19 F NMR (376MHz, DMSO-d6): δ-143.80.

[0320] Example II-2 Synthesis of Compound II-2

[0321]

[0322] In a 40 mL sealed tube, p-nitrophenyl chloroformate (241.6 mg, 1.20 mmol, 3.0 eq) was dissolved in tetrahydrofuran (2 mL), and added dropwise at 0 °C to a tetrahydrofuran solution (4 mL) of compound 1 (210.0 mg, 0.4 mmol, 1.0 eq) and pyridine (126.42 mg, 1.6 mmol, 4.0 eq). The reaction system was stirred at room temperature for 2 hours to give a brown solid compound 2 (200 mg, yield 72.47%). MS (ESI): m / z [M+H] + =691.

[0323] In a 40 mL sealed tube, 3-methyl-3-aminomethyl-1-oxetane (81 mg, 0.801 mmol, 1.32 eq) and N,N-diisopropylethylamine (155 mg, 1.2 mmol, 1.97 eq) were dissolved in tetrahydrofuran (2 mL), and then compound 2 (420 mg, 0.608 mmol, 1.0 eq) was added. The reaction system was stirred at room temperature for 2 hours, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, the organic phase was concentrated, and the crude product was purified by column chromatography to give solid compound 3 (100 mg, yield 25.19%). MS (ESI): m / z [M+H] + =653.

[0324] In a 10 mL sealed tube, 1 mL of trifluoroacetic acid was added to a 4 mL solution of compound 3 (50 mg) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (XBridge Prep OBD C18 Column). 150 mm 5 μm; Mobile phase A: undefined, Mobile phase B: undefined; Flow rate: 60 mL / min; Gradient: 15 B to 30 B in 8 min, 30 B to B in min, B to B in min, B to B in min, B to B in min; 254 nm) yielded a yellow solid compound II-2 (2.6 mg). MS (ESI): m / z [M+H] + =453. 1 H NMR (300MHz, DMSO-d6) δ9.42(s,1H),7.40(s,1H),7.35(s,1H),6.98(d,J=6.2Hz,1H),4.49(d,J=10 .8Hz,1H),4.40–4.20(m,3H),3.52(d,J=13.2Hz,1H),3.43–3.26(m,5H),1.92(s,3H),1.02(s,3H).

[0325] 19 F NMR (282MHz, DMSO-d6): δ-139.74.

[0326] Example II-3 Synthesis of Compound II-3

[0327]

[0328] In a 40 mL sealed tube, compound 1 (314 mg) was dissolved in 2.5 mL of dry N,N-dimethylformamide, and SM1 (138.2 mg) was added. Nitrogen gas was then introduced, and the mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water while shaking. The mixture was centrifuged, and the collected solid was dried to give a brownish-yellow solid, compound 2 (250 mg, yield 86%). MS (ESI): m / z [M+H] + =713.

[0329] In a 40 mL sealed tube, compound 2 (250 mg) and EDCI (165 mg) were dissolved in acetonitrile (5 mL), nitrogen gas was purged, and triethylamine (127 mg) was added. The mixture was stirred overnight. After the reaction was complete, the reaction solution was evaporated to dryness, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow solid compound 3 (165 mg, yield 92%). MS (ESI): m / z [M+H] + =679.

[0330] Compound 3 (80 mg) was dissolved in dichloromethane (3 mL) in an 8 mL sealed tube, nitrogen gas was purged, and trifluoroacetic acid (1 mL) was added. The reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, the crude product was washed with dichloromethane (3 x 10 mL), dried, and 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: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 13 min, 50% B; Wavelength: 254 nm) to give a pale yellow solid compound II-3 (45.4 mg 98%). MS (ESI): m / z [M+H) + =479. 1 H NMR (300MHz, DMSO-d6): δ9.24(s,1H),7.32(s,2H),6.76(d,J=6.3Hz,1H),4.30(t,J=4.4H z,2H),4.08(s,2H),3.57-3.68(m,4H),3.35–3.37(m,4H),1.93(s,3H),1.41-1.52(m,4H).

[0331] 19 F NMR (376MHz, CD3OD-d4): δ-141.67.

[0332] Example II-4 Synthesis of Compound II-4

[0333]

[0334] In a 50 mL reaction flask, compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL). SM1 (100 mg, 0.90 mmol) was added at room temperature, and the atmosphere was purged with nitrogen. The mixture was stirred at 60 °C for 3 h. After the reaction was complete, the reaction solution was diluted with ice water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed successively with saturated sodium chloride solution (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid compound 2 (246 mg, yield 80.2%). MS (ESI): m / z [M+H] + =679.

[0335] In a 50 mL reaction flask, compound 2 (246 mg, 0.36 mmol) was dissolved in acetonitrile (5 mL), and EDCI (173 mg, 0.91 mmol) and triethylamine (146 mg, 1.44 mmol) were added at room temperature. Nitrogen gas was introduced to purge the atmosphere, and the reaction mixture was stirred at 40 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by thin-layer chromatography to give a yellow solid compound 3 (200 mg, yield 85.1%). MS (ESI): m / z [M+H] + =645.

[0336] In a 10 mL reaction flask, compound 3 (200 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The reaction system was stirred at room temperature for 1 hour. After the reaction was complete, the system was evaporated to dryness, and the crude product was purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: ACN, Mobile phase B: Water (10 mmol / L NH4HCO3; Flow rate: 50 mL / min) to give a yellow solid compound II-4 (2.5 mg). MS (ESI): m / z [M+H) + =445; 1 H NMR (300MHz, CD3OD-d4): δ9.36(s,1H),7.46(s,2H),7.37(s,1H),4.41(t,J=4 .4Hz,2H),3.79(dt,J=17.3,13.6Hz,4H),3.50(t,J=4.4Hz,2H),2.02(s,3H). 19 F NMR (376MHz, CD3OD-d4): δ -115.14, -115.55, -144.40. Example II-5: Synthesis of Compound II-5.

[0337]

[0338] In a 40 mL sealed tube, compound 1 (314 mg) was dissolved in 2.5 mL of dry N,N-dimethylformamide, and SM1 (125.6 mg) was added. The mixture was then purged with nitrogen and stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was slowly added to ice water while shaking. The mixture was centrifuged, and the solid was collected and evaporated to dryness to give a yellow solid, compound 2 (250 mg, yield 76%). MS (ESI): m / z, [M+H] + =699.

[0339] In a 40 mL sealed tube, compound 2 (250 mg) and EDCI (165 mg) were dissolved in acetonitrile (5 mL), nitrogen was purged, and triethylamine (127 mg) was added. The reaction mixture was stirred overnight at 40 °C. After the reaction was complete, the reaction solution was evaporated to dryness, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow solid compound 3 (165 mg, yield 82%). MS (ESI): m / z, [M+H] + =665.

[0340] In an 8 mL sealed tube, compound 3 (150 mg) was dissolved in dichloromethane (3.5 mL), purged with nitrogen, and trifluoroacetic acid (1.1 mL) was added with stirring at room temperature. The reaction was continued for two hours with stirring at room temperature. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was washed with dichloromethane (3 x 10 mL), evaporated to dryness, and purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 10 min, 50% B; Wavelength: 254 nm) to give a yellow solid compound II-5 (40.9 mg, yield 83%). MS (ESI): m / z, [M+H) + =465. 1 H NMR (400MHz, CD3OD-d4): δ9.19 (s, 1H), 7.35 (s, 2H), 6.84 (d, J = 6.4Hz, 1H), 4.38-4.43 (m, 4H), 4.11-4. 17(m,1H),3.99-4.05(m,1H),3.72-3.80(m,2H),3.47(t,J=4.8Hz,2H),2.10-2.25(m,4H),2.00(s,3H).

[0341] 19 F NMR (376MHz, CD3OD-d4): δ-144.65.

[0342] Example II-6 Synthesis of Compound II-6

[0343]

[0344] Compound 1 (250 mg, 0.378 mmol, 1.0 equiv) and an alcohol (79.44 mg, 0.756 mmol, 2.0 equiv) were dissolved in DMF (2.0 mL), and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water, extracted multiple times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give compound 2 (300 mg) as a yellow solid. m / z (ES+), [M+H) + =673.

[0345] Compound 2 (340.0 mg, 0.505 mmol, 1.0 equiv) and EDC.HCl (232.5 mg, 1.22 mmol, 2.4 equiv) were dissolved in acetonitrile (8 mL). Triethylamine (179 mg, 1.769 mmol, 3.5 equiv) was added to the reaction solution at room temperature, and the reaction system was stirred at 40 °C for 12 hours. After the reaction was completed, the concentrated crude product was purified by column chromatography (dichloromethane / methanol = 0–10%) to give a yellow solid compound 3 (160 mg, yield 40.15%). m / z (ES+), [M+H) + =639.

[0346] In a 10 mL reaction flask, compound 3 (70.0 mg, 0.11 mmol, 1.0 equiv) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction system was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column). 150 nm 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10 B to 60 B in 15 min, 60 B to B in min, 254 nm) yielded a pale yellow solid compound II-6 (11 mg). m / z (ES+), [M+H) + =439.

[0347] 1 H NMR (300MHz, CD3OD-d4): δ1.95(s,3H),2.00-2.07(m,1H),2.11-2.12(m,1H),3.39-3.61(m,4H),3.80 (t,J=4.8Hz,2H),4.39(t,J=4.5Hz,3H),6.86(d,J=6.3Hz,1H),7.19(s,1H),7.37(s,1H),9.19(s,1H).

[0348] Example II-7 Synthesis of Compound II-7

[0349]

[0350] In a 50 mL reaction flask, compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL). SM1 (118 mg, 0.90 mmol) was added at room temperature, and nitrogen was purged. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was diluted with ice water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown solid, compound 2 (250 mg, yield 79.1%). MS (ESI): m / z [M+H] + =699.

[0351] In a 50 mL reaction flask, compound 2 (250 mg, 0.34 mmol) was dissolved in acetonitrile (5 mL). EDCI (162 mg, 0.85 mmol) and triethylamine (137 mg, 1.36 mmol) were added at room temperature. The reaction system was purged with nitrogen and stirred at 40 °C for 4 h. After the reaction was complete, the reaction solution was purified by thin-layer chromatography to give a yellow solid compound 3 (226 mg, yield 97.2%). MS (ESI): m / z [M+H] + =665.

[0352] In a 10 mL reaction flask, compound 3 (140 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 30 B to 50 B in 10 min, 50 B to B in min), yielding a yellow solid compound II-7 (40.4 mg). MS (ESI): m / z [M+H) + =465. 1H NMR (400MHz, CD3OD-d4) δ9.18(s,1H),7.36(s,1H),7.22(s,1H),6.86(d,J=6.2Hz,1H),4.48–4.34(m,2H),4.19–3.98(m,3H),3.82( d,J=9.9Hz,1H),3.68-3.55(m,2H),3.50(dd,J=5.4,3.4Hz,2H),2.34(ddd,J=13.4,6.7,3.6Hz,1H),2.18-2.25(m,3H),2.02(s,3H).

[0353] 19 F NMR (376MHz, CD3OD-d4): δ-144.68.

[0354] Example II-8 Synthesis of Compound II-8

[0355]

[0356] In a 100 mL reaction flask, compound 1 (500 mg, 1.0 equiv) and pyridine (226 mg, 3.0 equiv) were dissolved in tetrahydrofuran (35 mL). Phenylchlorothiocarbamate (213 mg, 1.3 equiv) was added under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a red solid, compound 2 (809 mg, yield 86%). m / z (ES+), [M+H) + =662.

[0357] In a 100 mL reaction flask, compound 2 (314 mg, 0.474 mmol, 1.0 equiv) and an alcohol (214 mg, 1.484 mmol, 3.13 equiv) were dissolved in 2.5 mL of DMF. Under nitrogen atmosphere, triethylamine (119.5 mg) was added at 60 °C. The reaction mixture was stirred at 60 °C for 2 hours. The reaction solution was quenched with ice water, filtered as a solid, and the filtrate was dried and concentrated to give a yellow solid, compound 3 (330 mg, yield 80.1%). m / z (ES+), [M+H) + =713.

[0358] In a 100 mL reaction flask, compound 3 (330 mg) and EDCI (213 mg) were dissolved in acetonitrile (5 mL), and triethylamine (164 mg) was added under nitrogen atmosphere. The reaction system was stirred overnight at 40 °C. The reaction solution was directly purified by thin-layer chromatography (dichloromethane / methanol = 12:1) to give a yellow solid compound 4 (155 mg, yield 76%). m / z (ES+), [M+H) +=679.

[0359] In a 100 mL reaction flask, compound 4 (155 mg) was dissolved in dichloromethane (4 mL) under nitrogen protection. Trifluoroacetic acid (2 mL) was added at room temperature, and the reaction mixture was stirred for 2 hours at room temperature. After the reaction was complete, the solvent was evaporated to dryness. The crude product was purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH – HPLC; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 13 min, 50% B; Wavelength: 254 nm) to give a pale yellow solid compound II-8 (22.5 mg). MS (ESI): m / z = 479. 1 HNMR (300MHz, CD3OD-d4): δ1.80-1.90(m,4H),2.00(s,3H),2.02-2.04(m,2H),3.48(t,J=4.5Hz,2H),3.56(t,J=6 .3Hz,2H),3.77-3.95(m,4H),4.39(t,J=4.5Hz,2H),6.85(d,J=6.3Hz,1H),7.21(s,1H),7.35(s,1H),9.20(s,1H). 19 F NMR (282MHz, CD3OD-d4): δ-144.45.

[0360] Example II-9 Synthesis of Compound II-9

[0361]

[0362] In a 50 mL reaction flask, compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL). SM1 (55 mg, 0.90 mmol) was added at room temperature, and nitrogen was used to replace the nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with ice water, extracted with ethyl acetate (3 x 10 mL), and the combined organic phases were washed with saturated sodium chloride solution (2 x 20 mL), dried, filtered, and the filtrate was concentrated to give a brown solid compound 2 (274 mg, yield 80.2%). MS (ESI): m / z [M+H] + =629.

[0363] In a 50 mL reaction flask, compound 2 (320 mg, 0.51 mmol) was dissolved in acetonitrile (5 mL). EDCI (242 mg, 1.27 mmol) and triethylamine (206 mg, 2.04 mmol) were added at room temperature, and the atmosphere was purged with nitrogen. The reaction mixture was stirred at 40 °C for 12 hours. After the reaction was complete, the reaction mixture was purified by thin-layer chromatography to give a yellow solid, compound 3 (190 mg, yield 56.1%). MS (ESI): m / z [M+H] + =595.

[0364] In a 10 mL reaction flask, compound 3 (140 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by reversed-phase preparative liquid chromatography (Column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 30 B to 45 B in 8 min; 254 nm) to give a yellow solid compound II-9 (54.7 mg). MS (ESI): m / z [M+H) + =395.

[0365] 1 H NMR (400MHz, CD3OD-d4): δ9.26(s,1H),7.35(s,1H),7.24(s,1H),6.88(d,J=6.2Hz,1H),4.55(t ,J=8.2Hz,2H),4.38(t,J=4.5Hz,2H),3.90(t,J=8.2Hz,2H),3.47(t,J=4.4Hz,2H),1.99(s,3H).

[0366] 19 F NMR (376MHz, CD3OD-d4): δ-143.78.

[0367] Example II-10 Synthesis of Compound II-10

[0368]

[0369] In a 40 mL sealed tube, compound 1 (300 mg) was dissolved in 1 mL of dry N,N-dimethylformamide, and SM1 (68.4 mg) was added. Nitrogen gas was then introduced to replace the nitrogen atmosphere, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was slowly added to ice water while shaking. The mixture was centrifuged, and the collected solid was evaporated to dryness to give a brownish-yellow solid, compound 2 (405.7 mg, yield 89%). MS (ESI): m / z, [M+H] + =643.

[0370] In a 40 mL sealed tube, compound 2 (290 mg) and EDCI (216 mg) were dissolved in acetonitrile (6 mL), nitrogen was purged, and triethylamine (168 mg) was added. The mixture was stirred overnight. After the reaction was complete, the reaction solution was evaporated to dryness, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow solid compound 4 (225.8 mg, 68% yield). MS (ESI): m / z, [M+H] + =609.

[0371] In an 8 mL sealed tube, compound 3 (230 mg) was dissolved in dichloromethane (3 mL), purged with nitrogen, and trifluoroacetic acid (1 mL) was added with stirring at room temperature. The reaction was allowed to proceed for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was washed with dichloromethane (3 x 10 mL), evaporated to dryness, and purified by preparative high-pressure liquid chromatography (HPLC) (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: 32% B to 50% B in 10 min, 50% B; Wavelength: 254 nm) to obtain a yellow solid compound II-10 (53.3 mg). MS (ESI): m / z, [M+H) + =409. 1 H NMR (400MHz, DMSO-d6): δ9.31(s,1H),7.32(s,1H),6.75(d,J=6.2Hz,1H),6.12(s,2H),5.66( s,1H),4.27–4.30(m,4H),3.66-3.90(m,1H),3.34(d,J=4.5Hz,2H),1.92(s,3H),1.23(s,3H).

[0372] 19 F NMR (376MHz, CD3OD-d4): δ-143.19.

[0373] Example II-11 Synthesis of Compound II-11

[0374]

[0375] In a 50 mL reaction flask, compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL). SM1 (106 mg, 0.90 mmol) was added at room temperature, and nitrogen was used to replace the nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was diluted with ice water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution (2 x 20 mL). The mixture was filtered, and the filtrate was concentrated to give compound 2 (327 mg, yield 86.1%), a brown solid. MS (ESI): m / z, [M+H] + =685.

[0376] In a 50 mL reaction flask, compound 2 (320 mg, 0.46 mmol) was dissolved in acetonitrile (5 mL). EDCI (217 mg, 1.12 mmol) and triethylamine (166 mg, 1.63 mmol) were added at room temperature, purging with nitrogen. The reaction mixture was stirred at 40 °C for 4 h. The crude product after concentration of the reaction mixture was purified by thin-layer chromatography to give a yellow solid compound 3 (226 mg, yield 97.2%). MS (ESI): m / z, [M+H] + =651.

[0377] In a 50 mL reaction flask, compound 3 (226 mg, 0.40 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The reaction system was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by high-performance liquid chromatography (HPLC) (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 35% B to 55% B in 8 min, 55% B; Wavelength: 254 nm) to obtain a yellow solid compound II-11 (54.4 mg). MS (ESI): m / z (ES+), [M+H) + =451. 1H NMR (400MHz, CD3OD-d4): δ9.22(s,1H),7.35(s,1H),7.21(s,1H),6.99(d,J=6.3Hz,1H),4.37-4.40(m,4H),4.04-4.6( m,1H),4.01-4.03(m,1H),3.77-3.95(m,2H),3.47(t,J=4.3Hz,2H),2.28-2.33(m,1H),2.15-2.18(m,1H),2.00(s,3H). 19 F NMR (376MHz, CD3OD-d4): δ-144.04.

[0378] Example II-12 Synthesis of Compound II-12

[0379]

[0380] Compound 1 (300 mg, 0.453 mmol, 1.0 equiv) and SM1 (68.10 mg, 0.906 mmol, 2.0 equiv) were dissolved in DMF (3 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine, dried, filtered, and the filtrate was concentrated to give compound 2 (327 mg) as a yellow oil. MS (ESI): m / z [M+H] + =643.

[0381] Compound 2 (300 mg, 0.467 mmol, 1.0 equiv) and EDCI (214.74 mg, 1.12 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (165.31 mg, 1.635 mmol, 3.5 equiv) was slowly added at room temperature. The reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then concentrated. The crude product was purified by thin-layer chromatography to give compound 3 (118.5 mg, yield 41.71%) as a yellow solid. MS (ESI): m / z [M+H] + =609.

[0382] Compound 3 (118 mg, 0.194 mmol, 1.0 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and nitrogen was purged. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (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: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 27% B to 57% B in 8 min, 57% B; Wavelength: 254 nm, 220 nm) to give a yellow solid compound II-12 (44.9 mg, yield 55.97%). MS (ESI): m / z [M+H) + =409. 1 H NMR (400MHz, Methanol-d4) δ9.13(s,1H),7.25(s,1H),7.10(s,1H),6.77(d,J=6.4Hz,1H),4.29(t,J=4.4 Hz, 2H), 3.82-3.87 (m, 1H), 3.38 (t, J = 4.4Hz, 2H), 3.30-3.34 (m, 2H), 1.90 (s, 3H), 1.38 (d, J = 6.0Hz, 3H).

[0383] 19 F NMR (282MHz, CD3OD-d4): δ-144.38.

[0384] Example II-13 Synthesis of Compound II-13

[0385]

[0386] Compound 1 (300 mg, 0.453 mmol, 1.0 equiv) and SM1 (80.7 mg, 0.91 mmol, 2.0 equiv) were dissolved in DMF (3 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were backwashed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2 (150 mg, yield 50.3%), which was a yellow oil. MS (ESI): m / z [M+H] + =657.

[0387] Compound 2 (130 mg, 0.198 mmol, 1.0 equiv) and EDCI (91.7 mg, 0.475 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (70.2 mg, 0.693 mmol, 3.5 equiv) was slowly added at room temperature. The reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The crude product was purified by thin-layer chromatography to give compound 3 (49.3 mg, yield 40.1%) as a yellow solid. MS (ESI): m / z [M+H] + =623.

[0388] Compound 3 (49.3 mg, 0.079 mmol, 1.0 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and nitrogen was purged. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction system was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (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: 44% B to 54% B in 8 min, 54% B; Wavelength: 254 / 220 nm) to give a yellow solid compound II-13 (10.4 mg, yield 31.5%). MS (ESI): m / z [M+H) + =423. 1 H NMR(300MHz,Methanol-d4)δ9.22(s,1H),7.35(s,1H),7.19(s,1H),6.85(d,J=6.3Hz,1 H), 4.39 (t, J = 4.5Hz, 2H), 3.60 (s, 2H), 3.47 (t, J = 4.5Hz, 2H), 2.00 (s, 3H), 1.53 (s, 6H). 19 F NMR (282MHz, CD3OD-d4): δ-144.45.

[0389] Example II-14 Synthesis of Compound II-14

[0390]

[0391] Compound 1 (300 mg, 0.453 mmol, 1.0 equiv) and SM1 (117.6 mg, 0.906 mmol, 2.0 equiv) were dissolved in DMF (3 mL), and the atmosphere was replaced with nitrogen. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed three times with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2 (322 mg) as a yellow oil. MS (ESI): m / z [M+H] + =671.

[0392] Compound 2 (300 mg, 0.447 mmol, 1.0 equiv) and EDCI (206 mg, 1.073 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (158.2 mg, 1.57 mmol, 3.5 equiv) was slowly added at room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by thin-layer chromatography to give a yellow solid compound 3 (154 mg, yield 54%). MS (ESI): m / z [M+H] + =637.

[0393] Compound 3 (150 mg, 0.235 mmol, 1.0 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and nitrogen was introduced. The reaction system was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (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: 48% B to 63% B in 8 min, 63% B; Wavelength: 254 / 220 nm) to give a yellow solid compound II-14 (53.6 mg, yield 52%). MS (ESI): m / z [M+H) + =437. 1H NMR (400MHz, CD3OD-d4): δ9.12(s,1H),7.25(s,1H),7.10(s,1H),6.75(d,J=6.4Hz,1H),4.32–4.38(m,1H),4.29(t,J=4.8Hz,2H),3.75(t ,J=8.8Hz,1H),3.46(t,J=8.8Hz,1H),3.38(t,J=4.4Hz,2H),1.90(s,3H),1.84–1.89(m,1H),0.98(d,J=6.8Hz,3H),0.91(s,J=6.8Hz,3H).

[0394] 19 F NMR (376MHz, CD3OD-d4): δ-144.43.

[0395] Example II-15 Synthesis of Compound II-15

[0396]

[0397] Compound 1 (300 mg, 0.453 mmol, 1.0 equiv) and SM1 (86.8 mg, 0.906 mmol, 2.0 equiv) were dissolved in DMF (3 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and 40 mL of water was added. The mixture was extracted three times with ethyl acetate (20 mL * 3). The combined organic phases were washed three times with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2 (340 mg) as a yellow oil. MS (ESI): m / z, [M+H] + =669.

[0398] Compound 2 (300 mg, 0.449 mmol, 1.00 equiv) and EDCI (207 mg, 1.078 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (159 mg, 1.572 mmol, 3.5 equiv) was slowly added to the solution at room temperature, and the reaction was carried out at 40 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, the reaction solution was concentrated, and purified by TLC to give a yellow solid compound 3 (174 mg, yield 61%). MS (ESI): m / z [M+H] + =635.

[0399] Compound 3 (150 mg, 0.237 mmol, 1.0 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and nitrogen was purged. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase preparative liquid chromatography (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: 45% B to 57% B in 8 min, 57% B; Wavelength: 254 / 220 nm) to give a yellow solid compound II-15 (44.4 mg, yield 43.1%). MS (ESI): m / z [M+H) + =435. 1 H NMR (400MHz, Methanol-d4) δ9.13(s,1H),7.25(s,1H),7.10(s,1H),6.76(d,J=6.0Hz,1H),4.29(t,J=4.4Hz,2H),3.78 (s,2H),3.38(t,J=4.4,2H),2.44-2.52(m,2H),2.18–2.24(m,2H),1.90(s,3H),1.81-1.84(m,1H),1.61-1.79(m,1H).

[0400] 19 F NMR (376MHz, CD3OD-d4): δ-144.34.

[0401] Example II-16 Synthesis of Compound II-16

[0402]

[0403] Compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL), and alcohol (125 mg, 0.9 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with ice water, then extracted successively with ethyl acetate, washed with saturated sodium chloride solution (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 2 (282 mg, 80% yield) as a brown solid. m / z(ES+), [M+H] + =683.

[0404] Compound 2 (282 mg, 0.41 mmol) was dissolved in acetonitrile (5 mL), and EDCI (189 mg, 0.99 mmol) and triethylamine (145 mg, 1.44 mmol) were added at room temperature. The reaction mixture was stirred at 40 °C for 4 h under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by thin-layer chromatography to give a yellow solid compound 3 (180 mg, yield 70.1%). m / z (ES+), [M+H) + =649.

[0405] Compound 3 (180 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase high-pressure preparative liquefaction to obtain a yellow solid compound II-16 (14.3 mg). m / z (ES+), [M+H) + =449.

[0406] 1 H NMR (400MHz, CD3OD-d4): δ1.69-1.82(m,6H),1.90(s,3H),2.01-2.06(m,2H),3.38(t,J=4.4Hz,2H) ,3.67(s,2H),4.29(t,J=4.4Hz,2H),6.75(d,J=6.0Hz,1H),7.07(s,1H),7.25(s,1H),9.12(s,1H).

[0407] 19 F NMR (376MHz, CD3OD-d4): δ-144.50.

[0408] Example II-17 Synthesis of Compound II-17

[0409]

[0410] Compound 1 (300 mg, 0.453 mmol, 1.0 equiv) and SM1 (118 mg, 0.906 mmol, 2.0 equiv) were dissolved in DMF (3 mL), and nitrogen was introduced to replace the atmosphere. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added. The mixture was extracted three times with ethyl acetate (3 x 20 mL). The combined organic phases were washed three times with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2 (289.7 mg, yield 91.7%), which was a yellow oil.

[0411] MS(ESI): m / z, [M+H] + =699.

[0412] Compound 2 (280 mg, 0.401 mmol, 1.0 equiv) and EDCI (184.8 mg, 0.962 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (142.8 mg, 1.404 mmol, 3.5 equiv) was slowly added at room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and the crude product was purified by thin-layer chromatography to give a yellow solid compound 3 (164 mg, yield 61.7%). MS (ESI): m / z, [M+H] + =665.

[0413] Compound 3 (150 mg, 0.226 mmol, 1.0 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL). Trifluoroacetic acid (2 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by reversed-phase preparative liquid chromatography (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: MeOH – HPLC; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 8 min, 48% B; Wavelength: 254 nm, 220 nm) to give a yellow solid compound II-17 (54.9 mg, yield 52.3%). MS (ESI): m / z, [M+H] + =465. 1 H NMR (300MHz, CD3OD-d4): δ9.23 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 6.86 (d, J=6.6Hz, 1H) 4.39 (t, J= 4.2Hz,2H),3.76–3.93(m,4H),3.65(s,2H),3.48(t,J=4.5Hz,2H),2.03(s,3H),1.87–1.97(m,4H).

[0414] 19 F NMR (282MHz, CD3OD-d4): δ-144.32.

[0415] Example II-18 Synthesis of compounds II-18-A and II-18-B

[0416]

[0417] Compound 1 (300 mg, 0.453 mmol, 1.00 equiv) and SM1 (117.9 mg, 0.906 mmol, 2 equiv) were dissolved in DMF (3 mL). The reaction flask was purged with nitrogen, and the mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 40 mL of water was added, and the mixture was extracted three times with ethyl acetate (20 mL each). The organic phases were combined and washed three times with saturated brine (30 mL each). The mixture was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off. The filtrate was concentrated to give compound 2 (280 mg) as a yellow oil. MS (ESI): [M+H] + =698.

[0418] Compound 2 (280 mg, 0.401 mmol, 1.00 equiv) and EDCI (184.8 mg, 0.962 mmol, 2.4 equiv) were dissolved in acetonitrile (3 mL), and nitrogen gas was introduced. Triethylamine (142.8 mg, 1.404 mmol, 3.5 equiv) was slowly added to the solution at room temperature, and the reaction was carried out at 40 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, the reaction solution was concentrated, and purified by TLC to obtain a yellow solid compound 3 (179.1 mg). MS (ESI): [M+H] + =665.

[0419] Compound 3 (170 mg, 0.256 mmol, 1.00 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (3 mL), and nitrogen was purged. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain 150 mg of crude product. The crude product was purified by Prep-HPLC (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: 23% B to 35% B in 10 min, 35% B; Wavelength: 254 / 220 nm; RT1 (min): 9.67) to obtain a yellow solid compound II-18-A (6.9 mg, 5.8%). 1HNMR (400MHz, CD3OD) δ9.14 (s, 1H), 7.26 (s, 1H), 7.08 (br.s, 1H), 6.77 (d, J = 6.4Hz, 1H), 4.29 (t, J = 4.4Hz, 2H), 3.97 (q, J = 8. 0Hz, 1H), 3.86–3.66 (m, 4H), 3.38 (t, J = 4.0Hz, 2H), 2.41–2.34 (m, 1H), 2.29–2.24 (m, 1H), 1.91 (s, 3H), 1.20 (d, J = 6.4Hz, 3H). MS(ESI):[M+H] + =465.

[0420] 19 F NMR (376MHz, CD3OD): δ-144.30.

[0421] Compound II-18-B (23.6 mg, 19.8%), 1 H NMR(400MHz,CD3OD)δ9.14(s,1H),7.25(s,1H),7.17(br.s,1H),6.77(d,J= 6.0Hz,1H),4.29(t,J=4.4Hz,2H),4.07(q,J=6.4Hz,1H),3.95(dt,J=8.4,2 .8Hz,1H),3.86–3.80(m,2H),3.65(d,J=10.4Hz,1H),3.38(t,J=4.4Hz,2H) ,2.36–2.30(m,1H),2.17–2.09(m,1H),1.90(s,3H),1.12(d,J=6.8Hz,3H). MS(ESI):[M+H] + =465.

[0422] 19 F NMR (376MHz, CD3OD): δ-144.18.

[0423] Example II-19 Synthesis of Compound II-19

[0424]

[0425] In a 50 mL reaction flask, compound 1 (300 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (4 mL). SM1 (125 mg, 0.90 mmol) was added at room temperature, and nitrogen was purged. The mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was diluted with ice water and then extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated sodium chloride solution (2 x 20 mL), and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a brown solid compound 2 (274 mg). MS (ESI): [M+H] + =669.

[0426] In a 50 mL reaction flask, compound 2 (274 mg, 0.41 mmol) was dissolved in acetonitrile (5 mL). EDCI (189 mg, 0.98 mmol) and triethylamine (145 mg, 1.43 mmol) were added at room temperature, purging with nitrogen. The mixture was stirred at 40 °C for 4 h. The reaction solution was purified by TLC to give a yellow solid, compound 3 (190 mg). MS (ESI): [M+H] + =635.

[0427] In a 50 mL reaction flask, compound 3 (190 mg, 0.29 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was evaporated to dryness and purified by high pressure under the following conditions: (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: MeOH; Flow rate: 60 mL / min; Gradient: 33% B to 63% B in 8 min, 63% B; Wavelength: 254, 220 nm; RT1 (min): 6.17), yielding a yellow solid compound II-19 (19.4 mg). MS (ESI): [M+H) + =435. 1 H NMR(400MHz, CD3OD)9.12(s,1H),7.25(s,1H),7.09(s,1H),6.76(d,J=6.4Hz,1H),5.07–5.04(m,1H),4.48–4.4 5(m,1H),4.29(t,J=4.4Hz,2H),3.38(t,J=4.4Hz,2H),2.01–1.98(m,1H),1.91–1.83(m,4H),1.66–1.61(m,4H).

[0428] 19F NMR (376MHz, CD3OD): δ-144.47.

[0429] Example II-20 Synthesis of Compound II-20

[0430]

[0431] In a 100 mL reaction flask, compound 1 (200 mg) was dissolved in tetrahydrofuran (10 mL). Nitrogen gas was introduced, and pyridine (90.1 mg) was added. SM1 (86 mg) was added dropwise while stirring at 0 °C. The reaction was carried out in an ice bath for one and a half hours. After the reaction was complete, the reaction solution was diluted with tetrahydrofuran, centrifuged, and the liquid was evaporated to dryness to give a red solid compound 2 (350 mg). MS (ESI): [M+H] + =662.

[0432] In a 40 mL sealed tube, compound 2 (300 mg) was dissolved in 2 mL of dry N,N-dimethylformamide, and SM1 (94.2 mg) was added. Nitrogen gas was introduced, and the mixture was reacted at 60 °C for two hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water while shaking. The mixture was centrifuged, and the solid was collected and evaporated to dryness to obtain a brownish-red solid, compound 3 (264.1 mg). MS (ESI): [M+H] + =671.

[0433] In a 40 mL sealed tube, compound 3 (255 mg) and EDCI (176 mg) were dissolved in acetonitrile (10 mL), nitrogen gas was introduced, and triethylamine (135 mg) was added. The reaction was carried out overnight at 40 °C. After the reaction was complete, the reaction solution was evaporated to dryness and purified by silica gel plate chromatography with dichloromethane:methanol = 12:1 to obtain a yellow solid compound 4 (190 mg). MS (ESI): [M+H] + =637.

[0434] Compound 4 (160 mg) was dissolved in dichloromethane (3.2 mL) in an 8 mL sealed tube. Nitrogen gas was introduced, and trifluoroacetic acid (1.1 mL) was added under stirring at room temperature for two hours. After the reaction was complete, the reaction mixture was evaporated to dryness and purified by high-performance liquid chromatography (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: MeOH; Flow rate: 60 mL / min; Gradient: 16% B to 46% B in 8 min, 46% B; Wavelength: 254 nm; 220 nm; RT1 (min): 7.92) to obtain a yellow solid compound II-20 (51 mg). MS (ESI): [M+H) +=437. 1 H NMR (400MHz, CD3OD) δ9.23(s,1H),7.35(s,2H),6.87(d,J=6.4Hz,1H),5.26(dd,J=7.6,3.6Hz,1H),4.71(dd,J=7.2,4.0Hz,1H) ,4.39(t,J=4.8Hz,2H),4.18(d,J=11.2Hz,1H),4.03(d,J=10.0Hz,1H),3.64–3.57(m,2H),3.48(t,J=4.4Hz,2H),2.00(s,3H).

[0435] 19 F NMR (376MHz, CD3OD): δ-144.22.

[0436] Example II-21 Synthesis of Compound II-21

[0437]

[0438] In a 100 mL reaction flask, compound 1 (200 mg) was dissolved in tetrahydrofuran (10 mL). Nitrogen gas was introduced, and pyridine (90.1 mg) was added. SM1 (86 mg) was added dropwise while stirring at 0 °C. The reaction was carried out in an ice bath for one and a half hours. After the reaction was complete, the reaction solution was diluted with tetrahydrofuran, centrifuged, and the liquid was evaporated to dryness to give a red solid compound 2 (350 mg). MS (ESI): [M+H] + =662.

[0439] In a 40 mL sealed tube, compound 2 (300 mg) was dissolved in 2 mL of dry N,N-dimethylformamide, and SM1 (94.2 mg) was added. Nitrogen gas was introduced, and the mixture was reacted at 60 °C for two hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water while shaking. The mixture was centrifuged, and the solid was collected and evaporated to dryness to obtain a brownish-red solid, compound 3 (264.1 mg). MS (ESI): [M+H] + =685.

[0440] In a 40 mL sealed tube, compound 3 (245 mg) and EDCI (165 mg) were dissolved in acetonitrile (8 mL), nitrogen gas was introduced, and triethylamine (127 mg) was added. The reaction was carried out overnight at 40 °C. After the reaction was complete, the reaction solution was evaporated to dryness and purified by silica gel plate chromatography with dichloromethane:methanol = 12:1 to obtain a yellow solid compound 4 (160 mg). MS (ESI): [M+H] + =651.

[0441] Compound 4 (160 mg) was dissolved in dichloromethane (3.2 mL) in an 8 mL sealed tube. Nitrogen gas was introduced, and trifluoroacetic acid (1.1 mL) was added under stirring at room temperature for two hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by high-pressure purification (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: 35% B to 50% B in 8 min, 50% B; Wavelength: 254 / 220 nm; RT1 (min): 7.48) to obtain a yellow solid compound II-21 (53.4 mg). MS (ESI): [M+H) + =451. 1 H NMR (400MHz, CD3OD) δ9.24(s,1H),7.35(s,1H),7.20(br.s,1H),6.87(d,J=6.4Hz,1H),4.82(q,J=5.2Hz,1H),4.38(t,J=4. 4Hz, 2H), 4.00 (q, J = 5.2Hz, 1H), 3.92 (dd, J = 12.4, 4.4Hz, 1H), 3.77–3.63 (m, 3H), 3.47 (t, J = 4.4Hz, 2H), 2.18–2.00 (m, 5H).

[0442] 19 F NMR (376MHz, CD3OD): δ-144.10.

[0443] Example II-22 Synthesis of Compound II-22

[0444]

[0445] In a 40 mL sealed tube, compound 1 (900 mg) was dissolved in 6 mL of dry N,N-dimethylformamide, and SM1 (205.2 mg) was added. Nitrogen gas was introduced, and the mixture was reacted at 60 °C for two hours. After the reaction was complete, a small amount of water was added, and the mixture was extracted with ethyl acetate and evaporated to dryness to give a brownish-red solid, compound 2 (350 mg). MS (ESI): [M+H] + =643.

[0446] In a 40 mL sealed tube, compound 2 (300 mg) was dissolved in dry tetrahydrofuran (3 mL), followed by the addition of carbonyl diimidazole (66 mg). Nitrogen gas was introduced, and triethylamine (72 mg) was added. The mixture was then reacted at 60 °C for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, evaporated to dryness, and purified by silica gel plate chromatography with dichloromethane:methanol (12:1) to give a yellow solid, compound 3 (100 mg). MS (ESI): [M+H] + =625.

[0447] In an 8 mL sealed tube, compound 3 (100 mg) was dissolved in dichloromethane (3.5 mL), nitrogen was introduced, and trifluoroacetic acid (1.3 mL) was added under stirring at room temperature for two hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by high-pressure purification (Column: X Bridge 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 8 min, 40% B; Wavelength: 254 nm; 220 nm; RT1 (min): 6.92) to obtain a yellow solid compound II-22 (31.9 mg). MS (ESI): [M+H) + =425. 1 H NMR (400MHz, CD3OD) δ9.10 (s, 1H), 7.25 (s, 1H), 7.10 (s, 1H), 6.77 (d, J = 6.4Hz, 1H), 4.29 (t, J = 4.4Hz, 2H),3.47(t,J=5.6Hz,2H),3.38(t,J=4.4Hz,2H),3.08–3.03(m,2H),2.08–2.02(m,2H),1.90(s,3H).

[0448] 19 F NMR (376MHz, CD3OD): δ-143.79.

[0449] Example II-23 Synthesis of Compound II-23

[0450]

[0451] Compound 1 (30 mg, 0.049 mmol, 1.00 eq) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.50 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by high pressure and freeze-dried to give compound II-23 (11.2 mg) as a yellow solid. MS (ESI): [M+H]+ =411; 1 H NMR (400MHz, CD3OD) δ9.13(s,1H),7.26(s,1H),7.23(s,1H),6.79(d,J=6.0Hz,1H),4.29(t, J=4.4Hz,2H),3.77(t,J=7.2Hz,2H),3.38(t,J=4.4Hz,2H),3.24–3.20(m,2H),1.91(s,3H).

[0452] 19 F NMR (376MHz, CD3OD): δ-143.84.

[0453] Example II-24 Synthesis of Compound II-24

[0454]

[0455] In a 50 mL reaction flask, compound 1 (300.00 mg, 0.571 mmol) and SM1 (215.98 mg, 0.571 mmol, 1.00 equiv) were dissolved in THF (6 mL) solution under N2 protection. Triethylamine (63.4 mg, 0.63 mmol, 1.1 equiv) was added to the reaction system. The reaction mixture was reacted overnight at 80 °C. After the reaction was complete, the reaction mixture was evaporated to dryness, water (150 mL) was added, and the mixture was washed with ethyl acetate (3 x 100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give crude compound 2 (150 mg). MS (ESI): [M+H] + =836.

[0456] Compound 2 (100 mg) was dissolved in dry methanol (3 mL), and a 10% palladium on carbon catalyst (88.69 mg, 0.466 mmol) was added under nitrogen protection. The reaction solution was reacted at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give a yellow crude compound 3 (70 mg). MS (ESI): [M+H) + =568.

[0457] Compound 3 (80 mg, 0.141 mmol), potassium tert-butoxide (47.45 mg, 0.423 mmol), and methyl glycolate (45 mg) were dissolved in 3 mL of tert-butanol. The mixture was reacted at 90 °C for 16 hours under N2 protection. After the reaction was completed, the solvent was evaporated and the mixture was purified by silica gel column chromatography to give compound 4 (25 mg) as a yellow solid. MS (ESI): [M+H] + =609.

[0458] Compound 4 (25 mg, 0.164 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 90 min. After the reaction was complete, the reaction solution was evaporated to dryness and purified by high-pressure purification (Xselect CSH OBD Column 30*150 mm 5 μm, n; mobile phase A: Water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 30% B in 8 min, 30% B; wavelength: 254 / 220 nm; RT1 (min): 6.18). The solution was then lyophilized to give a yellow solid compound II-24 (3.7 mg). MS (ESI): [M+H] + =409. 1 H NMR (300MHz, DMSO-d6) δ9.39(s,1H),8.06(br.s,1H),7.35(s,1H),6.97(d,J=6.0Hz,1H),4.71(s,2H),4.32(s,2H),3.39(s,2H),1.94(s,3H).

[0459] 19 F NMR (282MHz, DMSO-d6): δ-140.16.

[0460] Example II-25 Synthesis of Compound II-25

[0461]

[0462] Compound 1 (350 mg) and SM1 (217 mg) were dissolved in dichloromethane (5 mL), and the mixture was purged with nitrogen and reacted overnight at 50 °C. After the reaction was complete, the solution was evaporated to dryness. Compound 2 (637 mg) was obtained as a yellow solid. MS (ESI): [M+H] + =689.

[0463] Compound 2 (300 mg) and sodium methoxide (54 mg) were dissolved in 10 mL of water, and the mixture was purged with nitrogen and stirred overnight at room temperature. After the reaction was complete, the crude product was purified by reverse-phase column chromatography to give compound 3 (54.9 mg) as a yellow solid. MS (ESI): [M+H] + =585.

[0464] Compound 3 (50 mg), bromoacetic acid (12 mg), and N,N-diisopropylethylamine (11 mg) were dissolved in ethanol (2 mL) and reacted at room temperature for 3 hours. Purification by reversed-phase column chromatography yielded compound 4 (80 mg) as a yellow solid. MS (ESI): [M+H] + =625.

[0465] Compound 4 (80 mg) was dissolved in dichloromethane (3 mL), nitrogen gas was introduced, and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for two hours. After the reaction was complete, the solution was evaporated to dryness with dichloromethane (3 x 10 mL). The solution was then purified by preparative high-pressure chromatography (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: 9% B to 29% B in 8 min, 29% B; Wavelength: 254 nm) to give a yellow solid compound II-25 (6.4 mg). MS (ESI): [M+H] + =425. 1 H NMR (400MHz, DMSO-d6) δ11.87(br.s,1H),9.47(s,1H),7.36(s,1H),7.34(s,1H),6.93(d,J=6.4 Hz, 1H), 6.30 (s, 2H), 5.69 (s, 1H), 4.29 (t, J = 4.4Hz, 2H), 3.86 (s, 2H), 3.37 (s, 2H), 1.92 (s, 3H).

[0466] 19 F NMR (376MHz, DMSO-d6): δ-140.50.

[0467] Example II-26 Synthesis of Compound II-26

[0468]

[0469] Compound 1 (450 mg, 0.626 mmol, 1.00 equiv), compound SM1 (139 mg, 1.252 mmol, 2.00 equiv), and N,N-dimethylformamide (5 mL) were added to a 40 mL sealed tube. The reaction mixture was stirred at 60 °C for 2 hours, then cooled to room temperature. The reaction solution was added to water at 0 °C, filtered, and dried to obtain solid compound 2 (400 mg). MS (ESI): [M+H] + =737.

[0470] Compound 2 (400 mg, 0.544 mmol, 1.00 equiv), DIEA (262 mg, 1.360 mmol, 2.50 equiv), triethylamine (192 mg, 1.904 mmol, 3.50 equiv), and acetonitrile (4 mL) were added to a 40 mL sealed tube. The reaction mixture was stirred at 40 °C for 3 hours. After rotary evaporation and concentration, the mixture was subjected to preparative thin-layer chromatography to obtain a yellow solid compound 3 (150 mg). MS (ESI): [M+H) + =703.

[0471] In a 20 mL sealed tube, 1 mL of trifluoroacetic acid was added dropwise to a 2 mL solution of compound 3 (150 mg, 0.214 mmol, 1.00 equiv) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The mixture was then subjected to high-pressure chromatography (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 35% B in 8 min, 35% B; Wavelength: 220 nm; RT1 (min): 7.32) to give a white solid compound II-26 (3.4 mg). MS (ESI): [M+H) + =403; 1 H NMR(400MHz,CD3OD)δ9.31–9.24(m,1H),8.06(s,1H),7.79(s,1H),7.26(s,1H ),6.94–6.92(m,1H),4.44(t,J=10.8Hz,1H),3.88–3.73(m,3H),2.07(s,3H).

[0472] 19 F NMR (376MHz, CD3OD): δ-115.55,-144.82.

[0473] The remaining compounds were synthesized following the preparation examples above.

[0474] Example of effect: Biological experimental method

[0475] 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.

[0476] The experiment on the inhibition of HPK1 kinase activity by the compound was conducted using ADP-Glo TMPlatform. 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:

[0477] Table 1

[0478]

[0479]

[0480]

[0481] Where A represents IC 50 0.01-10 nM; B indicates IC 50 10-100nM; C represents IC 50 It ranges from 100 to 1000 nM.

Claims

1. A heterocyclic compound represented by Formula I: ###0001### Formula I or a pharmaceutically acceptable salt thereof, wherein, n is 0 or 1; X is CF.

2. The heterocyclic compound according to claim 1, wherein n is 0. R 1 is F; R 2 For R 2-2 ; R 2-2 For ; 3. The heterocyclic compound according to claim 1, wherein n is 1. Z 1 is O or S; Z 2 is CR 2-1-5 R 2-1-6 ; Z 3 is CR 2-1-7 R 2-1-8 ; Z 4 is CR 2-1-9 R 2-1-10 ; R 2-1-5 , R 2-1-6 , R 2-1-7 , R 2-1-8 , R 2-1-9 , and R 2-1-10 are independently H or halogen; R 3 is H; R 4 For ; X is CR 6 ; R 6 is halogen; R 5 is NH2.

2. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt thereof, according to Formula I, wherein when R 2-1-5 , R 2-1-6 , R 2-1-7 , R 2-1-8 , R 2-1-9 and R 2-1-10 are independently halogen, said halogen is F.

3. The heterocyclic compound of formula I as claimed in claim 1, characterized in that, 4. The heterocyclic compound according to claim 1, wherein X is CF.

4. The heterocyclic compound of formula I as claimed in claim 1, characterized in that, In the heterocyclic compound of Formula I, R 2 is , , , or .

5. The heterocyclic compound of formula I as claimed in claim 1, characterized in that, 5. The heterocyclic compound according to claim 1, wherein the heterocyclic compound is selected from any one of the following compounds: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### 。 ​ ​

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