A class of nitrogen-containing heterocyclic compounds

Abstract

Compounds of Formula I or pharmaceutically acceptable forms thereof, pharmaceutical compositions comprising the same, and medical uses thereof for preventing and / or treating HPK1-related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a class of nitrogen-containing heterocyclic compounds or pharmaceutically acceptable forms thereof, pharmaceutical compositions comprising them, and their medicinal uses for the prevention and / or treatment of HPK1-related diseases. 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 (HPK1KD) 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 HPK1KD, T cells exhibited strong tumor cell killing ability, while tumor cells expressing the immunosuppressive molecule PGE2 showed increased activity against HPK1KD. - / - Compared to wild-type HPK1KD mice, they grew more slowly. Analysis of the tumor microenvironment in HPK1KD 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] Through extensive research, this invention has discovered a class of nitrogen-containing heterocyclic compounds that have potential value in preventing and / or treating HPK1-related diseases.

[0008] In a first aspect, the present invention provides a compound having the structure of Formula I or a pharmaceutically acceptable form thereof:

[0009]

[0010] in

[0011] A 1 and A 3 Each is independently selected from N or CR 1-1 R 1-1 Selected from H, halogen, CN or C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be substituted with one or more halogens;

[0012] A 2 Selected from N or CR 2-1 R 2-1 Selected from H, OH, halogens, CN, C 1-4 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-4 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl groups are optionally surrounded by one or more R 3-1 Replace, each R 3-1 Independently selected from oxo groups, halogens, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl or NR 3-1-1 R 3-1-2 R 3-1-1 and R 3-1-2 Each is independently selected from H or C 1-6 alkyl;

[0013] A 4 Selected from N or CR 4-1 R 4-1 Selected from H, halogens, CN, OH, NH2, -NH-CH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy or C3-6 cycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens;

[0014] A 5 Selected from N or CR 5-1 R 5-1 Selected from H, halogens, CN, OH, NH2, -NH-CH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be replaced by one or more halogens;

[0015] A 6 Selected from N or CR 6-1 R 6-1 Selected from H, halogen, OH, CN, NO2, oxo group, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkoxy, -OR 6-2 -SR 6-2 -S(=O)R 6 -2 -S(=O)2R 6-2 NH2, -NHR 6-2 -NR 6-2 R 6-3 -C(=O)R 6-2 -C(=O)OR 6-2 -C(=O)NHR 6-2 -C(=O)NR 6-2 R 6-3 -NR 6-2 C(=O)R 6-2 or -NR 6-2 C(=O)NR 6-2 R 6-3 , where R 6-2 and R 6-3 Each is independently selected from H and C. 1-8 Alkyl, C 2-8alkynyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, or C 6-10 Aryl, the C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl or C 1-6 The alkoxy group is optionally selected by one or more groups independently chosen from H, halogen, CN, oxo group, -NR. 6-1-1 R 6-1-2 -OR 6-1-1 -SR 6-1-1 -S(=O)R 6-1-1 or -S(=O)2R 6-1-1 Substituents of R 6-1-1 and R 6-1-2 Each is independently selected from H and C. 1-4 Alkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 2-6 alkenyl or C 2-6 alkynyl group;

[0016] R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)OR 6-2 -C(=O)NR 6g R 6h C 1-4 Alkyl, C 3-8 cycloalkyl or The C 1-4 Alkyl or C 3-8 The cycloalkyl group is optionally selected independently by one or more elements chosen from CN, OH, halogen, CF3, -NR. 6e R 6f or -C(=O)NR 6g R 6h Substituents of the substituents;

[0017] R 1a and R 1b Each is independently selected from H and C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR 1c -NR 1c R 1d -S(=O)2R 1c-S(=O)2NR 1c R 1d -C(=O)R 1c -C(=O)NR 1c R 1d -NR 1c C(=O)R 1d or -NR 1c S(=O)2R 1d ;

[0018] R 1c and R 1d Each is independently selected from H and C. 1-8 Alkyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl, the C 1-8 Alkyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 The aryl group is optionally selected independently by one or more groups chosen from H, halogen, CN, oxo group, -NR. 6-1-1 R 6-1-2 -OR 6-1-1 -SR 6-1-1 -S(=O)R 6-1-1 or -S(=O)2R 6-1-1 Substituents of R 6-1-1 and R 6-1-2 Each is independently selected from H and C. 1-4 Alkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 2-6 alkenyl or C 2-6 alkynyl group;

[0019] Or, R 1a and R 1b Together with the atoms they are attached to, they form 5-8 membered rings containing one or two independent heteroatoms selected from N, O, or S;

[0020] R 6e R 6f R 6g and R 6h Each is independently selected from H, -S(=O)2R 7 C 3-6 cycloalkyl or C 1-6 Alkyl, the C 3-6 The cycloalkyl group is optionally selected independently by one or more of -OR 5 Het g Or Het eSubstituents of the C group, wherein the C 1-6 Alkyl groups are optionally selected independently from -OR 5 -NR 9a C(=O)R 9b Het g Or Het e The C substituents are substituted, and the C 1-6 Two substituents on the same carbon atom of an alkyl group may optionally form a C10 group together. 3-6 Cycloalkyl groups or 3-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O or S;

[0021] Or, R 6e and R 6f R 6g and R 6h Together with the N atoms they are attached to, they form 5-8 membered heterocyclic groups;

[0022] Each Het e A 5-12 membered heteroaryl group, independently comprising one N atom and optionally one or two other heteroatoms independently selected from N, O, or S, wherein the heteroaryl group is optionally selected from Het. f Or C 1-4 Alkyl substituents, wherein the C 1-4 Alkyl groups are optionally Het f replace;

[0023] Each Het g Independently comprising one, two, or three heteroatoms independently selected from N, O, or S, wherein the heterocyclic group is optionally selected from oxo, het, or s. f Or C 1-4 Alkyl substituents, wherein the C 1-4 Alkyl groups are optionally Het f replace;

[0024] Each Het f Independently comprising 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the heterocyclic group is optionally C 1-4 Alkyl substitution;

[0025] R 9a Selected from H or C 1-4 alkyl;

[0026] R 9b Selected from H or C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally substituted with one, two or three halogen atoms;

[0027] R 2a For H;

[0028] R 2b Selected from H or methyl;

[0029] R 4a Selected from H, C 1-4 Alkyl or C 3-6 cycloalkyl;

[0030] R 4b Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl groups, or 4-12 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0031] Or, R 2b and R 4b Together with the atoms they are attached to, they form 5-12 membered heteroaryl groups or 4-12 membered heterocyclic groups, each of which comprises one N atom and optionally one or two other heteroatoms independently selected from N, O, or S; wherein the heteroaryl group or heterocyclic group is optionally attached to one or more C atoms by one, two, or three other heteroatoms independently selected from OH, CN, halogen, R 7 -OR 7 -S(=O)2R 7 -C(=O)R 7 -NR 6c R 6d -C(=O)NR 6a R 6b Or Het c The substituents are substituted; wherein the heteroaryl or heterocyclic group is optionally replaced on an additional N atom by one or two atoms independently selected from R. 7 -S(=O)2R 7 -C(=O)R 7 -C(=O)NR 6a R 6b Or Het d Substituents of the substituents;

[0032] Towards R 2b The dotted bond is when R 2b and R 4b The bonds that exist can be chosen when forming a ring together;

[0033] In R 2b and R 4b When they form a ring together, R 4a For H; and when facing R 2b When the dotted bonds are bonds, R 2a Does not exist; or

[0034] R 4a and R4b Together with the N atoms to which they are attached, they form 5-12 membered heteroaryl groups or 4-12 membered heterocyclic groups, each of which comprises one N atom and optionally one or two other heteroatoms independently selected from N, O, or S; wherein the heteroaryl group or heterocyclic group is optionally surrounded on one or more C atoms by one, two, or three other heteroatoms independently selected from OH, CN, halogen, R 7 -OR 7 -S(=O)2R 7 -C(=O)R 7 -NR 6c R 6d -C(=O)NR 6a R 6b Or Het c The substituents are substituted; wherein the heteroaryl or heterocyclic group is optionally replaced on the N atom by one or two independently selected R atoms. 7 -S(=O)2R 7 -C(=O)R 7 -C(=O)NR 6a R 6b Or Het d Substituents of the substituents;

[0035] In R 4a and R 4b When they form a ring together, R 2a For H, and R 2b For H;

[0036] Each Het c Independently constitutes a 4-12 membered heterocyclic group comprising 1, 2, or 3 heteroatoms independently selected from N, O, or S;

[0037] Each Het d Independently constitutes a 4-12 membered heterocyclic group comprising 1, 2, or 3 heteroatoms independently selected from N, O, or S;

[0038] R 3 Selected from CN, halogens, -C(=O)NR 8a R 8b -CH2NR 8c R 8d Het a Het b -CH2-Het a -CH2-Het b -CH(R) 7-1 )-Het a -CH(R) 7-1 )-Het b -P(=O)-(C 1-4Alkyl)2、-S(=O)2-C 1-4 Alkyl group, -S (=O) (=NR) x )-C 1-4 Alkyl, C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally surrounded by one or two independently selected from halogen, OH, CN or -OC. 1-4 Alkyl substituents;

[0039] R 8a R 8c and R 8d Each is independently selected from H and C. 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally marked with OH or -OC. 1-4 Alkyl substitution;

[0040] R 8b Selected from C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally marked with OH or -OC. 1-4 Alkyl substitution;

[0041] Or, R 8a and R 8b 、or R 8c and R 8d Together with the N atoms to which they are attached, they form 4-12 membered heterocyclic groups, wherein the heterocyclic group comprises one N atom and optionally one or two other heteroatoms independently selected from N, O, or S; wherein the heterocyclic group is optionally surrounded by one, two, or three other heteroatoms independently selected from OH, CN, halogen, R on one or more C atoms. 7 -OR 7 -S(=O)2R 7 -C(=O)R 7 -NR 6c R 6d or -C(=O)NR 6a R 6b The heterocyclic group is substituted with one or two independently selected R atoms on the N atom. 7 -S(=O)2R 7 -C(=O)R 7 or -C(=O)NR 6a R 6b Substituents of the substituents;

[0042] Het b It is a 4-12 membered heterocyclic group, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms independently selected from N, O, or S; wherein the heterocyclic group is optionally surrounded by 1, 2, or 3 heteroatoms independently selected from OH, CN, halogen, R on one or more C atoms. 7 -OR 7 -S(=O)2R 7 -C(=O)R 7 -NR 6c R 6d or -C(=O)NR 6a R 6b The heterocyclic group is substituted with one or two independently selected R atoms on the N atom. 7 -S(=O)2R 7 -C(=O)R 7 or -C(=O)NR 6a R 6b Substituents of the substituents;

[0043] Each R x Independently selected from H or C 1-4 alkyl;

[0044] Each R 7 Selected independently from C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally separated from one or more halogens, OH, -OC. 1-4 Alkyl or CN substituents;

[0045] R 6a R 6b R 6c and R 6d Each is independently selected from H and C. 3-6 cycloalkyl or C 1-4 Alkyl, the C 3-6 cycloalkyl or C 1-4 Alkyl optional -OR 5 Instead, the C 1-4 Two substituents on the same carbon atom of an alkyl group may optionally form a C10 group together. 3-6 cycloalkyl;

[0046] Each R 5 Independently selected from H or C 1-4 alkyl;

[0047] Each R 7-1 Selected independently from C 1-4 Alkyl or C 3-6 cycloalkyl, the C1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens;

[0048] Het a for X is selected from N or CH, R 10 and R 11 Each is independently selected from H and C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 3-8 cycloalkyl;

[0049] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotope-labeled substances, metabolites, and prodrugs.

[0050] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and A 4 When it is CH, A 2 A 3 A 5 and A 6 Not both CH and A 2 Not N.

[0051] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 1 and A 3 Each is independently selected from N or CR 1-1 R 1-1 The group is selected from H, halogen, CN, methyl, ethyl, or isopropyl, wherein the methyl, ethyl, or isopropyl group is optionally substituted with one or more halogens.

[0052] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 1 and A 3 Each is independently selected from N or CR 1-1 R 1-1 Selected from H, halogen, CN or methyl; preferably, R 1-1 Selected from H, F, Cl, CN or methyl.

[0053] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 2Selected from N or CR 2 -1 R 2-1 Selected from H, OH, halogens, CN, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 The cycloalkyl group is optionally substituted by one or more substituents independently selected from oxo, halogen, OH, CN, NH2 or methyl.

[0054] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 2 Selected from N or CR 2-1 R 2-1 Selected from H, OH, halogen, CN, CF3, methoxy, ethoxy, methyl, ethyl, or cyclopropyl; preferably, R 2-1 Selected from H, OH, F, Cl, CN, CF3, methoxy, ethoxy, methyl, ethyl or cyclopropyl.

[0055] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 4 Selected from N or CR 4 -1 R 4-1 Selected from H, halogens, CN, OH, NH2, -NH-CH3, -N(CH3)2, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

[0056] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 4 Selected from N or CR 4-1 R 4-1 Selected from H, halogen, CN, OH, NH2, methyl or methoxy; preferably, R 4-1 Selected from H, F, Cl, CN, OH, NH2, methyl or methoxy.

[0057] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 5 Selected from N or CR 5 -1 R 5-1Selected from H, halogens, CN, OH, NH2, -NH-CH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 cycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

[0058] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 5 Selected from N or CR 5-1 R 5-1 Selected from H, halogen, CN, OH, NH2, -NH-CH3, -N(CH3)2, methyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl; preferably, R 5-1 Selected from H, F, Cl, CN, OH, NH2, -NH-CH3, -N(CH3)2, methyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl.

[0059] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 6 Selected from N or CR 6 -1 R 6-1 Selected from H, halogen, OH, CN, NO2, oxo group, C 1-8 Alkyl, C 3-8 cycloalkyl, -OR 6-2 -SR 6-2 -S(=O)R 6-2 -S(=O)2R 6-2 NH2, -NHR 6-2 -NR 6-2 R 6-3 -C(=O)R 6-2 -C(=O)OR 6-2 -C(=O)NHR 6-2 -C(=O)NR 6- 2 R 6-3 -NR 6-2 C(=O)R 6-2 or -NR 6-2 C(=O)NR 6-2 R 6-3 , where R 6-2 and R 6-3 Each is independently selected from H and C. 1-8 Alkyl or C 3-8 cycloalkyl, the C 1-8 Alkyl or C3-8 The cycloalkyl group is optionally surrounded by one or more radicals independently selected from H, halogen, CN, oxo group, -NR. 6-1-1 R 6-1-2 -OR 6-1-1 -SR 6-1-1 -S(=O)R 6-1-1 or -S(=O)2R 6-1-1 Substituents of R 6-1-1 and R 6 -1-2 Each is independently selected from H, methyl, or ethyl;

[0060] Preferably, R 6-1 Selected from H, halogen, OH, CN, NO2, oxo group, C 1-4 Alkyl, C 3-6 cycloalkyl, -OR 6-2 -SR 6-2 -S(=O)R 6-2 -S(=O)2R 6-2 NH2, -NHR 6-2 -NR 6-2 R 6-3 -C(=O)R 6-2 -C(=O)OR 6-2 -C(=O)NHR 6 -2 -C(=O)NR 6-2 R 6-3 -NR 6-2 C(=O)R 6-2 or -NR 6-2 C(=O)NR 6-2 R 6-3 , where R 6-2 and R 6-3 Each is independently selected from H and C. 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally surrounded by one or more radicals independently selected from H, halogen, CN, oxo group, -NR. 6-1-1 R 6-1-2 -OR 6-1-1 -SR 6-1-1 -S(=O)R 6-1-1 or -S(=O)2R 6-1-1 Substituents of R 6-1-1 and R 6-1-2 Each is independently selected from H, methyl, or ethyl.

[0061] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A6 Selected from N or CR 6-1 R 6-1 Selected from H, halogen, OH, CN, NO2, oxo group, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-4 Alkoxy, the C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-4 The alkoxy group is optionally substituted by one or more substituents independently selected from H, halogen, CN or oxo group.

[0062] In some more preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, A 6 Selected from N or CR 6-1 R 6-1 Selected from H, halogen, OH, CN, NO2, oxo group, methyl, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl; more preferably, R 6-1 Selected from H, F, Cl, OH, CN, NO2, methyl, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl.

[0063] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 1 Selected from H, halogens, CN, -C (=O) OR 6-2 C 1-4 Alkyl, C 3-8 cycloalkyl or The C 1-4 Alkyl or C 3-8 The cycloalkyl group is optionally substituted by one or more substituents independently selected from CN, OH, halogen, or CF3.

[0064] R 1a and R 1b Each is independently selected from H and C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl, R 6-2 Selected from H, C 1-8 Alkyl or C 3-8 Cycloalkyl.

[0065] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 1 Selected from H, halogens, CN, -C (=O) OR 6-2 C 1-4 Alkyl, C 3-6 cycloalkyl or The C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted by one or more substituents independently selected from CN, OH, halogen, or CF3.

[0066] R 1a and R 1b Each is independently selected from H and C. 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, R 6-2 Selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0067] In some preferred embodiments, in the compound of formula I or its pharmaceutically acceptable form, R 1 Selected from H, halogen, CN, methyl, ethyl, cyclopropyl, -CH2OH, -C(=O)OCH3, CF3, R 1a and R 1b Each is independently selected from H, methyl, or ethyl;

[0068] More preferably, R 1 Selected from H, F, Cl, CN, methyl, ethyl, cyclopropyl, -CH2OH, -C(=O)OCH3, CF3,

[0069] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form,

[0070] R 2a For H,

[0071] R 4a For H,

[0072] R 2b and R 4b Together with the atoms they are attached to, they form monocyclic 5-membered heteroaryl groups, monocyclic 4-, 5-, 6-, or 7-membered heterocyclic groups, bicyclic 6-12-membered heteroaryl groups, or bicyclic 6-12-membered heterocyclic groups, each of which comprises one N atom and optionally one or two other heteroatoms independently selected from N, O, or S, wherein the heteroaryl group or heterocyclic group is optionally surrounded on one or more C atoms by one, two, or three other heteroatoms independently selected from OH, CN, halogens, R... 7 -OR 7 -S(=O)2R 7 or -C(=O)R 7 The substituents are substituted; wherein the heteroaryl or heterocyclic group is optionally replaced on an additional N atom by one or two atoms independently selected from R.7 -S(=O)2R 7 or -C(=O)R 7 Substituents of the substituents

[0073] R 7 Selected independently from C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally separated from one or more halogens, OH, -OC. 1-4 Alkyl or CN substituents.

[0074] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 2b and R 4b Together with the atoms they are attached to, they form a monocyclic 4-, 5-, 6-, or 7-membered heterocyclic group, the heterocyclic group comprising one N atom and optionally one or two other heteroatoms independently selected from N, O, or S, wherein the heterocyclic group is optionally surrounded on one or more C atoms by one, two, or three other heteroatoms independently selected from OH, CN, halogen, R 7 -OR 7 -S(=O)2R 7 or -C(=O)R 7 The heterocyclic group is substituted with one or two independently selected R atoms on an optional additional N atom. 7 -S(=O)2R 7 or -C(=O)R 7 Substituents of the substituents

[0075] R 7 It is independently selected from methyl, ethyl or cyclopropyl.

[0076] In some preferred embodiments, in the compound of formula I or its pharmaceutically acceptable form, R 2b and R 4b Together with the atoms to which they are attached, they form a monocyclic 6-membered heterocyclic group, the heterocyclic group comprising one N atom and optionally one or two other heteroatoms independently selected from N, O, or S, wherein the heterocyclic group is optionally substituted on one or more C atoms by one, two, or three substituents independently selected from OH, CN, halogen, methyl, ethyl, or cyclopropyl; wherein the heterocyclic group is optionally substituted on an optional additional N atom by one or two substituents independently selected from methyl, ethyl, or cyclopropyl.

[0077] In some particularly preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 2b and R 4bTogether with the atoms they are attached to, they form morpholino, piperidino, or piperazine groups.

[0078] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 2a For H, R 2b For H, R 4a Selected from H, C 1-4 Alkyl or C 3-6 cycloalkyl, R 4b Selected from H, C 1-4 Alkyl or C 3-6 cycloalkyl; preferably, R 4a It is methyl, R 4b It is a methyl group.

[0079] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 2a For H, R 2b For H, R 4a and R 4b Together with the N atoms to which they are attached, they form 4-12 membered heterocyclic groups, each containing one N atom and optionally one or two additional heteroatoms independently selected from N, O, or S, wherein the heterocyclic group is optionally surrounded by one, two, or three additional heteroatoms independently selected from OH, CN, halogens, R on one or more C atoms. 7 -OR 7 -S(=O)2R 7 or -C(=O)R 7 Substituents; preferably, R 4a and R 4b Together with the N atoms to which they are attached, they form pyrrolidinyl groups, wherein the pyrrolidinyl groups are optionally surrounded by one, two, or three independent atoms selected from OH, CN, halogens, R on one or more C atoms. 7 -OR 7 -S(=O)2R 7 or -C(=O)R 7 Substituents of R; more preferably, R 4a and R 4b Together with the N atoms they are attached to, they form

[0080] In some embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 3 Selected from CN, Halogen, Het a Het b -CH2-Het a -CH2-Het b -CH(R) 7-1 )-Het a -CH(R)7-1 )-Het b -P(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally surrounded by one or two independently selected from halogen, OH, CN or -OC. 1-4 Alkyl substituents,

[0081] Het b The heterocyclic group is selected from monocyclic 4-, 5-, 6-, or 7-membered heterocyclic groups, or bicyclic 6- to 12-membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms independently selected from N, O, or S, and wherein the heterocyclic group is optionally substituted on one or more C atoms with 1, 2, or 3 substituents independently selected from OH, CN, halogen, methyl, or ethyl.

[0082] Het a for X is selected from N or CH, R 10 and R 11 Each is independently selected from H and C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 3-8 cycloalkyl,

[0083] R 7-1 Selected independently from C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

[0084] In some preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 3 Selected from CN, Halogen, Het b -CH2-Het b -CH(R) 7-1 )-Het b -P(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally surrounded by one or two independently selected from halogen, OH, CN or -OC. 1-4 Alkyl substituents,

[0085] Het b The heterocyclic group is selected from a monocyclic 6-membered heterocyclic group, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms independently selected from N, O, or S, and wherein the heterocyclic group is optionally substituted on one or more C atoms by 1, 2, or 3 substituents independently selected from OH, CN, halogen, methyl, or ethyl.

[0086] R 7-1 Selected independently from C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

[0087] In some preferred embodiments, in the compound of formula I or its pharmaceutically acceptable form, R 3 Selected from CN, Halogen, Het b -CH2-Het b -P(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, C 1-4 Alkyl or C 3-6 cycloalkyl, Het b It is selected from a monocyclic 6-membered heterocyclic group, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0088] In some particularly preferred embodiments, in the compound of formula I above or in its pharmaceutically acceptable form, R 3 Selected from CN, halogen, More preferably, R 3 Selected from CN, F, Cl,

[0089] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-1 or formula I-2 or a pharmaceutically acceptable form thereof:

[0090]

[0091] Among them, A 2 A 3 A 5 A 6 R 1 R 4-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I

[0092] The condition is when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4 -1 When it is H, A 2 A 3 A 5 and A 6 Not both CH and A 2 Not N.

[0093] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-3 or formula I-4 or a pharmaceutically acceptable form thereof:

[0094]

[0095] Among them, A 3 A 5 A 6 R 1 R 2-1 R 4-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I

[0096] The condition is when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4 -1 When it is H, A 3 A 5 and A 6 Not both CH, or R 2-1 Not H.

[0097] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-5 to I-7 or a pharmaceutically acceptable form thereof:

[0098]

[0099] Among them, A 5 A6 R 1 R 2-1 R 4-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I

[0100] The condition is in equation I-7, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4-1 When it is H, A 5 and A 6 Not both CH, or R 2-1 Not H.

[0101] In some embodiments, the compounds of formula I above, or their pharmaceutically acceptable forms, are compounds having structures of formulas I-8 to I-10, or their pharmaceutically acceptable forms:

[0102]

[0103] Among them, A 6 R 1 R 2-1 R 4-1 R 5-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I

[0104] The condition is in equation I-10, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4-1 When it is H, A 6 Not CH, or R 2-1 Not H, or R 5-1 Not H.

[0105] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-11 to I-13 or a pharmaceutically acceptable form thereof:

[0106]

[0107] Among them, R 1 R 2-1 R 4-1 R 5-1 R 6-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I

[0108] The condition is in equation I-13, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4-1 When it is H, R 2-1 Not H, or R 5-1 Not H, or R 6-1 Not H.

[0109] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-13-1 or a pharmaceutically acceptable form thereof:

[0110]

[0111] Among them, R 2-1 R 4-1 R 5-1 R 6-1 R 2a R 2b R 4a R 4b and R 3 As defined in Equation I.

[0112] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-14 to I-16 or a pharmaceutically acceptable form thereof:

[0113]

[0114] Among them, R 1 R 2-1 R4-1 R 5-1 R 6-1 and R 3 As defined in Equation I

[0115] The condition is in equation I-16, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4-1 When it is H, R 2-1 Not H, or R 5-1 Not H, or R 6-1 Not H.

[0116] In some embodiments, the compound of formula I or a pharmaceutically acceptable form thereof is a compound having the structure of formula I-17 to I-20 or a pharmaceutically acceptable form thereof:

[0117]

[0118] Among them, R 1 R 2-1 R 4-1 R 5-1 and R 6-1 As defined in Equation I

[0119] The condition is that in equations I-19 and I-20, when R 1 Selected from H, halogen, CN, -NR 6e R 6f -C(=O)NR 6g R 6h C 1-4 Alkyl or C 3-8 cycloalkyl and R 4-1 When it is H, R 2-1 Not H, or R 5-1 Not H, or R 6-1 Not H.

[0120] Those skilled in the art will understand that this invention covers compounds obtained by any combination of various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0121] Secondly, the present invention also provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs:

[0122]

[0123]

[0124]

[0125] Thirdly, the present invention provides a pharmaceutical composition comprising at least one compound of formula I, formula I-1 to formula I-20 or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

[0126] Fourthly, the present invention provides compounds of Formula I, Formula I-1 to Formula I-20 or their pharmaceutically acceptable forms, or pharmaceutical compositions thereof, for the prevention and / or treatment of diseases or conditions at least partially mediated by HPK1.

[0127] Fifthly, the present invention provides the use of the compounds of Formula I, Formula I-1 to Formula I-20 or their pharmaceutically acceptable forms, or the pharmaceutical compositions thereof, in the preparation of a medicament for the prevention and / or treatment of diseases or conditions at least partially mediated by HPK1.

[0128] In a sixth aspect, the present invention provides a method for preventing and / or treating at least part of a disease or condition mediated by HPK1, comprising the steps of: administering a preventive and / or therapeutically effective amount of the above-described compounds of Formula I, Formula I-1 to Formula I-20 or their pharmaceutically acceptable forms or the above-described pharmaceutical compositions to an individual in need of such treatment.

[0129] This invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for description only and not for limiting the specific embodiments.

[0130] Terminology Definition

[0131] Unless otherwise stated, the following terms have the following meanings in this invention.

[0132] The terms “comprising,” “including,” “having,” or “containing,” or any other variations thereof, are intended to cover non-exclusive or open-ended inclusions. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to the elements expressly listed, but may also include other elements not expressly listed or elements inherent in the aforementioned composition, method, or apparatus.

[0133] When the lower and upper limits of a numerical range are disclosed, any value or subrange falling within that range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b", or equivalently "approximately a to b", or equivalently "about ab") should be understood to encompass every value and subrange therein. For example, "C..." 1-4 "This should be understood as encompassing any subrange and every point value, such as C." 2-4 C 3-4 C 1-2 C 1-3 C 1-4 And so on, as well as C1, C2, C3, C4, etc.

[0134] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, comprising a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceuticalally acceptable carrier" refers to an excipient administered co-administered with a therapeutic agent, and which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that may be used in this invention include, but are not limited to: a) diluents; b) lubricants; c) binders; d) disintegrants; e) absorbents, colorants, flavoring agents, and / or sweeteners; f) emulsifiers or dispersants; and / or g) substances that enhance the absorption of the compound, etc.

[0135] The above-described pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as parenteral, local, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular, or as inhalers.

[0136] The above-mentioned routes of administration can be achieved through suitable dosage forms. Dosage forms that can be used in this invention include, but are not limited to: tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0137] When administered orally, the above-mentioned pharmaceutical composition may be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, and aqueous suspensions.

[0138] The above-described pharmaceutical compositions can also be administered in the form of sterile injectable formulations, including sterile injectable water or oil suspensions, or sterile injectable water or oil solutions. The carriers that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils, such as monoglycerides or diglycerides, can also be used as solvents or suspension media.

[0139] The pharmaceutical composition described above may contain 0.01 mg to 1000 mg of at least one compound of Formula I, Formula I-1 to Formula I-20 or a pharmaceutically acceptable form thereof.

[0140] The term "disease or condition mediated at least in part by HPK1" refers to diseases whose pathogenesis involves at least some HPK1-related factors, such as 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, cell tumors and sarcomas, multiple myeloma, leukemia, non-Hodgkin's lymphoma, or myelodysplastic syndrome.

[0141] The term "effective dose" refers to a dose that is sufficient to induce a biological or medical response in cells, tissues, organs, or organisms (e.g., individuals) and to achieve the desired preventive and / or therapeutic effects.

[0142] The dosing regimen can be adjusted to provide the optimal required response. For example, it can be administered as a single dose, divided into doses over time, or the dose can be reduced or increased proportionally as needed. It is understood that, for any given individual, the specific dosing regimen should be adjusted as required and with the professional judgment of the person administering the composition or supervising the administration of the composition.

[0143] The term “needs” refers to the judgment of a physician or other caregiver regarding an individual’s need for or potential benefit from preventive and / or therapeutic procedures, which is based on various factors within the physician’s or other caregiver’s area of ​​expertise.

[0144] The term "individual" (or subject) refers to a human or non-human animal. Individuals in this invention include individuals suffering from diseases and / or conditions (patients) and healthy individuals. Non-human animals in this invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0145] The term “treatment” means the reduction or elimination of a targeted disease or symptom. A subject is considered successfully “treated” if, after receiving a therapeutic amount of a compound of the present invention or its pharmaceutically acceptable form, or a pharmaceutical composition of the present invention, at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement. It is understood that treatment includes not only complete treatment but also the achievement of some biologically or medically relevant outcome without achieving complete treatment. Specifically, “treatment” means that a compound of the present invention or its pharmaceutically acceptable form, or a pharmaceutical composition of the present invention, can achieve at least one of the following effects, for example: (1) preventing the occurrence of disease in animals that may be predisposed to disease but have not yet experienced or displayed disease pathology or symptomology; (2) inhibiting disease in animals that are experiencing or displaying disease pathology or symptomology (i.e., preventing further development of pathology and / or symptomology); (3) improving disease in animals that are experiencing or displaying disease pathology or symptomology (i.e., reversing pathology and / or symptomology).

[0146] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases; such salts are also known as acid addition salts or base addition salts. For a review of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0147] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and hydrolyzes in vivo to form the compounds of the present invention or their salts. Pharmaceutically acceptable esters generally include, but are not limited to, esters formed by the compounds of the present invention and pharmaceutically acceptable carboxylic acids or sulfonic acids; such esters are also known as carboxylic acid esters or sulfonate esters.

[0148] The term "isomer" refers to a compound that has the same molecular weight due to having the same number and type of atoms, but with different spatial arrangements or configurations of atoms.

[0149] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that possesses at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) resulting in a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Unless otherwise stated, all stereoisomers of the compounds of this invention are within the scope of this invention.

[0150] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0151] The term "solvent" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanol compounds, acetone compounds, etc.

[0152] The term "nitrogen oxide" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds. For example, the nitrogen atom in the parent nucleus of compound I can form the corresponding nitrogen oxide.

[0153] The term "isotope-labeled compound" refers to a derivative compound formed by replacing specific atoms in the compounds of this invention with their isotopic atoms. Unless otherwise indicated, the compounds of this invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as, but not limited to, those of other isotopes. 2 H(D), 3 H(T), 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.

[0154] The term "metabolite" refers to derivative compounds formed after the compounds of this invention are metabolized. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9). th [M], McGraw-Hill International Editions, 1996. This invention covers all possible metabolite forms of the compounds of this invention, i.e., substances formed in the body of an individual administering the compounds of this invention. Metabolites of the compounds can be identified by techniques known in the art, and their activity can be characterized by testing.

[0155] The term "prodrug" refers to a derived compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, the present invention also covers compounds of the present invention containing a protecting group. In any process of preparing the compounds of the present invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in TW Greene, PGM Uts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protective bases can be removed at appropriate subsequent stages using methods known in the art.

[0156] The term "independently" means that at least two groups (or ring systems) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0157] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms (e.g., hydrogen atoms) or groups of atoms (e.g., trifluoromethanesulfonate groups) on a specified group with other atoms or groups of atoms, provided that the specified group satisfies the valence requirements in the present case and forms a stable compound after substitution. Combinations of substituents and / or variables are permitted only if the combination forms a stable compound. If a substituent is described as "optionally substituted with…", the substituent may be unsubstituted or substituted. If a first substituent is described as optionally substituted with one or more atoms from the second list of substituents, one or more hydrogen atoms in the first substituent may be substituted individually or independently with one or more atoms from the second list of substituents, or may not be substituted.

[0158] When used alone or in combination with other groups in this document, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0159] When used alone or in combination with other groups herein, the term "alkyl" refers to a straight-chain or branched aliphatic hydrocarbon group. For example, the term "C" as used in this invention... 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. Alkyl groups may be optionally substituted or unsubstituted.

[0160] When used alone or in combination with other groups in this document, the term "alkylene" refers to a straight-chain or branched divalent aliphatic hydrocarbon group to which the two groups (or segments) are attached can be attached to the same carbon atom or different carbon atoms. For example, the term "C" as used herein... 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms (such as methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.). Alkylenes can be optionally substituted or unsubstituted.

[0161] When used alone or in combination with other groups herein, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom. For example, the term "C" as used herein... 1-6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. For example, alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Alkoxy groups can be optionally substituted or unsubstituted.

[0162] When used alone or in combination with other groups herein, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, the term "C" as used herein...3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spiro rings, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. The cycloalkyl group in this invention may optionally be substituted by one or more substituents described in this invention.

[0163] When used alone or in combination with other groups herein, the term "heterocyclic group" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic group whose ring atoms consist of a carbon atom and at least one heteroatom selected from N, O, and S, wherein the S atom is optionally substituted to form S(=O), S(=O)2, or S(=O)(=NR). x ), R x Independently selected from H or C 1-4 Alkyl groups. If the valence requirements are met, the heterocyclic group can be connected to the rest of the molecule via any one ring atom. For example, the term "3-8 membered heterocyclic group" as used herein refers to a heterocyclic group having 3 to 8 ring atoms. Common heterocyclic groups include (but are not limited to) ethylene oxide, aziridine propane, aziridine butane, oxadiazine, tetrahydrofuranyl, dioxadiopentenyl, pyrrolyl, pyrrolidone, imidazoyl, pyrazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiaalkyl, or trithiaalkyl. The heterocyclic groups in this invention may optionally be substituted with one or more substituents described herein.

[0164] When used alone or in combination with other groups herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C" as used in this invention... 6-10 "Aryl" refers to an aryl group having 6 to 10 carbon atoms. Common aryl groups include (but are not limited to) phenyl, naphthyl, anthraceneyl, phenanthryl, acenaphthene, azulel, fluorenyl, indene, pyrene, etc. The aryl group in this invention may optionally be substituted by one or more substituents described in this invention.

[0165] When used alone or in combination with other groups herein, the term "heteroaryl" refers to an aromatic group that is a monocyclic or fused polycyclic ring with a conjugated π-electron system, the ring atoms of which consist of a carbon atom and at least one heteroatom selected from N, O, and S. If the valence requirement is met, the heteroaryl can be linked to the rest of the molecule through any one ring atom. For example, the term "5-10-membered heteroaryl" as used in this invention refers to a heteroaryl having 5 to 10 ring atoms. Common heteroaryls include (but are not limited to) thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl and their benzo[a] derivatives, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purine, etc. The heteroaryl group in this invention is optionally replaced by one or more substituents described in this invention (such as halogens, C...). 1-6 Alkyl groups, etc., are substituted.

[0166] When used alone or in combination with other groups herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, the term "C" as used in this invention... 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Common alkenyl groups include (but are not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl groups in this invention may optionally be substituted by one or more substituents described in this invention.

[0167] When used alone or in combination with other groups herein, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, the term "C" as used in this invention... 2-6 "Alynyl" refers to an alkynyl group having 2 to 6 carbon atoms. Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in this invention may optionally be substituted by one or more substituents described in this invention.

[0168] When used alone or in combination with other groups in this document, the term "oxo" refers to =O. Detailed Implementation

[0169] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention.

[0170] All reagents and instruments used in the examples are commercially available conventional products. Unless otherwise specified, all conditions were performed under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" as used in this invention refers to 20℃ ± 5℃. When used to modify a numerical value or range, the term "about" as used in this invention refers to the value or range and a range of errors acceptable to those skilled in the art, such as ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0171] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0172] The nuclear magnetic resonance (NMR) measurements were performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS).

[0173] The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings:

[0174] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quadruple doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad peak, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0175] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0176] The mass spectrometry (MS) measurements were performed using an Agilent 6120B mass spectrometer with an electrospray ionization (ESI) source.

[0177] Compound Synthesis

[0178] Example 1: Synthesis of Compounds A-1 and A-2

[0179]

[0180] Compound SM (10 g, 47.975 mmol, 1.00 equiv), compound (trimethylsilyl)acetylene (5.18 g, 52.773 mmol, 1.1 equiv), cuprous iodide (0.91 g, 4.798 mmol, 0.1 equiv), PdCl2(PPh3)2 (3.37 g, 4.798 mmol, 0.1 equiv), and triethylamine (12.14 g, 119.938 mmol, 2.5 equiv) were dissolved in toluene (125 mL) and reacted at room temperature under nitrogen protection for 3 hours. After the reaction was complete, water (75 mL) was added at room temperature to quench the reaction mixture. The reaction system was filtered, and the filtrate was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 1 (14 g) as a brown solid. m / z(ES+), [M+H] + =226.

[0181] Compound 1 (14 g, 62.016 mmol, 1.00 equiv), potassium tert-butoxide (10.44 g, 93.024 mmol, 1.5 equiv), and dimethylaniline (1.50 g, 12.403 mmol, 0.2 equiv) were dissolved in DMF (150 mL) and reacted at 120 °C under nitrogen protection for 2 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution at room temperature. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 50 mL). The filtrate was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off. The filtrate was concentrated, and the crude product was purified by column chromatography to give compound 2 (1.5 g, yield 15.75%), an orange-yellow oil. m / z(ES+), [M+H] + =154.

[0182] Compound 2 (1.5 g, 9.768 mmol, 1.00 equiv) and compound N-iodosuccinimide (2.31 g, 10.256 mmol, 1.05 equiv) were dissolved in DMF (15 mL) and reacted at 30 °C under nitrogen protection for 2 hours. After the reaction was complete, the system was cooled to room temperature and the reaction was quenched with water. The mixture was extracted with ethyl acetate (2 x 20 mL), and the combined organic phases were washed with saturated brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, concentrated the filtrate, and purified by column chromatography to give compound 3 (2 g, yield 73.27%) as a yellow solid. m / z (ES+), [M+H) + =280.

[0183] Compound 3 (2 g, 7.156 mmol, 1.00 equiv) was dissolved in DMF (20 mL), and sodium hydride (60%, 0.86 g) was added at 0 °C. The reaction system was stirred at room temperature for 30 min under nitrogen protection. Subsequently, 4-methylbenzenesulfonyl chloride (2.05 g, 10.734 mmol, 1.5 equiv) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution at 0 °C. The mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic phases were washed with saturated brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, concentrated the filtrate, and purified by column chromatography to give compound 4 (2.9 g, yield 93.45%) as a yellow solid. m / z (ES+), [M+H]+ = 434.

[0184] Compound 4 (500 mg, 1.153 mmol, 1.00 equiv) and methylboric acid (103.53 mg, 1.730 mmol, 1.5 equiv) were dissolved in 1,4-dioxane / water (5 mL: 1 mL), followed by the addition of Pd(PPh3)Cl2 (80.93 mg, 0.115 mmol, 0.1 equiv) and sodium carbonate (366.62 mg, 3.459 mmol, 3 equiv). The reaction mixture was carried out at 100 °C under nitrogen protection for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the crude product was purified by column chromatography to give compound 5 (60 mg, yield 16.17%) as a yellow oil. m / z (ES+), [M+H) + =322.

[0185] Compound 5 (60 mg, 0.186 mmol, 1.00 equiv) and intermediate I (69.61 mg, 0.186 mmol, 1 equiv) were dissolved in 1,4-dioxane / H₂O (1 ml: 0.2 ml). Then, Pd(dppf)Cl₂.CH₂Cl₂ (15.19 mg, 0.019 mmol, 0.1 equiv) and potassium carbonate (77.31 mg, 0.558 mmol, 3 equiv) were added to the reaction mixture, and the reaction was carried out overnight at 90 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by column chromatography to give a yellow oily compound 6 (36 mg, yield 36.25%). m / z (ES⁺), [M⁺H] + =533.

[0186] Compound 6 (30 mg, 0.028 mmol, 1.00 equiv) and sodium hydroxide solution (2 M, 0.5 mL) were dissolved in methanol (1 mL). The reaction system was reacted at 65 °C under nitrogen protection for 2 hours. After the reaction was completed, the system was cooled to room temperature. The reaction system was extracted with ethyl acetate (3 x 20 mL), the combined organic phases were washed with saturated brine (3 x 20 mL), dried with anhydrous sodium sulfate, the anhydrous sodium sulfate was filtered off, the filtrate was concentrated, and the crude product was purified by high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 14% B, 14% B over 10 min; wavelength: 254 nm; 220 nm; RT1 (min): 8.83, 9.15 (min)) to obtain off-white solid compound A-1 and white solid compound A-2.

[0187] Compound A-1 (0.8 mg, yield 3.55%). m / z (ES+), [M+H] + =379. 1 H NMR (400MHz, CD3OD-d4): δ (ppm) 8.33 (s, 1H), 8.25 (s, 1H), 8.10 (d, J = 8.6Hz, 1H), 7.68 (d, J = 8.6Hz, 1H), 7.67 (s, 1H ),4.23–4.05(m,5H),4.02–3.92(m,3H),3.74(t,J=11.6Hz,3H),3.62–3.44(m,3H),2.43(s,3H),2.08–1.84(m,4H).

[0188] Compound A-2 (4.2 mg, yield 19.6%). m / z (ES+), [M+H] + =365. 1 H NMR (400MHz, CD3OD-d4): δ (ppm) 8.51 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 8.2Hz, 1H), 7.93 (s, 1H), 7.68 (d, J = 8.3Hz, 1H), 6.76 ( s,1H),4.44-3.82(m,6H),3.74(t,J=12.0Hz,2H),3.60-3.49(m,2H),3.25(t,J=12.2Hz,1H),1.97–2.00(m,3H),1.73(d,J=13.5Hz,1H).

[0189] Example 2 Synthesis of compound A-3

[0190]

[0191] In a 250 mL reaction flask, compound 1 (5 g, 26.178 mmol, 1.00 equiv) and N-iodosuccinimide (6.18 g, 27.487 mmol, 1.05 equiv) were dissolved in acetic acid (60 mL). Trifluoroacetic acid (1 mL, 13.463 mmol, 0.51 equiv) was added at room temperature under nitrogen atmosphere, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched in ice water. The mixture was neutralized with ammonia water, and the pH was adjusted to 8-9. The precipitated solid was filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography to give a pale pink solid, compound 2 (2.95 g, yield 35.4%). m / z (ES+), [M+H) + =317.

[0192] In a 100 mL reaction flask, compound 2 (2.75 g, 8.675 mmol, 1.00 equiv) and trimethylsilylacetylene (4.87 g, 43.375 mmol, 5 equiv) were dissolved in DMF (10 mL). Potassium acetate (2.55 g, 26.025 mmol, 3 equiv), palladium acetate (0.19 g, 0.868 mmol, 0.1 equiv), and lithium chloride (0.37 g, 8.675 mmol, 1 equiv) were added. The reaction mixture was stirred overnight at 100 °C under nitrogen atmosphere. After the reaction was complete, the reaction solution was purified by reversed-phase column chromatography to give a brown oily compound 3 (515 mg, yield 19.7%). m / z (ES+), [M+H] + =302.

[0193] In a 40 mL sealed tube, compound 3 (500 mg, 1 equiv), tetrahydrofuran (6 mL), and hydrochloric acid (2 mol / L, 6 mL) were added, and the reaction mixture was stirred overnight at 70 °C. The reaction solution was poured into ice water, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 4 (160 mg, yield 42.2%) as a yellow solid. m / z(ES+), [M+H] + =230.

[0194] Add a mixture of compound 4 (68 mg, 0.297 mmol, 1.00 equiv), boron ester intermediate I (132.99 mg, 0.356 mmol, 1.2 equiv), potassium carbonate (123.99 mg, 0.891 mmol, 3 equiv), Pd(dppf)Cl2 (21.72 mg, 0.030 mmol, 0.1 equiv), and 1,4-dioxane / water (3 mL, 10 / 1) to an 8 mL sealed tube. Stir the reaction mixture overnight at 80 °C under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting mixture was purified by thin-layer chromatography (dichloromethane:methanol = 12:1) to obtain a crude product. The crude product was then purified by high-performance liquid chromatography (HPLC) (column: YMC-Actus Triart C18 ExRS, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25%B to 55%B, 55%B over 8min; wavelength: 254 / 220nm; RT1 (min): 7.82) to obtain a white solid compound A-3 (8mg, yield 7.7%). m / z (ES+), [M+H) + =396.

[0195] 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 1.57 (d, J = 13.0Hz, 1H), 1.62–1.85 (m, 3H), 2.37 (s, 3H), 2.9 7(d,J=12.0Hz,1H),3.02–3.20(m,2H),3.35(t,J=10.8Hz,1H),3.54-3.60(m,3H),3.77-3. 78(m,1H),3.82(d,J=11.5Hz,1H),3.95(d,J=10.7Hz,2H),4.29(dd,J=10.4,3.1Hz,1H),7. 04–7.33(m,1H),7.41(d,J=8.1Hz,1H),7.44–7.53(m,1H),7.76(s,1H),8.22–8.24(m,2H).

[0196] 19 F NMR (376MHz, DMSO-d6): δ (ppm)-122.51.

[0197] Example 3 Synthesis of compound A-4

[0198] The synthesis of compound 1 is similar to that of intermediate compound 4 in Example 2.

[0199]

[0200] In an 8 mL sealed tube, compound 1 (100 mg, 0.444 mmol, 1.00 equiv), intermediate I (497.54 mg, 1.332 mmol, 3 equiv), potassium carbonate (184.20 mg, 1.332 mmol, 3 equiv), and Pd(dppf)Cl2CH2Cl2 (36.19 mg, 0.044 mmol, 0.1 equiv) were dissolved in 1,4-dioxane / water solution (5 mL / 0.5 mL). The reaction system was stirred overnight at 80 °C under nitrogen protection. After the reaction, the system was concentrated and purified by thin-layer chromatography (dichloromethane:methanol = 12:1) to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (HPLC) (column: YMC-Actus Triart C18 ExRS, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 33%B to 45%B, 45%B over 8min; wavelength: 254 / 220nm; RT1 (min): 7.62) to obtain a white solid compound A-4 (7mg, yield 4%). m / z (ES+), [M+H) + =392. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.22 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.25 (d, J = 8.0Hz, 1H), 7.18 (s, 1H), 4.16 (d, J = 9.8Hz ,1H),3.86–4.06(m,2H),3.72-3.76(m,2H),3.50-3.55(m,3H),3.22-3.2 4(m,2H),2.68–3.02(m,3H),2.57(s,3H),2.46(s,3H),1.53–1.91(m,4H).

[0201] Example 4 Synthesis of compound A-5

[0202]

[0203] In a 100 mL reaction flask, compound 1 (4.5 g, 18.436 mmol, 1.00 equiv) was dissolved in hydrochloric acid solution (3 mol / L, 50 mL). Sodium nitrite (1.65 g, 23.967 mmol, 1.3 equiv) was slowly added to the reaction flask at 0 °C, purging with nitrogen gas, and then stirred at 0 °C for 2 hours. The above reaction solution was then added dropwise to an aqueous solution (10 mL) of potassium iodide (3.67 g, 22.123 mmol, 1.2 equiv) at 60 °C, and the reaction was carried out at 60 °C for 1.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography to give an orange-yellow oily compound 2 (5.84 g, yield 89.2%). m / z(ES+), [M+H] + =355. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 2.44 (s, 3H), 3.86 (s, 3H), 7.56 (s, 1H), 7.73 (s, 1H).

[0204] In a 40 mL sealed tube, compound 2 (2.3 g, 6.479 mmol, 1.00 equiv), Pd(dppf)Cl2 (0.24 g, 0.324 mmol, 0.05 equiv), and cuprous iodide (0.12 g, 0.648 mmol, 0.1 equiv) were dissolved in N,N-dimethylacetamide (15 mL). Zinc iodide (tetrahydro-2H-pyran-4-yl) (19.41 mL, 19.41 mmol, 3.00 equiv in DMA) was added, and the mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction system was quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography to give a yellow solid compound 3 (408 mg, yield 20.1%). m / z (ES+), [M+H) + =314.

[0205] In a 40 mL sealed tube, compound 3 (408 mg, 1.303 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (6 mL), and lithium aluminum hydride (49.44 mg, 1.303 mmol, 1 equiv) was slowly added at 0 °C. The mixture was stirred at 0 °C for 1.5 hours under nitrogen atmosphere. After the reaction was complete, the reaction system was quenched with ice water, extracted with ethyl acetate (2 x 80 mL), and the combined organic phases were concentrated under reduced pressure to give compound 4 (370 mg, 99.6% yield), a brownish-yellow oil.

[0206] In a 40 mL sealed tube, compound 4 (370 mg, 1.297 mmol, 1.00 equiv) and manganese dioxide (902.35 mg, 10.376 mmol, 8 equiv) were dissolved in dichloromethane (5 mL), and the mixture was stirred overnight at 30 °C under nitrogen atmosphere. After the reaction was complete, the reaction system was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid compound 5 (309 mg, yield 84.11%). m / z (ES+), [M] + =283.

[0207] In a 40 mL sealed tube, compound 5 (309 mg, 1.091 mmol, 1.00 equiv), 4A molecular sieve (100 mg), and compound SM1 (397.39 mg, 1.091 mmol, 1 equiv) were dissolved in dichloromethane (8 mL), and the mixture was stirred at 30 °C for 6 hours under nitrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The product obtained was dissolved in hexafluoroisopropanol (1 mL), and then added dropwise to a mixture of compound SM2 (78.93 mg, 0.218 mmol, 0.2 equiv) and copper trifluoromethanesulfonate (72.99 mg, 0.218 mmol, 0.2 equiv) in hexafluoroisopropanol (2 mL). The mixture was stirred overnight at room temperature under nitrogen atmosphere. After the reaction was complete, the reaction system was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain a yellow solid compound 6 (100 mg, yield 26.9%). m / z(ES+),[M) + =340.

[0208] In an 8 mL sealed tube, compound 6 (100 mg, 0.294 mmol, 1.00 equiv), compound SM3 (75.86 mg, 0.294 mmol, 1 equiv), Pd(dppf)Cl2 (23.94 mg, 0.029 mmol, 0.1 equiv), potassium carbonate (62.30 mg, 0.588 mmol, 2 equiv) were added to water (1 mL) and 1,4-dioxane (4 mL), and stirred at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, and the mixture was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. The crude product was then purified by high-pressure preparative liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25%B to 50%B, 50%B over 8min; wavelength: 220nm; RT1 (min): 7.30) to obtain a white solid compound A-5 (14.6mg, yield 12.7%). m / z (ES+), [M+H) + =392. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 1.55-1.65 (m, 2H), 2.09-2.13 (m, 2H), 2.30 (d, J = 1.0Hz, 3H),2.43(s,2H),2.54(s,1H),2.77(s,1H),2.92(s,2H),3.45-3.48(m,3H),3.55(s,1H ),3.66(s,1H),3.77(dd,J=10.4,2.8Hz,1H),4.01(dd,J=10.0,4.9Hz,2H),4.14-4.35( m,1H),7.27(s,1H),7.44(s,1H),7.78(s,1H),8.08(s,1H),8.45(s,1H),11.36(s,1H).

[0209] Example 5 Synthesis of Compound A-6

[0210] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0211]

[0212] In an 8 mL sealed tube, compound 1 (60 mg, 0.166 mmol, 1.00 equiv), compound SM1 (42.94 mg, 0.166 mmol, 1 equiv), Pd(dppf)Cl2 (13.55 mg, 0.017 mmol, 0.1 equiv), potassium carbonate (68.97 mg, 0.498 mmol, 3 equiv) were added to water (0.4 mL) and 1,4-dioxane (4 mL), and stirred at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. The crude product was then purified by preparative high-pressure liquid chromatography (PLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 30%B to 50%B over 8min) to give a white solid compound A-6 (6.2mg, yield 9.0%). m / z (ES+), [M+H) + =412. 1 H NMR(DMSO-d6,400MHz): δ(ppm)1.28–1.77(m,2H),2.09-2.10(m,1H),2.30(s,3H),2.65(s,1H),2.80–3.06(m,3H),3.23(s,1H),3.40–3.63 (m,4H),3.73-3.76(m,2H),4.00(s,2H),4.11–4.48(m,1H),7.27(s,1 H),7.66(s,1H),7.95(s,1H),8.15(s,1H),8.46(s,1H),11.40(s,1H).

[0213] Example 6 Synthesis of Compound A-7

[0214] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0215]

[0216] In an 8 mL sealed tube, compound 1 (30 mg, 0.092 mmol, 1.00 equiv), compound SM1 (50.63 mg, 0.184 mmol, 2 equiv), Pd(dppf)Cl2 (7.47 mg, 0.009 mmol, 0.1 equiv), and sodium carbonate (29.15 mg, 0.276 mmol, 3 equiv) were added to a 1,4-dioxane / water (4 mL / 1 mL) solution, and stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction system was concentrated, and the mixture was purified by column chromatography (dichloromethane / methanol = 10:1) to obtain a crude product. The crude product was then purified by high-pressure preparative liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25%B to 45%B, 45%B over 8min; wavelength: 254nm; RT1 (min): 6.93) to obtain a white solid compound A-7 (1.1mg, yield 2.89%). [M+H] + =397. 1 H NMR (400MHz, CD3OD-d4): δ (ppm) 8.81 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.78 (d, J =8.3Hz,1H),7.14(s,1H),4.48(dd,J=10.3Hz,3.3Hz,1H),4.11-4.19(m,2H),3.97(dd, J=11.7Hz,3.3Hz,1H),3.85–3.94(m,1H),3.58–3.72(m,3H),3.55(d,J=11.0Hz,1H),3. 09–3.22(m,3H),2.49(s,3H),1.95-1.99(m,1H),1.84-1.88(m,2H),1.71-1.74(m,1H).

[0217] 19 F NMR (376MHz, CD3OD-d4): δ (ppm)-120.61.

[0218] Example 7 Synthesis of Compound A-8

[0219]

[0220] In an 8 mL sealed tube, compound 1 (60 mg, 0.166 mmol, 1.00 equiv), SM1 (42.94 mg, 0.166 mmol, 1 equiv), Pd(dppf)Cl2 (13.55 mg, 0.017 mmol, 0.1 equiv), and sodium carbonate (52.89 mg, 0.498 mmol, 3 equiv) were added to a 1,4-dioxane / water (4 mL / 1 mL) solution, and stirred at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction system was concentrated and purified by column chromatography (dichloromethane / methanol = 10:1) to obtain the crude product. The crude product was then purified by high-pressure preparative liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 30%B to 50%B, 50%B over 8min; wavelength: 254nm; RT1 (min): 7.07) to obtain a white solid compound A-8 (3.1mg, yield 4.5%). [M+H] + =412. 1 H NMR (CD3OD-d4, 400MHz): δ (ppm) 1.69 (d, J = 13.1Hz, 1H), 1.76–1.99 (m, 3H), 2.02 (s, 1H),2.36(s,3H),2.96-3.01(m,1H),3.05–3.16(m,1H),3.22-3.24(m,1H),3.36–3. 50(m,1H),3.62-3.64(m,3H),3.75–3.88(m,2H),4.08(d,J=11.2Hz,2H),4.24(dd,J =10.0,3.0Hz,1H),7.19(s,1H),7.45(s,1H),7.63(s,1H),7.99(s,1H),8.20(s,1H).

[0221] Example 8 Synthesis of compounds A-9 and A-39

[0222] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0223]

[0224] In an 8 mL sealed tube, compound 1 (50 mg, 0.140 mmol, 1.00 equiv), compound SM1 (36.23 mg, 0.140 mmol, 1 equiv), Pd(dppf)Cl2.CH2Cl2 (20.54 mg, 0.028 mmol, 0.2 equiv), and potassium carbonate (58.19 mg, 0.420 mmol, 3 equiv) were added to a solution of 1,4-dioxane / water (4 mL / 1 mL). The reaction system was stirred at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction system was concentrated, and the mixture was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain a crude product. The crude product was then purified by high-pressure preparative liquid chromatography (column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25%B to 50%B, 50%B over 8min; wavelength: 220nm; RT1 (min): 7.43) to obtain white solid compound A-9 (1.9mg, yield 3.3%) and compound A-39 (0.5mg, yield 0.86%).

[0225] Compound A-9: m / z(ES+), [M+H] + =408. 1 H NMR(DMSO-d6,400MHz): δ(ppm)11.35(s,1H),8.49(s,1H),8.12(s,1H),7.56(s, 1H),7.27(s,1H),7.21(s,1H),4.18(d,J=9.7Hz,1H),3.95-3.97(m,2H),3.90(s, 3H),3.77(d,J=10.7Hz,1H),3.67(d,J=10.8Hz,1H),3.45-3.49(m,3H),3.22-3. 24(m,2H),2.92-2.97(m,3H),2.36-2.40(m,1H),2.32(s,3H),1.24-1.44(m,3H).

[0226] Compound A-39: m / z(ES+), [M+H] + =394.15.

[0227] Example 9 Synthesis of Compound A-10

[0228] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0229]

[0230] In a 40 mL sealed tube, compound 1 (100 mg, 0.291 mmol, 1.00 equiv), compound SM1 (74.99 mg, 0.291 mmol, 1 equiv), Pd(dppf)Cl2 (23.67 mg, 0.029 mmol, 0.1 equiv), and potassium carbonate (120.45 mg, 0.873 mmol, 3 equiv) were added to a 1,4-dioxane / water (5 mL / 0.5 mL) solution, and the mixture was reacted at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was complete, the reaction mixture was evaporated to dryness. The mixture was purified by column chromatography (dichloromethane:methanol = 15:1) to obtain a crude product. The crude product was then purified by preparative high-pressure liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 20% B to 45% B over 8 min) to obtain a white solid compound A-10 (11.7mg). m / z (ES+), [M+H) + =396. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 11.41 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.45 (t, J = 8.1Hz, 1H), 7.24–7.29 (m, 2H), 4.38 (d, J = 9.9Hz, 1H), 3.97-4.0 0(m,2H),3.71–3.78(m,3H),3.67(dd,J=10.8,3.4Hz,1H),3.44–3.58(m, 3H), 2.90 (d, J = 6.1Hz, 2H), 2.75 (s, 1H), 2.29 (s, 3H), 1.62–1.86 (m, 4H).

[0231] 19 F NMR(DMSO-d6,376MHz): δ(ppm)-118.68.

[0232] Example 10 Synthesis of Compound A-11

[0233]

[0234] In an 8 mL sealed tube, compound 1 (70.01 mg, 0.204 mmol, 1.05 equiv) was dissolved in a 1,4-dioxane / water (5 mL: 1 mL) solution. SM1 (50 mg, 0.194 mmol, 1.00 equiv), Pd(dppf)Cl2 (14.17 mg, 0.019 mmol, 0.1 equiv), and potassium carbonate (80.90 mg, 0.582 mmol, 3 equiv) were added. The reaction system was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was evaporated to dryness. The mixture was purified by column chromatography (dichloromethane / methanol = 15:1) to obtain the crude product, which was then purified by preparative liquid chromatography (PLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 35%B to 40%B, 40%B over 7min; wavelength: 220nm; RT1 (min): 6.32) to obtain a white solid compound A-11 (24.8mg, yield 30.8%). m / z (ES+), [M+H) + =396. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 11.44 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.77 (d, J = 8.6Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 8.6Hz, 1H), 4.12 (dd, J = 10.0, 3 .0Hz,1H),3.98(dt,J=13.7,4.4Hz,2H),3.84–3.60(m,2H),3.49-3.55(m, 3H),3.27-3.35(m,2H),2.82-2.97(m,3H),2.30(s,3H),1.49–1.95(m,4H).

[0235] 19 F NMR(DMSO-d6,376MHz): δ-120.44.

[0236] Example 11 Synthesis of Compound A-12

[0237]

[0238] Compound 1 (3 g, 8.451 mmol, 1.00 equiv), borate ester (1.95 g, 9.296 mmol, 1.1 equiv), palladium acetate (0.19 g, 0.845 mmol, 0.1 equiv), potassium phosphate (3.59 g, 16.902 mmol, 2 equiv), and triphenylphosphine (0.22 g, 0.845 mmol, 0.1 equiv) were dissolved in acetonitrile / water (40 mL / 10 mL) solution in a 50 mL reaction flask and stirred overnight at 65 °C under nitrogen atmosphere. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by column chromatography to give compound 2 (1.953 g, yield 73.1%) as a yellow solid. m / z (ES+), [M+H) + =313.

[0239] In a 50 mL reaction flask, compound 2 (1.11 g, 3.567 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum hydride (0.14 g, 3.567 mmol, 1 equiv) was slowly added at 0 °C. The reaction system was stirred at 0 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction was quenched with ice water, and the mixture was extracted with ethyl acetate (80 mL * 2). The combined organic phases were concentrated under reduced pressure to give compound 3 (944 mg, yield 93.5%), a pale yellow oil. m / z (ES+), [M+H] + =284.

[0240] In a 40 mL sealed tube, compound 3 (940 mg, 3.320 mmol, 1.00 equiv) and manganese dioxide (2308.76 mg, 26.560 mmol, 8 equiv) were dissolved in dichloromethane (15 mL). The reaction mixture was stirred overnight at 30 °C under nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated, and the mixture was subjected to thin-layer chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 4 (858 mg, yield 91.9%) as a yellow solid. m / z (ES+), [M] + =281.

[0241] In a 40 mL sealed tube, compound 4 (450 mg, 1.601 mmol, 1.00 equiv) and 4A molecular sieve (800 mg) were dissolved in dichloromethane (15 mL). Compound SM1 (582.87 mg, 1.601 mmol, 1 equiv) was added under nitrogen atmosphere, and the reaction mixture was reacted at 30 °C for 6 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The crude product was dissolved in hexafluoroisopropanol (10 mL), and copper trifluoromethanesulfonate (107.05 mg, 0.320 mmol, 0.2 equiv) and compound SM2 (115.78 mg, 0.320 mmol, 0.2 equiv) were added. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated, and the crude product was subjected to thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow solid compound 5 (300 mg, yield 55.4%). m / z(ES+),[M+2H) + =340.

[0242] In an 8 mL sealed tube, compound 5 (340 mg, 1.005 mmol, 1.00 equiv) was dissolved in a 1,4-dioxane / water (10 mL / 1 mL) solution. Compound SM3 (259.47 mg, 1.005 mmol, 1 equiv), Pd(dppf)Cl2 (73.55 mg, 0.100 mmol, 0.1 equiv), and potassium carbonate (419.81 mg, 3.015 mmol, 3 equiv) were added. The reaction system was carried out at 80 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction system was concentrated, and the mixture was purified by column chromatography (dichloromethane:methanol = 12:1) to obtain a crude product. The crude product was then purified by high-pressure preparative liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25%B to 50%B, 50%B over 8min; wavelength: 220nm; RT1 (min): 7.40) to obtain a white solid compound A-12 (7.8mg, yield 1.9%). m / z (ES+), [M+H) + =390. 1H NMR (DMSO-d6, 400MHz): δ (ppm) 11.36 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 5.62 (d, J=14.8Hz, 1H), 4.12–4 .38(m,2H),3.66–4.10(m,4H),3.38–3.69(m,3H),3.23(t,J=10.3Hz,1 H), 2.87 (d, J = 8.5Hz, 3H), 2.38 (s, 3H), 2.24 (s, 3H), 2.21-2.25 (m, 2H).

[0243] Example 12 Synthesis of Compound A-13

[0244] The synthesis of compound 1 is similar to that of intermediate compound 5 in Example 11.

[0245]

[0246] In a 40 mL sealed tube, compound 1 (250 mg, 0.697 mmol, 1.00 equiv), bis-pinacolborate (194.71 mg, 0.767 mmol, 1.1 equiv), Pd(dppf)Cl2 (113.56 mg, 0.139 mmol, 0.2 equiv), and potassium acetate (136.82 mg, 1.394 mmol, 2 equiv) were added to 1,4-dioxane (5 mL). The reaction was carried out overnight at 80 °C under nitrogen atmosphere with stirring. After the reaction was complete, the reaction mixture was evaporated to dryness, and the mixture was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound 2 (200 mg, yield 70.72%) as a yellow solid. m / z (ES+), [M+H) + =406.

[0247] In a 40 mL sealed tube, compound 2 (50 mg, 0.237 mmol, 1.00 equiv), compound SM1 (96.12 mg, 0.237 mmol, 1 equiv), Pd(dppf)Cl2 (19.30 mg, 0.024 mmol, 0.1 equiv), and potassium carbonate (98.22 mg, 0.711 mmol, 3 equiv) were added to a 1,4-dioxane / water (5 mL / 0.5 mL) solution. The reaction system was stirred at 80 °C for 6 hours under nitrogen atmosphere. After the reaction was complete, the reaction mixture was evaporated to dryness. The mixture was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain a crude product. The crude product was then purified by preparative high-pressure liquid chromatography (HPLC) (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 30%B to 50%B over 8min) to obtain a white solid compound A-13 (3.9mg, yield 3.99%). m / z (ES+), [M+H) + =410. 1 H NMR(DMSO-d6,400MHz): δ(ppm)11.43(s,1H),8.49(s,1H),8.18(s,1H),7.92(d, J=8.0Hz,1H),7.75(s,1H),7.30(s,1H),5.72(d,J=17.0Hz,1H),4.14–4.37(m,2 H),3.83-3.89(m,3H),3.65–3.79(m,2H),3.46–3.64(m,2H),3.42(d,J=10.5Hz, 1H), 3.26 (d, J = 10.2Hz, 1H), 2.79-2.88 (m, 2H), 2.33-2.49 (m, 4H), 2.26 (s, 1H).

[0248] Example 13 Synthesis of Compound A-14

[0249]

[0250] In a 40 mL sealed tube, compound 1 (2 g, 28.552 mmol, 1.00 equiv), dimethylamine (2.33 g, 28.552 mmol, 1 equiv), HATU (16.28 g, 42.828 mmol, 1.5 equiv), and DIEA (14.76 g, 114.208 mmol, 4 equiv) were dissolved in DMF (20 mL, 273.617 mmol, 9.58 equiv). The reaction was carried out under nitrogen atmosphere at room temperature for 3 h. After the reaction was complete, the mixture was extracted with water and ethyl acetate. The organic phase was concentrated by rotary evaporation and then subjected to preparative thin-layer chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a yellow solid compound 2 (2.2 g, yield 79.34%). MS (ESI): [M+H] + =98.

[0251] In a 40 mL sealed tube, compounds 2 (2.2 g, 22.653 mmol, 5.40 equiv), 3 (2 g, 4.192 mmol, 1.00 equiv), cuprous iodide (0.08 g, 0.419 mmol, 0.1 equiv), and Pd(PPh3)2Cl2 (0.48 g, 0.419 mmol, 0.1 equiv) were dissolved in triethylamine (20 mL). The reaction was carried out overnight at 60 °C under nitrogen atmosphere. After the reaction was complete, the solvent was evaporated by filtration, and the solution was analyzed by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a yellow solid compound 4 (740 mg, yield 40%). MS (ESI): [M+H] + =446.0.

[0252] In a 40 mL sealed tube, compounds 4 (740 mg, 1.658 mmol, 1.00 equiv), 5 (618.93 mg, 1.658 mmol, 1 equiv), Pd(dppf)Cl2 (135.06 mg, 0.166 mmol, 0.1 equiv), and potassium carbonate (687.44 mg, 4.974 mmol, 3 equiv) were dissolved in 1,4-dioxane (8 mL) and water (0.8 mL). The reaction was carried out under nitrogen atmosphere at 80 °C for 3 h. After the reaction was complete, the solvent was evaporated by filtration, and the solution was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain a yellow solid compound 6 (640 mg, yield 63%). MS (ESI): [M+H] + =613.4.

[0253] In a 40 mL sealed tube, compound 6 (640 mg, 1.044 mmol, 1.00 equiv) and NaOH (2 mL, 50.004 mmol, 47.87 equiv, 2 M) were added to methanol (7 mL), and the reaction was carried out under nitrogen atmosphere at 65 °C for 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and the crude product was obtained by column chromatography using dichloromethane / methanol (7:1). The crude product was then subjected to high-performance liquid chromatography (HPLC) (column: CHIRALPAK IG, 2*25cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH) – HPLC; mobile phase B: EtOH:DCM = 1:1 – HPLC; flow rate: 20mL / min; gradient: 40%B to 40%B over 15.5min; wavelength: 220 / 254nm; RT1 (min): 9.20; RT2 (min): 12.70; sample solvent: EtOH:DCM = 1:1 – HPLC; injection volume: 0.85mL) to obtain a white solid compound A-14 (100mg, yield 20.3%). MS (ESI): [M+H) + =459.2. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 12.56 (s, 1H), 8.62 (d, J = 2.0Hz, 1H), 8.20 (s, 1H), 8 .13(d,J=2.0Hz,1H),7.95(d,J=2.0Hz,1H),7.63(dd,J=8.0,2.0Hz,1H),7.42(d,J =8.0Hz,1H),4.18–4.16(m,1H),4.02–3.98(m,2H),3.79–3.76(m,1H),3.72–3.68( m,1H),3.57–3.52(m,3H),3.35–3.15(m,5H),3.02–2.88(m,6H),1.86–1.56(m,4H).

[0254] Example 14 Synthesis of Compound A-15

[0255] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0256]

[0257] Compound 1 (80 mg, 0.132 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 49% B, 49% B over 8 min; wavelength: 254 nm; RT1 (min): 7.28) to give a white solid compound A-15 (32.6 mg, yield 60.31%). MS (ESI): m / z [M+H) + =405. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.45 (s, 1H), 8.98 (s, 1H), 8.60 (s, 1H), 7.92 (d, J = 8.2Hz, 1 H),7.80(d,J=8.3Hz,1H),7.20(s,1H),4.29(d,J=9.6Hz,1H),3.98(d,J=10.9Hz,2H),3.88( d,J=11.0Hz,1H),3.77(d,J=10.2Hz,1H),3.42-3.59(m,4H),3.12-3.19(m,1H),2.97(s,2H ),2.65(s,1H),2.00-2.11(m,1H),1.63-1.85(m,4H),0.87-0.93(m,2H),0.67-0.71(m,2H).

[0258] Example 15 Synthesis of Compound A-16

[0259] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0260]

[0261] Compound 1 (80 mg, 0.132 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 49% B, 49% B over 8 min; wavelength: 254 nm; RT1 (min): 7.30) to give a white solid compound A-16 (30.7 mg, yield 56.80%). MS (ESI): m / z [M+H) + =405. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.45 (s, 1H), 8.98 (s, 1H), 8.60 (s, 1H), 7.92 (d, J = 8.2Hz, 1H ),7.80(d,J=8.3Hz,1H),7.20(s,1H),4.29(d,J=8.4Hz,1H),3.98(d,J=11.1Hz,2H),3.88(dd ,J=11.2,3.1Hz,1H),3.77(d,J=11.1Hz,1H),3.45-3.59(m,4H),3.13-3.20(m,1H),2.98(s,2 H),2.68(s,1H),2.02-2.10(m,1H),1.61-1.82(m,4H),0.84-0.92(m,2H),0.65-0.73(m,2H).

[0262] Example 16 Synthesis of Compound A-17

[0263] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0264]

[0265] Compound 1 (50 mg, 0.079 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative 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: 20% B to 50% B, 50% B over 8 min; wavelength: 220 nm; RT1 (min): 7.58) to give a white solid compound A-17 (4.5 mg, yield 12.3%). MS (ESI): m / z [M+H) + =433. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.17 (s, 1H), 8.60 (s, 1H), 8.23 ​​(s, 1H), 7.99 (d, J = 8.2Hz, 1H), 7.84 (d, J = 8.3Hz, 1H), 4.30 (d, J = 9.9Hz, 1H), 3.99 (dd,J=10.9,3.4Hz,2H),3.89(d,J=11.1Hz,1H),3.78(d,J=10.4Hz,1H),3.45-3.63(m,4H),3.17-3.22(m,1H),2.98(s,2H),1.63-1.86(m,4H).

[0266] 19 F NMR (376MHz, DMSO-d6): -55.10.

[0267] Example 17 Synthesis of Compound A-18

[0268] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0269]

[0270] Compound 1 (100 mg, 0.158 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative 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: 20% B to 50% B, 50% B over 8 min; wavelength: 220 nm; RT1 (min): 7.58) to give a white solid compound A-18 (22.1 mg, yield 31.98%). MS (ESI): m / z [M+H) + =433. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.69 (s, 1H), 9.18 (s, 1H), 8.61 (s, 1H), 8.23 ​​(s, 1H) ,7.99(d,J=8.2Hz,1H),7.85(d,J=8.3Hz,1H),4.30(d,J=9.9Hz,1H),3.99(dd,J=10. 9,3.4Hz,2H),3.89(dd,J=11.1,3.1Hz,1H),3.78(d,J=10.4Hz,1H),3.45-3.63(m,4 H),3.16-3.22(m,1H),2.98-3.00(m,2H),1.75-1.81(m,3H),1.63(d,J=12.8Hz,1H).

[0271] 19 F NMR (376MHz, DMSO-d6): -55.12.

[0272] Example 18 Synthesis of compounds A-19 and A-20

[0273] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0274]

[0275] Compound 1 was purified by chiral high-performance liquid chromatography (HPLC) (column: CHIRALPAK IG, 2*25cm, 5μm; mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20mL / min; gradient: 90%B to 90%B over 20min; wavelength: 220 / 254nm; RT1(min): 5.45; RT2(min): 15.32; mobile phase solvent: EtOH:DCM=1:1--HPLC; injection volume: 2mL; number of runs: 1) to obtain white solid compounds A-19 (8.5mg) and A-20 (8.3mg).

[0276] A-19:

[0277] MS(ESI): m / z[M+H] + =399. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.96 (s, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 7.98 (d, J = 8.1Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.75 (s, 1H), 4. 30(d,J=9.9Hz,1H),3.98(d,J=11.0Hz,2H),3.60-3.89(m,2H),3.46-3.57(m,5H),3.16-3.21(m,1H),2.97(s,2H),1.61-1.79(m,4H).

[0278] A-20:

[0279] MS(ESI): m / z[M+H] + =399. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.17 (s, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 7.98 (d, J=8.3Hz,1H),7.82(d,J=8.3Hz,1H),7.75(s,1H),4.30(dd,J=10.2Hz,3.2Hz,1H) ,3.98(dd,J=10.1,2.9Hz,2H),3.88(dd,J=11.1,3.1Hz,1H),3.77(dd,J=10.6,2 .5Hz,1H),3.47-3.61(m,5H),3.15-3.19(m,1H),2.99(s,2H),1.56-1.80(m,4H).

[0280] Example 19 Synthesis of Compound A-21

[0281] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0282]

[0283] Compound 1 (20 mg, 0.034 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 31% B, 31% B over 8 min; wavelength: 254 nm; RT1 (min): 7.45 / 9.37) to give a white solid compound A-21 (1.5 mg, yield 9.74%). MS (ESI): m / z [M+H) + =395. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.58 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H), 7.89 (d, J = 8. 2Hz,1H),7.81(d,J=8.3Hz,1H),7.41(s,1H),4.94(t,J=5.5Hz,1H),4.70(d,J=5.5Hz ,2H),4.30(d,J=9.9Hz,1H),3.98(d,J=11.0Hz,2H),3.88(d,J=11.3Hz,1H),3.78(d, J=11.3Hz,1H),3.45-3.61(m,4H),3.17-3.21(m,1H),2.98(s,2H),1.63-1.78(m,4H).

[0284] Example 20 Synthesis of Compound A-22

[0285] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0286]

[0287] Compound 1 (80 mg, 0.159 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 48% B, 48% B over 8 min; wavelength: 254 nm; RT1 (min): 7.50) to give a white solid compound A-22 (28.8 mg, yield: 44.77%). MS (ESI): m / z [M+H) + =403. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.42 (s, 1H), 8.90 (s, 1H), 8.58 (s, 1H), 7.90 (d,J=8.2Hz,1H),7.78(d,J=8.2Hz,1H),7.20(s,1H),3.99(d,J=10.8Hz,2H), 3.90(s,2H),3.41-3.52(m,2H),3.20-3.23(m,1H),2.51-2.55(m,4H),1.98- 2.05(m,1H),1.65-1.82(m,8H),0.89(t,J=9.9Hz,2H),0.65(t,J=9.9Hz,2H).

[0288] Example 21 Synthesis of compound A-23

[0289] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0290]

[0291] Compound 1 (50 mg, 0.094 mmol, 1.0 equiv) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative 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: 23% B to 50% B, 50% B over 7 min; wavelength: 220 nm; RT1 (min): 6.23) to give a white solid compound A-23 (10.1 mg, yield: 24.47%). MS (ESI): m / z [M+H) + =431. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.64 (s, 1H), 9.09 (s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 8.1H z,1H),7.82(d,J=8.1Hz,1H),3.81-4.05-(m,5H),3.36-3.62(m,4H),1.64-1.92(m,9H),1.24(s,1H). 19 F NMR (376MHz, DMSO-d6): -55.18.

[0292] Example 22 Synthesis of Compound A-24

[0293] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0294]

[0295] Compound 1 (60 mg, 0.116 mmol, 1.0 equiv) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 60% B in 8 min, 60% B to 70% B in 9 min, 70% B; wavelength: 254 nm; RT1 (min): 8.43) to give a white solid compound A-24 (25 mg, yield: 51.89%). MS (ESI): m / z [M+H) + =417. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.42 (s, 1H), 8.90 (s, 1H), 8.58 (s, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.78(d,J=8.2Hz,1H),7.20(s,1H),4.38(d,J=11.9Hz,1H),4.00(dd,J=11.1,3.6Hz,2H),3.34 -3.53(m,4H),2.67-2.69(m,1H),2.26-2.31(m,1H),1.87-2.03(m,2H),1.60-1.77(m,4H),1.4 8-1.64(m,2H),1.26-1.41(m,1H),1.19(d,J=5.9Hz,3H),0.80-0.95(m,2H),0.60-0.73(m,2H).

[0296] Example 23 Synthesis of Compound A-25

[0297] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0298]

[0299] Compound 1 (60 mg, 0.077 mmol, 1.0 equiv) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 60% B in 8 min, 60% B to 70% B in 9 min, 70% B; wavelength: 254 nm; RT1 (min): 8.32) to give a white solid compound A-25 (23.3 mg, yield: 48.17%). MS (ESI): m / z [M+H) + =417. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.42 (s, 1H), 8.90 (s, 1H), 8.58 (s, 1H), 7.90 (d, J = 8.1Hz, 1 H),7.78(d,J=8.2Hz,1H),7.20(s,1H),4.38(d,J=12.0Hz,1H),4.00(dd,J=11.1,3.6Hz,2H ),3.34-3.57(m,4H),2.69(t,J=7.7Hz,1H),2.26-2.41(m,1H),1.90-2.07(m,2H),1.43-1. 83(m,6H),1.20-1.34(m,1H),1.19(d,J=5.9Hz,3H),0.87-0.92(m,2H),0.65-0.69(m,2H).

[0300] Example 24 Synthesis of Compound A-26

[0301] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0302]

[0303] Compound 1 (100 mg, 0.210 mmol, 1 equiv) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14% B to 38% B, 38% B over 11 min; wavelength: 254 nm; RT1 (min): 10.30) to give a white solid compound A-26 (44 mg, yield: 55.59%). MS (ESI): m / z [M+H) + =377. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.40 (s, 1H), 8.91 (s, 1H), 8.51 (s, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.78 (d, J = 8.2H z,1H),7.27(s,1H),3.85-4.03(m,5H),3.43-3.56(m,4H),3.21-3.29(m,2H),2.32(s,3H),1.59-1.77(m,8H).

[0304] Example 25 Synthesis of Compound A-27

[0305] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0306]

[0307] Compound 1 (38 mg, 0.07 mmol, 1.0 equiv) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative 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: 22% B to 52% B, 52% B over 8 min; wavelength: 220 nm; RT1 (min): 7.37) to give a white solid compound A-27 (1.9 mg, yield: 5.72%). MS (ESI): m / z [M+H) + =447. 1H NMR (400MHz, DMSO-d6): δ (ppm) 9.14 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 7.72 (s ,1H),4.63(s,1H),4.54(dd,J=10.1,3.2Hz,1H),4.15(dd,J=11.6,4.3Hz,2H), 3.87-4.05(m,2H),3.55-3.73(m,4H),3.37-3.48(m,1H),3.12-3.18(m,2H),2 .61(s,3H),2.28-2.41(m,2H),1.75(d,J=13.2Hz,1H),1.66(d,J=13.6Hz,1H).

[0308] 19 F NMR(376MHz,CD3OD-d4):-58.47.

[0309] Example 26 Synthesis of Compound A-28

[0310] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0311]

[0312] Compound 1 (60 mg, 0.119 mmol, 1.0 equiv) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 51% B, 51% B over 8 min; wavelength: 254 nm; RT1 (min): 7.55) to give a white solid compound A-28 (6 mg, yield: 9.9%). MS (ESI): m / z [M+H) + =405. 1H NMR (400MHz, DMSO-d6): δ (ppm) 12.65 (s, 1H), 9.09 (s, 1H), 8.62 (s, 1H), 8.23 ​​(s, 1H), 7.99 (d, J = 8.1Hz, 1H), 7.84 (d, J = 8.2Hz, 1 H),3.99(dd,J=10.6,3.8Hz,2H),3.69(s,2H),3.47(dd,J=11.5,2.6Hz,2H),3.29-3.31(m,1H),2.23(s,6H),1.67-1.83(m,4H).

[0313] 19 F NMR (376MHz, DMSO-d6): -55.55.

[0314] Example 27 Synthesis of Compound A-29

[0315] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0316]

[0317] Compound 1 (20 mg, 0.032 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 42% B, 42% B over 8 min; wavelength: 254 nm; RT1 (min): 7.32) to give a white solid compound A-29 (5.2 mg, yield 38.25%). MS (ESI): m / z [M+H) + =423. 1H NMR (400MHz, DMSO-d6): δ (ppm) 12.65 (s, 1H), 9.10 (s, 1H), 8.91 (s, 1H), 8.28 (s,1H),7.93(d,J=8.2Hz,1H),7.84(d,J=8.3Hz,1H),4.31(dd,J=10.4,3.1H z,1H),3.95-4.03(m,3H),3.87(s,3H),3.85-3.86(m,1H),3.39-3.53(m,4H) ,3.15-3.21(m,1H),2.87-2.98(m,2H),1.97-2.01(m,1H),1.62-1.79(m,4H).

[0318] Example 28 Synthesis of Compound A-30

[0319]

[0320] Compound 1 (200 f mg, 0.345 mmol, 1 equiv) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography (HPLC) (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 53% B, 53% B over 8 min; wavelength: 254 nm; RT1 (min): 7.32) to give a white solid compound A-30 (29.1 mg, yield: 17.6%). MS (ESI): m / z [M+H) + =473. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.93 (s, 1H), 9.03 (s, 1H), 8.55 (s, 1H), 7.90 (d, J = 8.2Hz, 1H),7.83(d,J=8.3Hz,1H),7.65(s,1H),4.29(d,J=9.6Hz,1H),3.99(d,J=10.6Hz,2H),3. 89(dd,J=11.1,3.2Hz,1H),3.78(d,J=10.5Hz,1H),3.52–3.59(m,3H),3.33-3.47(m,1H), 3.22–3.33(m,1H),2.89-3.00(m,2H),1.62–1.80(m,4H),1.38-1.41(m,2H),1.17(s,2H). 19F NMR (376MHz, DMSO-d6): δ (ppm)-68.46.

[0321] Example 29 Synthesis of compounds A-32 and A-33

[0322]

[0323] The synthesis of compound 1 is similar to that of intermediate compound 6 in Example 4.

[0324] In a sealed tube, compound 1 (80 mg, 0.235 mmol, 1.0 equiv), potassium carbonate (97.48 mg, 0.705 mmol, 3.0 equiv), Pd(dppf)Cl2.CH2Cl2 (19.15 mg, 0.024 mmol, 0.1 equiv), and compound SM1 (106.61 mg, 0.259 mmol, 1.1 equiv) were dissolved in 1,4-dioxane:water / 5:1 (2.5 mL) and reacted at 80 °C for two hours under nitrogen atmosphere. After the reaction was complete, the solution was purified by thin-layer chromatography (dichloromethane:methanol / 5:1) to give a yellow solid compound 2 (60 mg, yield 37.65%). m / z (ES+), [M+H]+ = 546.

[0325] Compound 2 was chirally resolved (column: CHIRALPAK IG, 2*25cm, 5μm; mobile phase A: Hex (0.2% DEA) -- HPLC, mobile phase B: EtOH:DCM = 1:1 -- HPLC; flow rate: 20mL / min; gradient: 30% B to 30% B over 10min; wavelength: 220 / 254nm; RT1 (min): 5.18; RT2 (min): 7.74; sample solvent: EtOH:DCM = 1:1 -- HPLC; injection volume: 0.7mL; number of runs: 4) to obtain compounds 3A (25mg) and 3B (30mg).

[0326] Compound 3A (25 mg, 0.045 mmol, 1 equiv) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was evaporated to dryness. The crude product was purified using high-pressure purification (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B over 7 min; wavelength: 220 nm; RT1 (min): 7.07) to obtain a white solid compound A-32 (4.1 mg, yield: 20%). m / z (ES+), [M+H) + =446. 1 H NMR(400MHz,DMSO-d6)δ(ppm):12.60(s,1H),8.65(s,1H),8.21(s,1H),8.14(s,1H),7.78(s,1H),7.46(s,1H),4.07-4.2(m,1 H),4.01-4.04(m,2H),3.77-3.80(m,1H),3.68(s,1H),3.51-3.57(m,4H),2.94(s,3H),2.08-2.33(m,4H),1.54-1.77(m,2H). 19 F NMR (376MHz, DMSO-d6): δ (ppm): -55.07.

[0327] Compound 3B (30 mg, 0.073 mmol, 1 equiv) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was subjected to high-pressure treatment (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: 35% B to 43% B, 43% B over 7 min; wavelength: 220 nm; RT1 (min): 7.58) to obtain a white solid compound A-33 (3.3 mg, yield: 10.09%) m / z (ES+), [M+H]+ = 446. 1H NMR(400MHz,DMSO-d6)δ(ppm):12.60(s,1H),8.65(s,1H),8.21(s,1H),8.14(s,1H),7.78(s,1H),7.46(s,1H),4.07-4.2(m,1 H),4.01-4.04(m,2H),3.77-3.80(m,1H),3.68(s,1H),3.51-3.57(m,4H),2.94(s,3H),2.08-2.33(m,4H),1.54-1.77(m,2H). 19 F NMR (376MHz, DMSO-d6): δ (ppm): -55.07.

[0328] Example 30 Synthesis of compounds A-34 and A-35

[0329]

[0330] The synthesis method of compound 1 is the same as that of intermediate 2 in Example 30.

[0331] Compound 1 was chirally resolved (column: CHIRALPAK IG, 2*25cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH) -- HPLC, mobile phase B: EtOH:DCM = 1:1 -- HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B over 9 min; wavelength: 220 / 254 nm; RT1 (min): 4.58; RT2 (min): 6.17; sample solvent: EtOH:DCM = 1:1 -- HPLC; injection volume: 0.45 mL) to obtain compounds 1A (18 mg) and 1B (20 mg).

[0332] Compound 1A (18 mg, 0.032 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was evaporated to dryness. The crude product was purified by high-pressure purification (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 60% B, 60% B over 7 min; wavelength: 220 nm; RT1 (min): 7.40) to give a white solid compound A-34 (6.7 mg, yield 44.48%). MS (ESI): m / z = 462. 1HNMR (400MHz, DMSO-d6): δ (ppm) 12.62 (s, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.55 (s, 1H), 4.22 (s, 1H), 3.93-4.00 (m, 2H), 3.91 (s, 3H) ),3.79(d,J=10.8Hz,1H),3.68(d,J=10.9Hz,1H),3.33-3.50(m,4H),3.10(s,2H),2.99(s,2H),2.43(d,J=12.7Hz,1H),1.35(d,J=12.9Hz,2H). 19 F NMR (376MHz, DMSO-d6): δ (ppm)-55.02.

[0333] Compound 1B (20 mg, 0.034 mmol, 1 equiv) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was evaporated to dryness. The crude product was purified by high-pressure purification (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 55% B, 55% B over 7 min; wavelength: 220 nm; RT1 (min): 7.37) to give a white solid compound A-35 (7.9 mg, yield 52.61%). MS (ESI): m / z = 462. 1 HNMR (400MHz, DMSO-d6): δ (ppm) 12.62 (s, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.55 (s, 1H), 4.22 (s, 1H), 3.93-4.00 (m, 2H), 3.91 (s, 3H) ),3.79(d,J=10.8Hz,1H),3.68(d,J=10.9Hz,1H),3.33-3.50(m,4H),3.10(s,2H),2.99(s,2H),2.43(d,J=12.7Hz,1H),1.35(d,J=12.9Hz,2H). 19 F NMR (376MHz, DMSO-d6): δ (ppm)-55.03.

[0334] Example 31 Synthesis of compound A-36

[0335]

[0336] 10 mg of A-5 was separated using a chiral column (CHIRALPAK IG, 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: 70% B to 70% B over 10 min; wavelength: 220 / 254 nm; RT1 (min): 6.31; RT2 (min): 8.58; sample solvent: EtOH:DCM = 1:1 – HPLC; injection volume: 1.55 mL) to yield compound A-36 (3 mg, yield 30%). 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 1.55-1.65 (m, 2H), 2.09-2.13 (m, 2H), 2.30 (d, J = 1.0Hz, 3H),2.43(s,2H),2.54(s,1H),2.77(s,1H),2.92(s,2H),3.45-3.48(m,3H),3.55(s,1H ),3.66(s,1H),3.77(dd,J=10.4,2.8Hz,1H),4.01(dd,J=10.0,4.9Hz,2H),4.14-4.35( m,1H),7.27(s,1H),7.44(s,1H),7.78(s,1H),8.08(s,1H),8.45(s,1H),11.36(s,1H).

[0337] Example 32 Synthesis of compound A-38

[0338]

[0339] 10 mg of compound 1 was chirally resolved: Column: CHIRALPAK IG, 5*15cm, 10μm; Mobile phase A: CO2, Mobile phase B: Methanol:Dichloromethane = 1:1 (0.1% 2M ammonia-methanol); Flow rate: 200 mL / min; Gradient curve: Constant solvent composition 50% B; Temperature (°C): 35; Pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 6.13; RT2 (min): 9.48; Sample solvent: Methanol:Dichloromethane = 1:1 (0.1% 2M ammonia-methanol); Injection volume: 19 mL. Compound A-38 (4 mg, yield 40%) was obtained. MS (ESI): [M+H]+ = 408.2. 1H NMR(DMSO-d6,400MHz): δ(ppm)1.46-1.73(m,2H),2.09(s,2H),2.32(s,3H) ,2.35-2.41(m,1H),2.81-3.02(m,2H),3.23-3.25(m,2H),3.41-3.50(m,3H) ,3.65-3.88(m,2H),3.90(s,3H),3.91-3.99(m,2H),4.17-4.19(m,1H),7.2 1(s,1H),7.26(s,1H),7.55(s,1H),8.11(s,1H),8.49(s,1H),11.35(s,1H).

[0340] Example of effect: Biological experimental method

[0341] 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.

[0342] The experiment on the inhibition of HPK1 kinase activity by the compound was conducted using ADP-Glo TM Platform. The reaction was carried out in 384-well plates, each well containing 0.3 nM HPK1, 5 μM ATP, 0.05 mg / ml MBP, 0-10 μM of the compound, and 1% DMSO. The reaction buffer consisted of 50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 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:

[0343] A-3 B A-6 A A-5 A A-7 C A-8 C A-9 B A-10 C A-11 C A-12 A A-13 B A-14 A A-15 A A-16 C A-18 A

[0344] A-20 A A-21 B A-22 A A-23 B A-24 B A-25 A A-26 C A-27 A A-28 C A-29 A A-30 A A-31 C A-32 B A-33 A A-34 A A-35 C A-36 A A-37 A A-38 A A-39 A

[0345] Where A represents 0.01nM≤IC 50 <5nM; B means 5nM≤IC 50 <10nM; C means 10nM ≤ IC 50 <100nM.

[0346] Mouse pharmacokinetics (PK) experiment

[0347] Male CD1 mice (5-8 weeks old) were administered the compound intravenously (IV) at a dose level of 1 mg / kg via tail vein bolus, or orally (PO) at dose levels of 5 mg / kg, 30 mg / kg, and 100 mg / kg via gavage. For the IV and 5 mg / kg PO dose groups, the compound was reconstituted in a solvent of 2% DMSO + 98% saline containing 10% HP-β-CD. For the 30 mg / kg and 100 mg / kg PO dose groups, the compound was reconstituted in a solvent of 0.5% MC + 0.1% Tween 80 aqueous solution. All animals had free access to food and water during the experiment. Blood samples were collected via the dorsal metatarsal vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours (IV) or 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours (PO) after administration. Approximately 0.03 mL (n = 3 mice) of blood was collected at each time point and placed in tubes containing EDTA-K2 as an anticoagulant. After centrifugation at 4000×g for 5 minutes, the resulting plasma samples were analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software (Phoenix). TM Version 8.3) is calculated using a non-room model analysis method.

[0348] Some of the compounds of the present invention showed clearance rates (CL) of less than 30 ml / min / kg after intravenous administration at a dose level of 1 mg / kg, and some compounds even showed clearance rates (CL) of less than 10 ml / min / kg.

[0349] Some compounds of this invention, when administered intravenously at a dose level of 1 mg / kg, showed an area under the curve (AUC) of over 500 ng*h / ml. -last Some compounds even showed an area under the curve (AUC) exceeding 1000 ng*h / ml. -last ).

[0350] Some of the compounds of the present invention showed bioavailability (F) of more than 70% after oral administration at a dose level of 5 mg / kg, and some compounds even showed bioavailability (F) of more than 100%.

[0351] Inhibitory effect of the compound on human hERG potassium ion channels

[0352] The potential inhibitory effect of the compounds on human hERG potassium channels was evaluated using an automated patch-clamp system. Cisapride was used as a positive control, and a CHO cell line stably expressing the hERG gene was used as the experimental material. Cells were cultured in a medium containing F12 (HAM), 10% FBS, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin, and 100 μg / mL G418. An hERG current was generated by depolarizing the membrane to +30 mV for 4.8 seconds, followed by restoring the voltage to -50 mV for 5.2 seconds to remove inactivation, and the inactivation tail current was measured. Sampling intervals were 15 seconds, and the maximum magnitude of the tail current was used to determine the hERG current amplitude. The percentage of hERG inhibition and compound concentration data were fitted to a dose-response curve using Graphpad Prism 8.0 to obtain IC50 values.

[0353] Some compounds of this invention exhibit IC50 values ​​above 6 μM for inhibiting human hERG potassium ion channels, while some compounds even exhibit IC50 values ​​above 15 μM for inhibiting human hERG potassium ion channels.

Claims

1. The following compounds or their pharmaceutically acceptable forms: , , , , or , The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic markers.

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

3. Use of the compound of claim 1 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the prevention and / or treatment of diseases or conditions at least partially mediated by HPK1. The diseases mentioned are selected from non-small cell lung cancer, small cell lung cancer, head and neck cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, liver cancer, colon cancer, rectal cancer, choriocarcinoma of the colon, breast cancer, 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, cell tumors and sarcomas, leukemia, non-Hodgkin's lymphoma, or myelodysplastic syndrome.

4. The use according to claim 3, wherein the disease is selected from squamous cell carcinoma, gastrointestinal stromal tumor, breast ductal carcinoma, or multiple myeloma.

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