A CD73 inhibitor, methods of making and uses thereof

Abstract

The application discloses a CD73 inhibitor with a structure of formula (IIc), a preparation method and application thereof. The series of compounds can be widely applied to preparation of medicines for treating cancers or tumors, autoimmune diseases and disorders, metabolic diseases which are at least partially mediated by CD73, in particular, medicines for treating melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma, and are expected to develop into a new generation of CD73 inhibitor medicines.

Description

[0001] This application is a divisional application of the Chinese Invention Application No. 202080010129.4, filed on April 27, 2020, entitled “A CD73 Inhibitor, Its Preparation Method and Application”. TECHNICAL FIELD

[0002] The present application belongs to the field of drug synthesis, and particularly relates to a CD73 inhibitor, its preparation method and application. TECHNICAL BACKGROUND

[0003] CD73, also known as ecto-5'-nucleotidase (eNT), is a 70 kDa protein molecule. It is normally expressed on vascular endothelial cells and some blood cells. It is anchored to the cell membrane surface by a glycosylphosphatidylinositol (GPI) anchor and regulates the metabolism of adenosine triphosphate (ATP) together with CD39. Among them, CD39 (also known as ecto-diphosphohydrolase-NTPDase 1) can catalyze ATP to generate adenosine monophosphate (AMP), and only a small amount of adenosine diphosphate (ADP) is produced, while the main function of CD73 is to catalyze the conversion of extracellular nucleotides (such as 5'AMP) to their corresponding nucleosides (such as adenosine).

[0004] The nucleosides catalyzed by CD73, especially adenosine, are considered to be internal regulatory molecules of many different physiological functions. Adenosine can regulate the cardiovascular system, central nervous system, respiratory system, kidney, adipocytes, platelets and immune system. In the immune system, extracellular adenosine can act on many different immune cells and mediate anti-inflammatory responses. In many tissues, adenosine can also promote the process of fibrosis.

[0005] CD73 expression has been found in many tumor cells, including leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer and breast cancer. At the same time, CD73 expression has also been found on the surface of immunosuppressive cells, including regulatory T cells (Treg) and myeloid suppressor cells (MDSC). High expression of CD73 has also been found to be related to angiogenesis, infiltration, resistance to chemotherapy, tumor metastasis and shorter survival of cancer patients in various tumors including breast cancer and melanoma.

[0006] Mechanistic studies have shown that malignant tumor cells release large amounts of ATP under chemotherapy and other stress, which is rapidly converted into adenosine and accumulates in the tumor microenvironment. While the release of extracellular ATP due to cell death or intracellular stress activates the immune response, adenosine, a metabolite of ATP, has immunosuppressive activity. Importantly, tumor-bound adenosine inhibits infiltrating effector T lymphocytes by activating adenosine receptors (such as A2A), thereby promoting tumor development. Therefore, the accumulation of extracellular adenosine in tumor tissue is a crucial mechanism for tumor immune escape.

[0007] Lowering CD73 expression using interfering RNA or overexpressing CD73 in tumor cells can regulate tumor growth and migration; CD73 knockout mice are less likely to experience organ transplant rejection and spontaneous tumors; deleting the A2A receptor gene genetically can induce T-cell-dependent tumor rejection. In mouse models, treatment with antibodies that bind to mouse CD73 can inhibit the growth and migration of breast tumors.

[0008] Therefore, targeting CD73 represents a potential therapeutic strategy that can enhance the efficacy of anti-tumor therapies and provide a new approach to limiting further tumor progression. Simultaneously, targeting CD73 can also be used to treat other adenosine-mediated diseases, such as enhancing immune responses, improving immune efficacy, increasing inflammatory responses, and treating neurological disorders, neurodegenerative diseases, and central nervous system disorders, including depression, Parkinson's disease, sleep disorders, fibrosis, and other immune-inflammatory diseases.

[0009] Therefore, developing CD73-targeted drugs as promising drug candidates could meet the demand for targeted therapies in the treatment of cancer and other related diseases, and offer advantages such as good safety and high specificity. Summary of the Invention

[0010] The inventors of this application, through extensive and in-depth research, have for the first time developed a CD73 inhibitor with the structure of formula (Ⅰ), its preparation method, and its application. The compounds of this invention exhibit strong inhibitory activity against CD73 enzyme activity and can be widely used in the preparation of drugs for treating at least partially CD73-mediated cancers or tumors, immune-related diseases and disorders, and metabolic diseases, particularly for treating melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumors, lymphoma, ovarian cancer, and Kaposi's sarcoma. They hold promise for development into a new generation of CD73 inhibitor drugs. Based on this, this invention was completed.

[0011] The first aspect of the present invention provides a compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof:

[0012]

[0013] in, It is either a double bond or a single bond;

[0014] X1 is N or CR 17 ;

[0015] X2 and X3 are each independently N or C;

[0016] X4 and X5 are each independently N or CR 18 ;

[0017] Y is CH2, NH, O, or S;

[0018] m can be 0, 1, 2, or 3; n can be 0, 1, 2, or 3; the condition is that m + n does not exceed 5;

[0019] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -SF5, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21Alternatively, when m ≥ 2, the two R1 groups and their directly attached portions form a 4-10 membered cycloalkyl, 4-10 membered aryl, 4-10 membered heterocyclic, or 4-10 membered heteroaryl group, wherein the above groups are optionally further surrounded by one or more elements selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0020] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -NR 22 R 23 Alternatively, R2, together with R3 and the carbon atom directly attached to it, forms a 3-10 membered cycloalkyl or a 3-10 membered heterocyclic group; or, one of R2 and R3, together with R1 and the group directly attached to it, forms a 4-10 membered cycloalkyl or a 4-10 membered heterocyclic group, the other being selected from hydrogen, deuterium, halogen, or C. 1-10 Alkyl groups, optionally further divided by one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0021] R4 is selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8-S(O) r R 19 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -C(=NR 22 )R 21 or -C 0-8 -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0022] R5 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10Aryl, 5-10 heteroaryl, -SF5, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0023] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8-C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0024] R8 and R9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0025] R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 or -C 0-8 -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-4 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8-NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0026] R 13 R 14 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -NR 22 R 23 Or, R 13 With R 14 Together with the carbon atom directly attached thereto, they form a 3-10 membered cycloalkyl group or a 3-10 membered heterocyclic group, which may optionally be further surrounded by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O)r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0027] R 15 R 16 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 Or, R 15 With R 16 Together with the carbon atom directly attached thereto, they form a 3-10 membered cycloalkyl group or a 3-10 membered heterocyclic group, which may optionally be further surrounded by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0028] R 17 R 18 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -SF5, -C 0-8 -S(O)r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0029] Each R 19 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, or -NR 22 R 23 The above groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0030] Each R 20 Each is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 aryl or 5-10 heteroaryl, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0031] Each R 21 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C5-10 Aryl, C 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy or -NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0032] Each R 22 R 23 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino, or C 1-10 Alkyl group, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, hydroxyl, C 1-8 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 Aryl, C 5-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 The alkyl acyl group is replaced by a substituent;

[0033] Or, R 22 R 23 Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group is formed, which may optionally be further bonded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 Aryl, C 5-10Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 The alkyl acyl group is substituted by substituents; each r is independently 0, 1 or 2.

[0034] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof in R 15 R 16 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 Or, R 15 With R 16 Together with the carbon atom directly attached thereto, it forms a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, which may optionally be further bonded by one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 The substituents are replaced by R, where R 20 R 22 R 23 As described in compound (I).

[0035] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, R 15 R 16 Each is independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuterylmethyl, methoxy, trifluoromethoxy, trideuterylmethoxy, amino or dimethylamino, or R 15 With R 16 Together with the carbon atom directly attached to it, it forms a 3-4 membered cycloalkyl group or a 4-5 membered heterocyclic group.

[0036] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, R 13 R 14 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 Or, R 13 With R 14 Together with the carbon atom directly attached thereto, it forms a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, which may optionally be further bonded by one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 The substituents are replaced by R, where R 20 R 22 R 23 As described in compound (I).

[0037] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof in R 13 R 14 Each is independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuterylmethyl, methoxy, trifluoromethoxy, trideuterylmethoxy, amino or dimethylamino, or R 13 With R 14 Together with the carbon atom directly attached to it, it forms a 3-4 membered cycloalkyl group or a 4-5 membered heterocyclic group.

[0038] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof in R 17 R18 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 quinone heteroaryl, -SF5, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced by R, where R 19 R 20 R 21 R 22 R 23 As described in compound (I).

[0039] As a preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, R6 and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 or -C 0-4 -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O) r R 19 -C 0-4-OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced;

[0040] R8 and R9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 or -C 0-4 -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O)r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced by R, where R 19 R 20 R 21 R 22 R 23 As described in compound (I).

[0041] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof in R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 or -C 0-4 -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced by R, where R 19 R 20 R 21 R 22 R 23 As described in compound (I).

[0042] As a preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 Alternatively, R2, together with R3 and its directly attached carbon atom, forms a 3-8 membered cycloalkyl or 3-8 membered heterocyclic group; or, one of R2 and R3, together with R1 and its directly attached group, forms a 4-10 membered cycloalkyl or 4-10 membered heterocyclic group, the other being selected from hydrogen, deuterium, fluorine, or C. 1-4Alkyl groups, optionally further divided by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23 The substituents are replaced by, among which, R1, R 20 R 22 R 23 As described in compound (I);

[0043] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyanomethyl, trifluoromethyl, trideuterylmethyl, methoxy, trifluoromethoxy, trideuterylmethoxy, amino, methylamino or dimethylamino; or, R2 together with R3 and the carbon atom directly attached thereto forms a 3-4 membered cycloalkyl or a 4-5 membered heterocyclic group; or, one of R2 and R3 together with R1 and the group directly attached thereto forms a 4-6 membered cycloalkyl or a 4-6 membered heterocyclic group, the other being selected from hydrogen, deuterium or methyl; wherein, R1 is as described in the compound of formula (I).

[0044] As a preferred embodiment, R4 in the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 -S(O) r R 19 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -C(=NR 22 )R 21 or -C 0-4 -C(O)NR 22 R 23The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced by R, where R 19 R 20 R 21 R 22 R 23 As described in compound (I).

[0045] As a preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, wherein R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 -SF5, -C 0-4 -S(O) r R 19 -C0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 Alternatively, when m ≥ 2, the two R1 groups and their directly attached portions form a 4-8 membered cycloalkyl, 5-8 membered aryl, 4-8 membered heterocyclic, or 5-8 membered heteroaryl group, wherein the aforementioned groups are optionally further surrounded by one or more elements selected from deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 -S(O) r R 19 -C 0-4 -OR 20 -C 0-4 -C(O)OR 20 -C 0-4 -C(O)R 21 -C 0-4 -OC(O)R 21 -C 0-4 -NR 22 R 23 -C 0-4 -C(=NR 22 )R 21 -C 0-4 -N(R 22 )-C(=NR 23 )R 21 -C0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 The substituents are replaced by R, where R 19 R 20 R 21 R 22 R 23 As described in compound (I).

[0046] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, has the structure of a compound of formula (IIa), formula (IIb), or formula (IIc):

[0047]

[0048] Each X1 is independently N or CH; each X4 is independently N or CH; each Y is independently CH2 or O.

[0049] Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 quinone heteroaryl, -SF5, -S(O) r R 19 -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 or -NR 22 R 23 Alternatively, when m ≥ 2, the two R1 groups and their directly attached portions form a 5-6 membered cycloalkyl, 5-6 membered aryl, 5-6 membered heterocyclic, or 5-6 membered heteroaryl group, wherein the aforementioned groups are optionally further influenced by one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 heteroaryl, =O, -S(O) r R 19 -OR 20 -C(O)OR 20 -C(O)R21 -OC(O)R 21 or -NR 22 R 23 The substituents are replaced;

[0050] R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyanomethyl, trifluoromethyl, trideuterylmethyl, methoxy, trifluoromethoxy, trideuterylmethoxy, amino, methylamino, or dimethylamino;

[0051] Each R4 is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 aryl or 5-6 heteroaryl groups, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 heteroaryl, =O, -S(O) r R 19 -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 or -NR 22 R 23 The substituents are replaced;

[0052] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -SF5, methylthio, methanesulfonyl, isopropanesulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, hydroxyl, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxy, amino, dimethylamino, -C(=NR) 22 )R 21 -N(R) 22 )-C(=NR 23 )R 21 , aminocarbonyl, dimethylaminocarbonyl or acetamido, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Substituents include cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, =O, methylthio, methanesulfonyl, isopropanesulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxy, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetamino.

[0053] Each R6 and R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, hydroxyl, methoxy, or acetoxy, and the above groups may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuterylmethyl, hydroxyl, methoxy, or acetoxy.

[0054] Each R8 and R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, cyclopropyl, hydroxyl, methoxy, or acetoxy, and the above groups may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuterylmethyl, hydroxyl, methoxy, or acetoxy;

[0055] Each R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 quinone heteroaryl, -C(O)OR 20 -C(O)R 21 or -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 heteroaryl, =O, -S(O) r R 19 -OR20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 -NR 22 R 23 -C(O)NR 22 R 23 or -N(R) 22 )-C(O)R 21 The substituents are replaced;

[0056] Each R 19 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-6 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 quinone heteroaryl or -NR 22 R 23 The above groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 aryloxy, 5-6 heteroaryl, 5-6 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0057] Each R 20 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 aryl or 5-6 heteroaryl, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 aryloxy, 5-6 heteroaryl, 5-6 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0058] Each R 21 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 1-4Alkoxy, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 aryloxy, 5-6 heteroaryl, 5-6 heteroaryloxy or -NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 aryloxy, 5-6 heteroaryl, 5-6 heteroaryloxy or -NR 22 R 23 The substituents are replaced;

[0059] Each R 22 R 23 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 heteroaryl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino, or C 1-4 Alkyl group, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 Aryloxy, 5-6-membered heteroaryl, 5-6-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-4 The alkyl acyl group is replaced by a substituent;

[0060] Or, R 22 R 23 Together with the nitrogen atom directly attached thereto, a 4-6 membered heterocyclic group is formed, which may optionally be further bonded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-6 Aryl, C 5-6 Aryloxy, 5-6-membered heteroaryl, 5-6-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-4 The alkyl acyl group is replaced by a substituent;

[0061] Each q is independently 0, 1, 2, or 3;

[0062] Each m is independently 0, 1, 2, or 3;

[0063] Each r is independently 0, 1, or 2.

[0064] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, each R1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 quinone heteroaryl, -SF5, -S(O) r R 19 -OR 20 -C(O)OR 20 -C(O)R 21 -OC(O)R 21 or -NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, =O, -OR 20 -C(O)OR 20 or -C(O)R 21 The substituents are replaced;

[0065] Each R4 is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 aryl or 5-6 heteroaryl groups, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, =O, -OR 20 -C(O)OR 20or -C(O)R 21 The substituents are replaced;

[0066] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -SF5, methylthio, methanesulfonyl, isopropanesulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxy, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetamino, wherein the above groups may optionally be further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Substituted with cycloalkyl, 3-6 membered heterocyclic, =O, methoxy, ethoxy, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl or acetoxy substituents;

[0067] Each R6 and R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, or acetoxy, and the above groups may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuterylmethyl, hydroxy, methoxy, or acetoxy.

[0068] Each R8 and R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxy, methoxy, or acetoxy, and the above groups may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropylcyclopropyl, trifluoromethyl, trideutermethyl, hydroxy, methoxy, or acetoxy.

[0069] Each R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 Aryl, 5-6 quinone heteroaryl, -C(O)OR 20 -C(O)R 21 or -C(O)NR 22 R 23 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, =O, -S(O) r R 19 -OR 20 -C(O)OR 20 -C(O)R 21 or -OC(O)R 21 The substituents are replaced;

[0070] Each R 19 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl or C 3-6 cycloalkyl groups, optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0071] Each R 20 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0072] Each R 21 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl or C 1-4 alkoxy groups, optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0073] Each R 22 R 23 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or C 1-4 Alkyl group, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic groups or C 1-4 The alkyl group is replaced by a substituent.

[0074] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, has the structure of a compound of formula (IIIa1) or formula (IIIa2):

[0075]

[0076] Each R1 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuterylmethyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0077] Each R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, ethynyl, cyclopropyl, or hydroxymethyl;

[0078] Each R4 is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 2-4 alkenyl or C 3-6 cycloalkyl;

[0079] Each R5 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, ethyl, n-propyl, isopropyl, C 2-6 Alkenyl, C 2-6 Alkyne or C 3-6 cycloalkyl;

[0080] Each R6 is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0081] Each R8 is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0082] Each R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, or isopropyl;

[0083] Each m can be 0, 1, 2, or 3 independently.

[0084] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, has the following structure:

[0085]

[0086] Where X1 is N or CH;

[0087] Wherein, R1 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuterylmethyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0088] R4 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 2-4 alkenyl or C 3-6 cycloalkyl;

[0089] R5 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, ethyl, n-propyl, isopropyl, and C. 2-6 Alkenyl, C 2-6 Alkyne or C 3-6 cycloalkyl;

[0090] R7 is selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0091] R9 is selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0092] R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, or isopropyl;

[0093] m can be 0, 1, 2, or 3.

[0094] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, has the following structure as a compound of formula (IIIc):

[0095]

[0096] Where X1 is N or CH;

[0097] R1 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuterylmethyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0098] R4 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 2-4 alkenyl or C 3-6 cycloalkyl;

[0099] R5 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, ethyl, n-propyl, isopropyl, and C. 2-6 Alkenyl, C 2-6 Alkyne or C 3-6 cycloalkyl;

[0100] R6 is selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0101] R8 is selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, or hydroxyl;

[0102] R 10 R 11 R 12 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, or isopropyl;

[0103] m can be 0, 1, 2, or 3.

[0104] As the most preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

[0105]

[0106]

[0107]

[0108]

[0109] A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers, a prodrug, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0110]

[0111] Wherein, Pg is a hydroxyl protecting group, preferably an alkyl or silane protecting group; X1, X2, X3, X4, X5, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 m and n are as described in compound (I).

[0112] A third aspect of the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0113] The fourth aspect of the present invention provides the use of a compound of formula (I), its stereoisomer, prodrug, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating at least partially CD73-mediated cancer or tumor, immune-related diseases and disorders, and metabolic diseases.

[0114] As a preferred embodiment, the cancer or tumor is selected from prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining carcinoma, leukemia (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, and testicular seminoma.

[0115] As a further preferred option, the cancer or tumor is selected from melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.

[0116] As a preferred embodiment, the immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

[0117] The fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof as a medicament for treating at least partially CD73-mediated cancers or tumors, autoimmune diseases and disorders, and metabolic diseases.

[0118] The sixth aspect of this invention provides a compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof for use in the treatment of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining carcinoma, leukemia (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, and bone cancer. Drugs for brain tumors, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, seminoma, rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis. Detailed Implementation

[0119] Detailed explanation: Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0120] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, for example, "C 1-10 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 10 carbon atoms and branched alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-Dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers, etc. "C 0-8 "Refers to C" 0-8 Alkyl, "C 0-4"Refers to C" 0-4 Alkyl, C0 means there are 0 carbon atoms, "C 1-4 "Refers to C" 1-4 Alkyl group, as defined above.

[0121] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0122] "Cycloalkyl" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, for example, "C 3-10 "Cycloalkyl" refers to cycloalkyl groups comprising 3 to 10 carbon atoms, and is classified into monocyclic and polycyclic cycloalkyl groups, among which:

[0123] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl.

[0124] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which the monocyclic rings share a single carbon atom (called a spiro atom). These groups may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to:

[0125]

[0126] "Fused cyclic alkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system. One or more rings may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a fully conjugated π-electron system. Based on the number of constituent rings, fused cyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cyclic alkyl groups include, but are not limited to:

[0127]

[0128] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0129]

[0130] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0131] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cyano, nitro, azido, and C64. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0132] "Heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. For example, "5-10 membered heterocyclic group" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclic group" refers to a cyclic group containing 3 to 10 ring atoms.

[0133] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.

[0134] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). r (Where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiroatoms between rings. Spiroheterocyclic groups include, but are not limited to:

[0135]

[0136] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more (preferably 1, 2, 3 or 4) rings may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include, but are not limited to:

[0137]

[0138] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These groups may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. One or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). r Bridged heterocyclic groups consist of heteroatoms (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0139]

[0140] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0141]

[0142] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0143] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, or a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, for example, "C 5-10 "Aryl" refers to a fully carbon-containing aryl group with 5-10 carbon atoms, and "5-10-membered aryl" refers to a fully carbon-containing aryl group with 5-10 carbon atoms, including but not limited to phenyl and naphthyl groups. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0144]

[0145] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21-C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0146] "Heteroaryl" refers to a heteroaryl system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, or 2). For example, 5-8-membered heteroaryl refers to a heteroaryl system containing 5-8 ring atoms, and 5-10-membered heteroaryl refers to a heteroaryl system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0147]

[0148] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0149] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, C 2-10 Alkenyl groups refer to straight-chain or branched alkenyl groups containing 2-10 carbon atoms. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0150] The alkenyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21-C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0151] "Alkyne" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C 2-10 Alkynyl groups refer to straight-chain or branched alkynyl groups containing 2-10 carbon atoms. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0152] The alkynyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0153] "Alkoxy" refers to -O- (alkyl), where alkyl is defined as described above, for example, "C 1-10 "Alkoxy" refers to alkyloxy groups containing 1-10 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0154] The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent, preferably one or more (preferably 1, 2, 3, or 4) groups, is independently selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0155] "Cycloalkoxy" refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is defined as described above, for example, "C 3-10 "Cycloalkoxy" refers to cycloalkyloxy groups containing 3-10 carbon atoms, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0156] The cycloalkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0157] "3-10-membered heterocyclic group" refers to -O- (unsubstituted 3-10-membered heterocyclic group), wherein the definition of 3-10-membered heterocyclic group is as described above. The 3-10-membered heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8-S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0158] “C 5-10 "Aryloxy group" refers to -O- (unsubstituted C) 5-10 Aryl), of which C 5-10 The definition of aryl is as described above, C 5-10 The aryloxy group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21 The substituents are replaced by the substituents.

[0159] "5-10-membered heteroaryl group" refers to -O- (unsubstituted 5-10-membered heteroaryl group), wherein the definition of 5-10-membered heteroaryl group is as described above. The 5-10-membered heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 -S(O) r R 19 -C 0-8 -OR 20 -C 0-8 -C(O)OR 20 -C 0-8 -C(O)R 21 -C 0-8 -OC(O)R 21 -C 0-8 -NR 22 R 23 -C 0-8 -C(=NR 22 )R 21 -C 0-8 -N(R 22 )-C(=NR 23 )R 21 -C 0-8 -C(O)NR 22 R 23 or -C 0-8 -N(R 22 )-C(O)R 21The substituents are replaced by the substituents.

[0160] “C 1-8 "alkylyl" refers to C 1-8 The monovalent group remaining after removing the hydroxyl group from an alkyl acid is usually also represented by "C". 0-7 "-C(O)-", for example, "C1-C(O)-" refers to acetyl; "C2-C(O)-" refers to propionyl; "C3-C(O)-" refers to butyryl or isobutyryl.

[0161] -C 0-8 -S(O) r R 19 "Referring to -S(O)" r R 19 The sulfur atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0162] -C 0-8 -OR 20 "referring to -OR" 20 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0163] -C 0-8 -C(O)OR 20 "Refers to -C(O)OR 20 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0164] -C 0-8 -C(O)R 21 "Referring to -C(O)R" 21 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0165] -C 0-8 -OC(O)R 21 "Refers to -OC(O)R 21 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0166] -C 0-8 -NR 22 R 23 "Referring to -NR" 22 R23 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0167] -C 0-8 -C(=NR 22 )R 21 "Refers to -C(=NR)" 22 )R 21 The carbon atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0168] -C 0-8 -N(R 22 )-C(=NR 23 )R 21 "Referring to -N(R)" 22 )-C(=NR 23 )R 21 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0169] -C 0-8 -C(O)NR 22 R 23 "Referring to -C(O)NR" 22 R 23 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0170] -C 0-8 -N(R 22 )-C(O)R 21 "Referring to -N(R)" 22 )-C(O)R 21 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C0 alkyl refers to a bond, C 1-8 The definition of alkyl is as described above.

[0171] "Hydrogen replaces C" 1-10 "Alkyl" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atoms are optionally replaced by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

[0172] "Hydrogen replaces C" 1-10"Alkoxy" refers to 1-10 carbon alkoxy groups on an alkyl group, optionally substituted with fluorine, chlorine, bromine, or iodine atoms. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0173] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0174] “MeOH” refers to methanol. “DMF” refers to N,N-dimethylformamide. “DCE” refers to 1,2-dichloroethane. “THF” refers to tetrahydrofuran. “PE” refers to petroleum ether. “EA / EtOAc” refers to ethyl acetate. “DCM” refers to dichloromethane. “LiOH” refers to lithium hydroxide. “NaOH” refers to sodium hydroxide. “NaNO2” refers to sodium nitrite. “CuI” refers to cuprous iodide. “Na2SO4” refers to sodium sulfate. “HOAc” refers to acetic acid. “NH4Oac” refers to ammonium acetate. “Et3N” refers to triethylamine. “NH4Cl” refers to ammonium chloride. “TFA” refers to trifluoroacetic acid. “m-CPBA” refers to m-chloroperoxybenzoic acid. “Pd(PPh3)4” refers to tetrakis(triphenylphosphine)palladium. “Pd(PPh3)2Cl2” refers to bis(triphenylphosphine)palladium dichloride.

[0175] "Optional" or "optionally" means that the event or environment described below may but does not have to occur. This description includes the possibility that the event or environment may or may not occur, that is, it includes both substituted and unsubstituted cases. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0176] "Substituted" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0177] Stereoisomers, also known as cis-trans isomers, are isomers formed by different spatial arrangements of atoms in a molecule. They can be classified into two main categories: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers resulting from bond length, bond angle, the presence of double bonds, or rings within the molecule are called configurational stereo-isomers. Configurational stereo-isomers are further divided into two categories. Those resulting from the inability of single bonds in double bonds or cyclic carbon atoms to rotate freely are called geometrical isomers, also known as cis-trans isomers, and have two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical properties due to the lack of antiaxial symmetry in their molecules are called optical isomers, which are classified into R and S configurations. In this invention, unless otherwise specified, "stereoisomer" can be understood to include one or more of the enantiomers, configuration isomers, and conformational isomers described above.

[0178] In this invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0179] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0180] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0181] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0182] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0183] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0184] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0185] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0186] I. Preparation of intermediates

[0187] Intermediate 1(R)-1-(3-(pentafluoro-λ) 6 Preparation of 1-thioalkyl)phenyl)ethane-1-amine

[0188]

[0189] Step 1: (3-(1-ethoxyvinyl)phenyl)pentafluoro-λ 6 -Synthesis of thioanes

[0190]

[0191] (3-bromophenyl)pentafluoro-λ 6 1,N-Thane (1.0 g, 3.53 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of tributyl(1-ethoxyvinyl)tin (1.4 g, 3.89 mmol) and bis(triphenylphosphine)palladium dichloride (248 mg, 0.353 mmol). The mixture was heated to 80 °C and stirred for 18 hours. After the reaction was complete, the solution was used directly for the next reaction.

[0192] Step 2: 1-(3-(pentafluorine-λ) 6 Synthesis of thioalkyl)phenyl)ethane-1-one

[0193]

[0194] Add 2 mL of dioxane hydrochloride solution (4 N) dropwise to the above reaction solution and stir at 0 °C for 2 hours. After the reaction is complete, quench the reaction solution with saturated sodium bicarbonate solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate to dryness, and separate by column chromatography [eluent: ethyl acetate / petroleum ether = 0–10%] to obtain 1-(3-(pentafluoro-λ) 6 -Thioalkyl)phenyl)ethane-1-one (670 mg, yield 77%).

[0195] Step 3: (R)-2-methyl-N-(1-(3-(pentafluoro-λ) 6 Synthesis of 2-sulfinamide (-thioalkyl)phenyl)ethylidene)propane-2-sulfinamide

[0196]

[0197] 1-(3-(pentafluoro-λ) 6 (R)-(+)-tert-butylsulfinamide (396 mg, 3.27 mmol) and tetraethyl titanate (3.76 g, 5.44 mmol) were dissolved in tetrahydrofuran (10 mL), and then heated to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (150 mL), quenched with saturated sodium bicarbonate solution, filtered, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: ethyl acetate / petroleum ether = 0–30%] to give (R)-2-methyl-N-(1-(3-(pentafluoro-λ) 6 2-Thioalkyl)phenyl)ethylidene)propane-2-sulfinamide (789 mg, yield 83%). MS m / z (ESI): 350 [M+H] + .

[0198] Step 4: (R)-2-methyl-N-((R)-1-(3-(pentafluoro-λ) 6 Synthesis of 2-sulfinamide (-thioalkyl)phenyl)ethyl)propane-2-sulfinamide

[0199]

[0200] (R)-2-methyl-N-(1-(3-(pentafluoro-λ) 6(R)-2-methyl-N-((R)-1-(3-(pentafluoro-λ)-propane-2-sulfinamide) (400 mg, 1.15 mmol) was dissolved in tetrahydrofuran (10 mL, 20% water content), cooled to -50 °C, and sodium borohydride (130 mg, 3.44 mmol) was added. The mixture was then stirred at this temperature for 1 hour, followed by stirring at room temperature for another hour. After the reaction was complete, the reaction solution was diluted with dichloromethane, the insoluble matter was filtered off, dried over anhydrous sodium sulfate, concentrated to dryness, and then separated by column chromatography [eluent: ethyl acetate / petroleum ether = 0–80%] to give (R)-2-methyl-N-((R)-1-(3-(pentafluoro-λ)-) 6 2-Thioalkyl)phenyl)ethyl)propane-2-sulfinamide (300 mg, yield 74%). MS m / z (ESI): 352 [M+H] + .

[0201] Step 5: (R)-1-(3-(pentafluorine-λ) 6 Synthesis of 1-thioalkyl)phenyl)ethane-1-amine

[0202]

[0203] (R)-2-methyl-N-((R)-1-(3-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)propane-2-sulfinamide (300 mg, 0.85 mmol) was dissolved in dioxane hydrochloride solution (4 N, 5 mL) and stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to dryness to obtain (R)-1-(3-(pentafluoro-λ) 6 1-Thioalkyl)phenyl)ethane-1-amine hydrochloride (270 mg) was used directly in the next reaction. MS m / z (ESI): 248 [M+H] + .

[0204] The preparation of intermediates 2-4 follows the same method as intermediate 1:

[0205]

[0206] Intermediate 5(S)-1-(2-fluoro-4-(pentafluoro-λ) 6 Preparation of 1-thioalkyl)phenyl)ethane-1-amine

[0207]

[0208] Step 1: 2-Fluoro-N-methoxy-N-methyl-4-(pentafluoro-λ) 6 Synthesis of β-thioalkyl)benzeneamide

[0209]

[0210] 2-Fluoro-4-(pentafluoro-16-thioalkyl)benzoic acid (2 g, 7.6 mmol) was dissolved in N-methylpyrrolidone (10 mL), and O-(7-azabenzotriazol-1-YL)-N,N,N,N-tetramethylglucuronide cationic hexafluorophosphate (4.32 g, 11.3 mmol), methoxymethylamine hydrochloride (1.08 g, 11.3 mmol), and triethylamine (1.53 g, 15.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The solution was then separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (30%)] to give 2-fluoro-N-methoxy-N-methyl-4-(pentafluoro-λ) 6 (-Thioalkyl)benzamide (1.8 g, yield 76%). MS m / z (ESI): 309.8 [M+H] + .

[0211] Step 2: 1-(2-Fluoro-4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethane-1-one

[0212]

[0213] 2-fluoro-N-methoxy-N-methyl-4-(pentafluoro-λ) 6 1-(2-fluoro-4-(pentafluoro-λ)benzamide (1.8 g, 5.8 mmol) was dissolved in tetrahydrofuran (40 mL), and methyl magnesium bromide solution (12 mL, 12 mmol) was added under ice bath. The mixture was stirred for 1 hour. After the reaction was completed, the solution was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The solution was then separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (5%)] to give 1-(2-fluoro-4-(pentafluoro-λ)]. 6 -Thioalkyl)phenyl)ethane-1-one (1.2 g, yield 78%).

[0214] Step 3: (S,E)-N-(1-(2-fluoro-4-(pentafluoro-λ)) 6 Synthesis of 2-thioalkyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0215]

[0216] 1-(2-fluoro-4-(pentafluoro-λ) 6(S)-2-methylpropane-2-sulfinamide (417 mg, 3.44 mmol) and tetraethyl titanate (2 mL) were dissolved in tetrahydrofuran (30 mL), and then heated to 50 °C and stirred for 5 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium carbonate solution, filtered, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (30%)] to give (S,E)-N-(1-(2-fluoro-4-(pentafluoro-λ)). 6 (-Thioalkyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, yield 72%). MS m / z (ESI): 367 [M+H] + .

[0217] Step 4: (S)-N-((S)-1-(2-Fluoro-4-(pentafluoro-λ)) 6 Synthesis of 2-thioalkyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0218]

[0219] (S,E)-N-(1-(2-fluoro-4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, 1.91 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -50 °C, and sodium borohydride (195 mg, 5.73 mmol) was added. The mixture was then stirred at this temperature for half an hour. After the reaction was complete, the reaction solution was quenched with saturated brine, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (60%)] to give (S)-N-((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 99% yield). MS m / z (ESI): 370 [M+H] + .

[0220] Step 5: (S)-1-(2-Fluoro-4-(pentafluoro-λ) 6 Synthesis of 1-thioalkyl)phenyl)ethane-1-amine

[0221]

[0222] (S)-N-((S)-1-(2-fluoro-4-(pentafluoro-λ) 6(S)-1-(2-fluoro-4-(pentafluoro-λ)-2-methylpropane-2-sulfinamide (700 mg, 1.89 mmol) was dissolved in dioxane hydrochloride solution (2 N, 30 mL). The solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain (S)-1-(2-fluoro-4-(pentafluoro-λ)-2-sulfinamide. 6 1-Thioalkyl)phenyl)ethane-1-amine (600 mg, 95% yield). MS m / z (ESI): 266 [M+H] + .

[0223] Intermediate 6(R)-1-(2-fluoro-4-(pentafluoro-λ) 6 Preparation of 1-thioalkyl)phenyl)ethane-1-amine

[0224]

[0225] Step 1: (R,E)-N-(1-(2-Fluoro-4-(pentafluoro-λ)) 6 Synthesis of 2-thioalkyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0226]

[0227] 1-(2-fluoro-4-(pentafluoro-λ) 6 (R)-2-methylpropane-2-sulfinamide (291 mg, 2.46 mmol) and tetraethyl titanate (2 mL) were dissolved in tetrahydrofuran (30 mL), and then heated to 50 °C and stirred for 5 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium carbonate solution, filtered, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (30%)] to give (R,E)-N-(1-(2-fluoro-4-(pentafluoro-λ)). 6 (-Thioalkyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (450 mg, yield 65%). MS m / z (ESI): 368 [M+H] + .

[0228] Step 2: (R)-N-((R)-1-(2-Fluoro-4-(pentafluoro-λ) 6 Synthesis of 2-thioalkyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0229]

[0230] (R,E)-N-(1-(2-fluoro-4-(pentafluoro-λ) 6(R)-N-((R)-1-(2-fluoro-4-(pentafluoro-λ))-phenyl(ethylene)-2-methylpropane-2-sulfinamide (450 mg, 1.22 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -50 °C, and sodium borohydride (125 mg, 3.67 mmol) was added. The mixture was then stirred at this temperature for half an hour. After the reaction was complete, the reaction solution was quenched with saturated brine, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (60%)] to give (R)-N-((R)-1-(2-fluoro-4-(pentafluoro-λ)) 6 (-Thioalkyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (380 mg, yield 84%). MS m / z (ESI): 370 [M+H] + .

[0231] Step 3: (R)-1-(2-Fluoro-4-(pentafluoro-λ) 6 Synthesis of 1-thioalkyl)phenyl)ethane-1-amine

[0232]

[0233] (R)-N-((R)-1-(2-fluoro-4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (380 mg, 1.03 mmol) was dissolved in dioxane hydrochloride solution (2 N, 30 mL). The solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain (R)-1-(2-fluoro-4-(pentafluoro-λ) 6 1-Thioalkyl)phenyl)ethane-1-amine (300 mg, 96% yield). MS m / z (ESI): 266 [M+H] + .

[0234] Intermediate 7(2-(pentafluoro-λ) 6 Preparation of thioalkyl)phenyl)methylamine hydrochloride

[0235]

[0236] Step 1: (2-(pentafluorine-λ) 6 Synthesis of thioalkyl)phenyl)hydrazine hydrochloride

[0237]

[0238] Pentafluoro(2-fluorophenyl)-λ 62-(pentafluoro-λ)thione (3.0 g, 13.5 mmol) was dissolved in dimethyl sulfoxide (15 mL), and hydrazine hydrate (30 mL) was added. The reaction mixture was sealed at 100 °C and reacted for 20 hours. The reaction solution was cooled to room temperature, and 150 mL of 1 N sodium hydroxide aqueous solution and 150 mL of saturated water were added. The solution was extracted with methyl tert-butyl ether (2 x 100 mL), washed with saturated brine (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was added to dioxane hydrochloride solution (4 N, 5 mL, 20 mmol), stirred at room temperature for 20 minutes, and concentrated to dryness to obtain (2-(pentafluoro-λ)). 6 (-Thioalkyl)phenyl)hydrazine hydrochloride (3.5 g, 96% yield). MS m / z (ESI): 235 [M+H] + .

[0239] Step 2: 2-(pentafluoro-λ) 6 Synthesis of thioalkyl)aniline hydrochloride

[0240]

[0241] (2-(pentafluorine-λ) 6 2-(thioalkyl)phenyl)hydrazine hydrochloride was dissolved in methanol (50 mL), Raney nickel was added, and the reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was added to a dioxane hydrochloride solution (4 N, 5 mL, 20 mmol), stirred at room temperature for 20 minutes, and concentrated to dryness to give 2-(pentafluoro-λ) 6 (-Thioalkyl) aniline hydrochloride (3.7 g crude) was used directly in the next reaction. MS m / z (ESI): 220 [M+H] + .

[0242] Step 3: Pentafluoro(2-iodophenyl)-λ 6 -Synthesis of thioanes

[0243]

[0244] 2-(pentafluorine-λ) 6 3.7 g crude thioalkyl)aniline hydrochloride was dissolved in tetrafluoroboric acid solution (30 mL) and heated until completely dissolved. The reaction solution was cooled to 0 °C (ice bath), and sodium nitrite solution (2.0 g, 29 mmol, 10 mL water) was added dropwise with stirring in the ice bath. After the addition was complete, stirring in the ice bath continued for 30 minutes. Potassium iodide solution (7.2 g, 43.4 mmol, 15 mL water) was slowly added. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (2 x 100 mL) and washed with saturated sodium bicarbonate solution and sodium thiosulfate solution (2 x 100 mL). The organic phase was concentrated, and the residue was separated by column chromatography [eluent: petroleum ether / ethyl acetate = 0–5%] to obtain pentafluoro(2-iodophenyl)-λ.6 -Thioane (3.3 g, two-step yield 77%).

[0245] 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 8.4, 1.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H).

[0246] Step 4: 2-(pentafluorine-λ) 6 Synthesis of thioalkyl)benzonitrile

[0247]

[0248] Pentafluoro(2-iodophenyl)-λ 6 A mixture of N-methylpyrrolidone (12 mL) of thion (1.85 g, 5.6 mmol) and cuprous cyanide (2.0 g, 22.4 mmol) was reacted in a microwave at 100 °C for 2.5 h. Ethyl acetate (100 mL), concentrated ammonia (15 mL), and water (100 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. The layers were separated. The organic layer was washed with saturated brine (100 mL), concentrated, and the residue was separated by column chromatography [eluent: petroleum ether / ethyl acetate = 0–10%] to obtain 2-(pentafluoro-λ) 6 β-thioalkyl)benzonitrile (0.94 g, yield 73%).

[0249] 1 H NMR (400MHz, Chloroform-d) δ7.95 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H).

[0250] Step 5: (2-(pentafluorine-λ) 6 Synthesis of thioalkyl)phenyl)methylamine hydrochloride

[0251]

[0252] 2-(pentafluorine-λ) 6(2-(thioalkyl)benzonitrile) (1.88 g, 8.2 mmol) was dissolved in tetrahydrofuran (5 mL), and a borane tetrahydrofuran complex solution (1 N, 50 mL, 50 mmol) was added. The reaction mixture was refluxed for 20 hours, and a borane tetrahydrofuran complex solution (1 N, 50 mL, 50 mmol) was added, and the mixture was refluxed for another 20 hours. The reaction mixture was cooled to room temperature, and methanol (30 mL) and dioxane hydrochloride solution (4 N, 4 mL, 16 mmol) were slowly added. After the addition was complete, the mixture was refluxed for another hour, and then concentrated by rotary evaporation. The residue was added to n-pentane (50 mL), stirred at room temperature for half an hour, filtered, and the filter cake was washed with n-pentane (20 mL) and dried to obtain (2-(pentafluoro-λ) 6 (2.22 g) thioalkyl)phenyl)methylamine hydrochloride was used directly in the next reaction. MS m / z (ESI): 234 [M+H] + .

[0253] Preparation of intermediate 8(R)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0254]

[0255] Step 1: Synthesis of (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

[0256]

[0257] 5-Fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and (R)-2-methylpropane-2-sulfinamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol) were added. The reaction solution was heated under reflux for 24 h under a nitrogen atmosphere. After the reaction was completed, it was cooled to 0 °C, and sodium borohydride (5.04 g, 133.2 mmol) was added in batches. The mixture was stirred at 0 °C for 3 h until the intermediate was completely reacted. The reaction was then quenched dropwise with saturated brine. The reaction system was filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography [eluent: petroleum ether / ethyl acetate = 70 / 30] to give (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.4 g, yield: 28%), MS m / z (ESI): 256 [M+H]. + .

[0258] Step 2: Synthesis of (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0259]

[0260] (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.4 g, 9.40 mmol) was dissolved in methanol (10 mL), and a 4 M methanol solution (10 mL) was added with stirring. The mixture was stirred for 1 hour at room temperature. After concentrating the reaction mixture, water (10 mL) and ethyl acetate (10 mL) were added. The aqueous phase was separated and lyophilized to give (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (1.6 g, yield: 91%), MS m / z (ESI): 135 [M+H-NH3]. + .

[0261] The preparation of intermediates 9-12 follows the same method as that used for intermediate 8.

[0262]

[0263] Preparation of intermediate 13(S)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0264]

[0265] Step 1: Synthesis of (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

[0266]

[0267] 5-Fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and (S)-2-methylpropane-2-sulfinamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol) were added. The reaction solution was heated under reflux for 24 h under a nitrogen atmosphere. After the reaction was completed, it was cooled to 0 °C, and sodium borohydride (5.04 g, 133.2 mmol) was added in batches. The mixture was stirred at 0 °C for 3 h until the intermediate was completely reacted. Finally, saturated brine was added dropwise to quench the reaction. The reaction system was filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography [eluent: petroleum ether / ethyl acetate (70 / 30)] to give (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.4 g, yield: 28%), MS m / z (ESI): 256 [M+H]. + .

[0268] Step 2: Synthesis of (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0269]

[0270] (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.4 g, 9.40 mmol) was dissolved in methanol (10 mL), and a 4 M methanol solution (10 mL) was added with stirring. The mixture was stirred for 1 hour at room temperature. After concentrating the reaction mixture, water (10 mL) and ethyl acetate (10 mL) were added. The aqueous phase was separated and lyophilized to give (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (1.5 g, yield: 85%), MS m / z (ESI): 135 [M+H-NH3]. + .

[0271] The preparation of intermediates 14-17 follows the same method as that used for intermediate 13:

[0272]

[0273]

[0274] Preparation of intermediate 18(R)-N-methyl-2,3-dihydro-1H-inden-1-amine

[0275]

[0276] Step 1: Synthesis of (R)-N-Boc-2,3-dihydro-1H-indene-1-amine

[0277]

[0278] (R)-2,3-dihydro-1H-indene-1-amine hydrochloride (1.0 g, 5.89 mmol) was dissolved in tetrahydrofuran (15 mL), and triethylamine (1.79 g, 17.68 mmol) and Boc anhydride (1.42 g, 6.48 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction system was directly concentrated, and the crude product was separated by column chromatography [eluent: ethyl acetate / petroleum ether (5 / 95)] to obtain (R)-N-Boc-2,3-dihydro-1H-indene-1-amine (1.38 g, 100% yield).

[0279] Step 2: Synthesis of tert-butyl(R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate

[0280]

[0281] (R)-N-Boc-2,3-dihydro-1H-indene-1-amine (1.38 g, 5.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). Sodium hydride (60%, 355 mg, 8.87 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Iodimethane (2.52 g, 17.74 mmol) was then added, and the reaction was brought to room temperature and stirred for another 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water, dried, and concentrated. The crude product was separated by column chromatography [eluent: ethyl acetate / petroleum ether (10 / 90)] to obtain tert-butyl(R)-(2,3-dihydro-1H-indene-1-yl)(methyl)carbamate (1.3 g, 89% yield).

[0282] Step 3: Synthesis of (R)-N-methyl-2,3-dihydro-1H-inden-1-amine

[0283]

[0284] 1.3 g (5.26 mmol) of tert-butyl(R)-(2,3-dihydro-1H-indene-1-yl)(methyl)carbamate was dissolved in acetonitrile (10 mL), and concentrated hydrochloric acid (5 mL) was added. After stirring at room temperature for three hours, most of the acetonitrile was removed under reduced pressure. The aqueous phase was lyophilized to give (R)-N-methyl-2,3-dihydro-1H-indene-1-amine (950 mg, 98% yield), MS m / z (ESI): 148 [M+H]. + .

[0285] The preparation of intermediate 19 follows the same method as that used for the synthesis of intermediate 18.

[0286]

[0287] Preparation of intermediate 20 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine

[0288]

[0289] Step 1: Synthesis of (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopentadieno[d][1,3]dioxazol-4-one

[0290]

[0291] Under nitrogen protection, sec-butyllithium (74.6 mL, 97 mmol) was added dropwise at -70 °C to a methyl tert-butyl ether solution (400 mL) of potassium tert-butoxide (10.9 g, 97 mmol). After stirring at -70 °C for 3 hours, a tetrahydrofuran solution (100 mL) of lithium bromide (16.82 g, 190 mmol) was added. The reaction mixture was then heated to -15 °C and stirred for 30 minutes. The reaction solution was cooled again to -70°C, and a diisopropyl sulfide solution (70 mL) of cuprous bromide dimethyl sulfide complex (9.98 g, 48 mmol) was added. After stirring for 10 minutes, a tetrahydrofuran solution (50 mL) of (3aR,6aR)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-4-one (5 g, 32 mmol) was added. The reaction solution was then cooled to -30°C and stirred for 30 minutes. After the reaction was complete, the solution was distilled off with methanol and acetic acid (1:1). Quench the mixture (50 mL), pour in a mixture of ammonium chloride and 3% ammonia (1:1), remove the aqueous layer, wash the organic layer with a saturated ammonium chloride solution and a mixture of 3% ammonia (1:1) and brine, dry with anhydrous sodium sulfate, concentrate and separate by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (15%)] to give (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopentadieno[d][1,3]dioxazol-4-one (6.8 g, yield 85%).

[0292] Step 2: Synthesis of (3aR,6R,6aR)-6-(tert-butoxymethyl)-4-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopentadieno[d][1,3]dioxazol-4-ol

[0293]

[0294] Under nitrogen protection, 22.8 mL (56.9 mmol) of n-butyllithium was added dropwise at -70 °C to a tetrahydrofuran solution (300 mL) of 2,4-dichloro-7-iodopyrrolo[2,1-f][1,2,4]triazine (13.7 g, 43.8 mmol). After stirring at -70 °C for 2 hours, a tetrahydrofuran solution (40 mL) of (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopentadieno[d][1,3]dioxazol-4-one (10.6 g, 43.8 mmol) was added, and stirring was continued at -70 °C for 1 hour. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was concentrated and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (15%)] to give (3aR,6R,6aR)-6-(tert-butoxymethyl)-4-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopentadienzo[d][1,3]dioxazol-4-ol (12 g, yield 64%). MS m / z (ESI): 430 [M+H] + .

[0295] Step 3: Synthesis of 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine

[0296]

[0297] Burgess reagent (14.3 g, 56 mmol) was added to a tetrahydrofuran solution (200 mL) of (3aR,6R,6aR)-6-(tert-butoxymethyl)-4-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopentadieno[d][1,3]dioxazol-4-ol (12 g, 28 mmol), and then heated to 50 °C and stirred for 4 hours. After the reaction was complete, the solution was concentrated to dryness and separated by column chromatography [petroleum ether to petroleum ether / ethyl acetate (15%)] to give 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (7 g, yield 61%). MS m / z (ESI): 412 [M+H] + .

[0298] Preparation of intermediate 21(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0299]

[0300] Step 1: Synthesis of ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester

[0301]

[0302] (4-Methoxybenzyl)hydrazine hydrochloride (100.0 g, 0.53 mol) was dissolved in anhydrous ethanol (1.6 L), and triethylamine (81.0 g, 0.80 mol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and ethyl (ethoxymethylene)cyanoacetate (98.0 g, 0.58 mol) was added. The reaction mixture was refluxed and stirred overnight, and the ethanol was removed by concentration. The solid residue was extracted with water (500 mL) and ethyl acetate (2 x 500 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester (135.0 g, 92% yield). MS m / z (ESI): 276 [M+H] + .

[0303] Step 2: Synthesis of ethyl 1-(4-methoxybenzyl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ester

[0304]

[0305] Sodium ethoxide (84.0 g, 1.24 mmol) was dissolved in ethanol (600 mL) and cooled to 0 °C (ice bath). Diethyl malonate (198 g, 1.24 mol) was added, the ice bath was removed, and the mixture was stirred at room temperature for 20 minutes. Ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester (85 g, 0.31 mol) was added, and the reaction mixture was refluxed and stirred for 4 days. The ethanol was removed by concentration under reduced pressure, and the residue was added to water (1.5 L), neutralized to pH ~5 with acetic acid, and filtered off the white solid. The solid was washed with water (500 mL) and dried under vacuum to give ethyl 1-(4-methoxybenzyl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-1H-pyrazole[3,4-b]pyridine-5-carboxylic acid ester (100.8 g, 95% yield). MS m / z (ESI): 344 [M+H] + .

[0306] Step 3: Synthesis of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol

[0307]

[0308] Ethyl 1-(4-methoxybenzyl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ester (100.8 g, 0.29 mol) was dissolved in 700 mL of 25% NaOH aqueous solution and refluxed for 15 hours. The reaction solution was cooled to 0 °C, diluted with water (1 L), and slowly neutralized with acetic acid to pH ~5. The white solid was filtered, washed with water (1 L), and the filter cake was dried under vacuum to give 78.0 g of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (98% yield). MS m / z (ESI): 272 [M+H] + .

[0309] Step 4: Synthesis of 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine

[0310]

[0311] 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (30.0 g, 110 mmol) and phenylphosphonodichloro (62.7 mL, 442 mmol) were reacted at 170 °C with stirring for 7 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL), and the mixture was slowly poured into a vigorously stirred ice-water mixture. The mixture was neutralized with concentrated ammonia to pH ~7, extracted with dichloromethane (2 x 300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography [petroleum ether / ethyl acetate = 0–8%] to give 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (18.3 g, 53% yield). MS m / z (ESI): 308 / 310 [M+H] + .

[0312] Step 5: Synthesis of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine

[0313]

[0314] 4,6-Dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (28.0 g, 90.9 mmol) was dissolved in trifluoroacetic acid (84 mL) and reacted with stirring at 60 °C for 17 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated by column chromatography [eluent: petroleum ether / ethyl acetate = 0–8%] to obtain 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine (15.3 g, 90% yield). MS m / z (ESI): 188 / 190 [M+H] + .

[0315] Step 6: Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0316]

[0317] 4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine (3.0 g, 16.0 mmol) was dissolved in hexamethyldisilazane (30 mL), and ammonium sulfate (421 mg, 3.2 mmol) was added. The mixture was stirred at 150 °C for 3.5 h, and hexamethyldisilazane was removed by rotary evaporation under reduced pressure. The residue was dissolved in acetonitrile (60 mL), and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-trimethyltriacetate (5.59 g, 17.6 mmol) was added. The reaction mixture was cooled to 0 °C (ice bath), and trimethylsilyl trifluoromethanesulfonate (4.33 mL, 24.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was added to ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution (150 mL), and separated. The aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to column chromatography [eluent: petroleum ether / ethyl acetate = 0–15%] to give (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (4.98 g, 70% yield). MS m / z (ESI): 446 / 448 [M+H] + Preparation of intermediate 22(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0318]

[0319] Step 1: Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0320]

[0321] 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 13.2 mmol) was dissolved in hexamethyldisilazine (15 mL), and a catalytic amount of ammonium sulfate (20 mg, 0.15 mmol) was added. The mixture was then heated to reflux (135 °C) for 3 hours. The reaction mixture was then evaporated to dryness, and acetonitrile (30 mL) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-trimethyltriacetate (5.06 g, 15.9 mmol) were added. The mixture was cooled to 0 °C, and trimethylsilyl trifluoromethanesulfonate (2.7 mL) was added. The mixture was then heated to room temperature and stirred for 24 hours. After the reaction was complete, the mixture was quenched with saturated brine, extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (5.0 g, 84%). MS m / z (ESI): 447 [M+H] + .

[0322] II. Preparation of Compounds in Specific Examples

[0323] Example 1 (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 Preparation of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid

[0324]

[0325] Step 1: (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0326]

[0327] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (200 mg, 0.55 mmol) and (R)-1-(4-(pentafluoro-λ) 6 (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ))-1-amine (140 mg, 0.46 mmol) was dissolved in tetrahydrofuran (5 mL), and then N,N-diisopropylethylamine (217 mg, 1.68 mmol) was added. The mixture was heated to 60 °C and stirred for 2 hours. After the reaction was completed, the solution was concentrated to dryness to obtain ((2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ))-1-amine). 6 (-Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetic acid ester, used directly in the next reaction. MS m / z (ESI): 658 [M+H] + .

[0328] Step 2: (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

[0329]

[0330] ((2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (0.30 g, 0.45 mmol) was dissolved in methanol (5 mL), excess sodium methoxide solid was added, and the reaction was carried out at room temperature for 3 hours. Then, the reaction was quenched by adding 1 / 1000 aqueous formic acid solution (200 mL). After lyophilization, the mixture was separated by reverse-phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (0 to 100)] to obtain (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (120 mg, yield 49%). MS m / z (ESI): 532 [M+H + .

[0331] Step 3: (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid

[0332]

[0333] (2R,3R,4S,5R)-2-(6-chloro-4-((1-(4-(pentafluoro-λ) 6 (-thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (60 mg, 0.12 mmol) was dissolved in trimethyl phosphate (2.5 mL), and a solution of methylene dichloride (112 mg, 0.48 mmol) in trimethyl phosphate (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was kept at this temperature for 3 hours. A small amount of ice was added to quench the reaction, and then the mixture was separated by reversed-phase column chromatography. [C 18 Column, eluent: water ~ water / acetonitrile (5:1)] to obtain (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ) 6 -Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid (30 mg, yield 18%). MS m / z (ESI): 690 [M+H] + .

[0334] 1 H NMR(400MHz,D2O)δ8.14(s,1H),7.81–7.60(m,2H),7.57–7.35(m,2H),6.21-5.88(m,1H),5.44-5.16(m,1H),4.99 -4.76(m,1H),4.54-4.40(m,1H),4.26-4.11(m,1H),4.02-3.83(m,2H),2.13(t,J=20.1Hz,2H),1.73-1.30(m,3H).

[0335] Compounds in Examples 2-4 were prepared according to the synthetic method described in Example 1:

[0336]

[0337]

[0338] The NMR data of the compounds obtained in the above-prepared examples are as follows:

[0339]

[0340] Example 5 (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 Preparation of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid

[0341]

[0342] Step 1: (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate

[0343]

[0344] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (730 mg, 1.65 mmol) and (S)-1-(2-fluoro-4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethane-1-amine (600 mg, 1.98 mmol) was dissolved in N-methylpyrrolidone (15 mL), and then N,N-diisopropylethylamine (608 mg, 4.95 mmol) was added. The mixture was heated to 90 °C and stirred for 40 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, and the combined organic phases were concentrated and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (40%)] to give (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ)) 6 (Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (360 mg, yield 32%). MS m / z (ESI): 675 [M+H] + .

[0345] Step 2: (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6Synthesis of 1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

[0346]

[0347] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 (-Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-dimethyldiacetate (0.32 g, 0.48 mmol) was dissolved in methanol (20 mL), potassium carbonate (0.19 g, 1.44 mmol) was added, and the reaction was carried out at room temperature for 1 hour. Then, the reaction was quenched by adding 1 / 1000 formic acid aqueous solution (200 mL). After lyophilization, the mixture was separated by reverse-phase column chromatography [C 18 [Column, eluent: water to water / acetonitrile (0 to 70%)] to give (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ)] 6 (-Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (240 mg, 91% yield). MS m / z (ESI): 549 [M+H] + .

[0348] Step 3: (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid

[0349]

[0350] (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 (-thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (240 mg, 0.44 mmol) was dissolved in trimethyl phosphate (3 mL), and a solution of methylene dichloride (436 mg, 1.75 mmol) in trimethyl phosphate (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was kept at this temperature for 1 hour, and a small amount of ice was added to quench the reaction. Then, the mixture was separated by reversed-phase column chromatography. [C 18[Column, eluent: water ~ water / acetonitrile (5:1)] yields (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ) 6 -Thioalkyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)hydroxy)phospho)methyl)phosphonic acid (90 mg, yield 29%). MS m / z (ESI): 707 [M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d6+D2O) δ8.38 (s, 1H), 7.96 (dd, J = 10.4, 1.6Hz, 1H), 7.76 (dd,J=8.4,1.6Hz,1H),7.62(t,J=8.0Hz,1H),6.08(d,J=4.4Hz,1H),6.03(s, 1H),5.15-5.13(m,1H),4.53(t,J=4.8Hz,1H),4.26(t,J=4.0Hz,1H),4.04-4 .02(m,2H),3.86-3.83(m,1H),2.12(t,J=20.0Hz,2H),1.59(d,J=6.8Hz,3H).

[0352] Compounds in Examples 6-22 were prepared according to the synthetic method described in Example 5:

[0353]

[0354]

[0355]

[0356]

[0357] The NMR data of the compounds obtained in the above-prepared examples are as follows:

[0358]

[0359]

[0360] Example 23 Preparation of (((((2R,3S,4R,5R)-5-(4-((((R)-5,7-difluoro-2,3-dihydro-1H-indene-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phospho)methyl)phosphonic acid

[0361]

[0362] Step 1: Synthesis of (2R,3R,4S,5R)-2-(4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

[0363]

[0364] Dissolve (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (0.48 g, 1.06 mmol) in dioxane / water (8 mL / 2 mL), and add potassium carbonate (0.44 g, 3...) under nitrogen atmosphere. 0.18 mmol), tetraphenylphosphine palladium (0.37 g, 0.32 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (0.40 g, 3.18 mmol) were sealed and microwaved at 130 °C for 3 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed successively with water and saturated brine, dried over sodium sulfate, filtered, concentrated, and then separated by reverse-phase column chromatography [C]. 18 [Column, eluent: water to water / acetonitrile (0-100%)] to give (2R,3R,4S,5R)-2-(4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (255 mg, 53% yield). MS m / z (ESI): 433 [M+H] + .

[0365] Step 2: Synthesis of (((((2R,3S,4R,5R)-5-(4-((((R)-5,7-difluoro-2,3-dihydro-1H-indene-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phospho)methyl)phosphonic acid

[0366]

[0367] (2R,3R,4S,5R)-2-(4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (255 mg, 0.59 mmol) was dissolved in trimethyl phosphate (3.0 mL). A solution of methylene dichloride (515 mg, 2.06 mmol) in trimethyl phosphate (2.0 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was maintained at this temperature for 1 hour. A small amount of ice was added to quench the reaction, and the mixture was stirred at this temperature for 10 minutes. Saturated sodium bicarbonate solution was added to adjust the pH to ≥8, and the mixture was stirred at room temperature for 5 hours. Then, reverse-phase column chromatography was used to separate [C]. 18 [Column, eluent: water ~ water / acetonitrile (5:1)] yielded (((((2R,3S,4R,5R)-5-(4-((((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phospho)methyl)phosphonic acid (136.5 mg, 35% yield). MS m / z (ESI): 591 [M+H] + .

[0368] 1 H NMR(400MHz,D2O)δ8.15(s,1H),6.99(d,J=8.8Hz,1H),6.83(t,J=9.8Hz,1H),6.48(d,J=3 .0Hz,1H),6.39(d,J=5.4Hz,1H),5.51(s,1H),4.93(t,J=5.6Hz,1H),4.62(t,J=5.0Hz,1H ),4.33(q,J=4.9Hz,1H),4.07(hept,J=5.4Hz,2H),3.24–3.11(m,1H),3.04–2.93(m,1H), 2.64(dq,J=15.4,8.1,7.4Hz,1H),2.53(s,3H),2.25–2.15(m,1H),2.05(t,J=19.6Hz,2H).

[0369] Example 24: Preparation of the compound according to the synthetic method of Example 23:

[0370]

[0371] The NMR data of the compounds obtained in the examples prepared above are as follows:

[0372]

[0373]

[0374] Example 25 (((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4])

[0375] Preparation of triazine-7-yl)-2,3-dihydroxycyclopentyl)methoxy)hydroxy)phospho)methyl)phosphonic acid

[0376]

[0377] Step 1: Synthesis of 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-indene-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine

[0378]

[0379] 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (500 mg, 1.21 mmol) and (R)-2,3-dihydro-1H-indene-1-amine (326 mg, 2.42 mmol) were dissolved in 1,4-dioxane (20 mL), and then N,N-diisopropylethylamine (446 mg, 3.63 mmol) was added. The solution was incubated at room temperature. After stirring for 4 hours, the reaction was completed, diluted with water, extracted with ethyl acetate, and the combined organic phases were concentrated and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (20%)] to give 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (670 mg, yield 91%). MS m / z (ESI): 509 [M+H] + .

[0380] Step 2: Synthesis of (1R,2S,5R)-5-(tert-butoxymethyl)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl)cyclopent-3-ene-1,2-diol

[0381]

[0382] 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopentadieno[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-indene-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (670 mg, 1.31 mmol) was dissolved in 90% acetic acid (40 mL) and heated to 60 °C. The mixture was stirred at ℃ for 16 hours. After the reaction was completed, the solution was concentrated and separated by column chromatography [eluent: dichloromethane ~ dichloromethane / methanol (10%)] to give (1R,2S,5R)-5-(tert-butoxymethyl)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopent-3-en-1,2-diol (600 mg, yield 97%). MS m / z (ESI): 469 [M+H] + .

[0383] Step 3: Synthesis of (1S,2R,3R,5S)-3-(tert-butoxymethyl)-5-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopentane-1,2-diol

[0384]

[0385] (1R,2S,5R)-5-(tert-butoxymethyl)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopent-3-ene-1,2-diol (600 mg, 1.28 mmol) and Crabtree catalyst (100 mg) were dissolved in dichloromethane (100 mL), and then hydrogenated at room temperature with stirring for 16 minutes. After several hours, the reaction was concentrated and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (50%)] to give (1S,2R,3R,5S)-3-(tert-butoxymethyl)-5-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopentane-1,2-diol (500 mg, yield 83%). MS m / z (ESI): 471 [M+H] + .

[0386] Step 4: Synthesis of (1R,2S,3S,5R)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol

[0387]

[0388] (1S,2R,3R,5S)-3-(tert-butoxymethyl)-5-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopentane-1,2-diol (500 mg, 1.06 mmol) was dissolved in acetonitrile (4 mL), and dioxane hydrochloride solution (4 mL, 1 N) was added. The mixture was reacted at room temperature for 1 hour, then concentrated and separated by reverse-phase column chromatography [C 18 [Column, eluent: water to water / acetonitrile (0-50%)] to give (1R,2S,3S,5R)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (200 mg, 46% yield). MS m / z (ESI): 415 [M+H] + .

[0389] Step 5: Synthesis of (((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phospho)methyl)phosphonic acid

[0390]

[0391] (1R,2S,3S,5R)-3-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (200 mg, 0.48 mmol) was dissolved in trimethyl phosphate (3 mL). A solution of methylene dichloride (481 mg, 1.93 mmol) in trimethyl phosphate (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was maintained at this temperature for 1 hour. A small amount of ice was added to quench the reaction, followed by reverse-phase column chromatography to separate [C]. 18[Column, eluent: water ~ water / acetonitrile (5:1)] to give (((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-indene-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phospho)methyl)phosphonic acid (65 mg, yield 24%). MS m / z (ESI): 573 [M+H] + .

[0392] 1 H NMR (400MHz, DMSO-d6+D2O) δ7.31-7.17(m,4H),6.99(d,J=4.4Hz,1H),6.54(d,J=4.4Hz,1H),5.82(t,J=8.0 Hz,1H),4.00-3.90(m,3H),3.80-3.78(m,1H),3.59-3.51(m,1H),3.05-3.00(m,1H),2.93-2.85(m,1H),2.56 -2.51(m,2H),2.33-2.19(m,3H),2.04-2.00(m,1H),1.30 -1.27(m,1H).

[0393] Compounds 26-39 were prepared according to the synthetic method described in Example 25:

[0394]

[0395]

[0396] The NMR data of the compounds obtained in the examples prepared above are as follows:

[0397]

[0398]

[0399] Biological test evaluation

[0400] I. Evaluation of CD73 in vitro enzyme activity

[0401] This invention uses the malachite green assay for soluble CD73 synthesized in vitro to determine the inhibitory activity of compounds against CD73. The experimental procedure is as follows:

[0402] 1. The enzyme reaction in this experiment was carried out in a 384-well plate. CD73 (R&D systems#5795-EN-010) at a concentration of 36 ng / mL, different concentrations of compounds, and 50 μM AMP were incubated in a 40 μL reaction system (25 mM Tris pH 7.5, 5 mM MgCl2, 0.005% Tween-20) at 25 °C for 30 minutes.

[0403] 2. The reaction was then terminated by adding 10 μL of malachite green solution (Sigma) to each well.

[0404] 3. Determine the concentration of the generated organic phosphate according to the reagent manufacturer's instructions;

[0405] 4. The CD73 enzyme activity was calculated based on the concentration of the product, and then nonlinear regression analysis was used to determine the inhibition percentage at different concentrations of the compound of this invention to determine the IC50. 50 Values. The experimental results of the compounds in the embodiments of the present invention are shown in Table 1.

[0406] II. Evaluation of CD73 enzyme activity on cell surface (Cell Titer Glo (CTG) assay)

[0407] This invention uses MDA-MB-231 human breast cancer cells endogenously expressing CD73 to evaluate the inhibitory effect of compounds on the activity of CD73 enzyme expressed on the cell surface. The cells used were obtained from the Chinese Academy of Sciences Cell Bank. The experimental procedure is as follows:

[0408] 1. Before testing, seed 20,000 MDA-MB231 cells per well into a 96-well plate;

[0409] 2. In RPMI 1640, 10% fetal bovine serum (Gibco, 10099-141), incubate overnight at 37°C in a 5% CO2 incubator (wash cells 3 times with serum-free RPMI medium before testing).

[0410] 3. Add 50 μl of serum-free culture medium containing different concentrations of diluted compounds to the cells and incubate for 15 minutes;

[0411] 4. Add 25 μL of 1.2 mM AMP and incubate at 37°C for 2 hours. Take 25 μL of the supernatant from the cells and mix it with 25 μL of 100 μM ATP. Then, determine the concentration of AMP in the sample using the CTG (Promega, #G7573) method.

[0412] 5. The inhibitory effect of the compounds and positive compounds of the present invention on the activity of CD73 enzyme on the cell surface was then evaluated by quantitatively measuring the reduction ratio of substrate AMP levels in the cell culture supernatant after the reaction.

[0413] 6. Finally, four-parameter curve fitting in Graphpad Prism was used to determine the concentration of the compound that caused the half-maximal inhibition of enzyme activity (IC50). 50 The experimental results of the compounds in the embodiments of the present invention are shown in Table 1.

[0414] Table 1: Results of Biological Tests

[0415]

[0416]

[0417] Based on the compound activity data from specific embodiments, the compounds of this invention exhibit strong inhibitory effects on CD73 enzymatic activity and cell activity.

[0418] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating at least partially CD73-mediated tumors, immune-related diseases, and metabolic diseases.

4. The application according to claim 3, characterized in that, The tumors mentioned are selected from prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial lining carcinoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, kidney cancer, bone cancer, mesothelioma, sarcoma, and choriocarcinoma.

5. The application according to claim 3, characterized in that, The tumors mentioned are selected from melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.

6. The application according to claim 4, characterized in that, The skin cancer is melanoma or basal cell carcinoma; the leukemia is lymphoma or leukemia; the lung cancer is small cell lung cancer or non-small cell carcinoma; and the sarcoma is Kaposi's sarcoma.

7. The application according to claim 3, characterized in that, The tumors mentioned are selected from glioblastoma, seminoma, thyroid cancer, epidermal basal cell carcinoma, and renal cell carcinoma.

8. The application according to claim 3, characterized in that, The immune-related diseases mentioned are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, Crohn's disease, ulcerative colitis, systemic sclerosis, and multiple sclerosis.

9. The application according to claim 3, characterized in that, The immune-related diseases mentioned are selected from allergic contact dermatitis and eczema.

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