CD73 inhibitors, their production methods and applications

Abstract

To provide compounds that can be widely applied in the preparation of drugs for treating cancers, tumors, autoimmune diseases and disorders, and metabolic diseases, which are at least partially mediated by CD73, in particular, drugs for treating melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma and can be developed as a new generation of CD73 inhibitor drugs.SOLUTION: The present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof. (X1 represents N or CR17; X2 and X3 independently represent N or C; X4 and X5 independently represent N or CR18; Y represents CH2, NH, O or S).SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of drug synthesis, specifically to CD73 inhibitors, their preparation methods and applications.

[0002] [Background technology] CD73, also known as ecto-5'-nucleotidase (eNT), is a 70 kDa protein molecule. It is normally expressed in vascular endothelial cells and some blood cells. It is anchored to the cell membrane surface via glycosylphosphatidylinositol (GPI) and regulates the metabolism of adenosine triphosphate (ATP) together with CD39. Among them, CD39 (also known as extramembrane nucleotide triphosphate hydrolase - NTPDase 1) catalyzes ATP to produce adenylic acid (AMP) and only a small amount of adenosine diphosphate (ADP). On the other hand, the main function of CD73 is to catalyze extracellular nucleotides (such as 5'AMP) to be converted into the corresponding nucleosides (such as adenosine).

[0003] Nucleosides generated by CD73 catalysis, especially adenosine, are thought to be internal regulators with 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 fibrotic processes.

[0004] Expression of CD73 is found on many tumor cells, including leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer, and breast cancer. Expression of CD73 is also found on the surface of immune suppressor cells, including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). High expression of CD73 is also known to be associated with angiogenesis, invasion, resistance to chemotherapy, tumor metastasis, and shortened survival of cancer patients in many tumors, including breast cancer and melanoma.

[0005] Mechanism-based studies suggest that malignant tumor cells release large amounts of ATP under the action of chemotherapy and other pressures, which is rapidly converted into adenosine and accumulates in the tumor microenvironment. The release of extracellular ATP due to cell death or intracellular pressure activates immune responses, while adenosine, an ATP metabolite, has immunosuppressive effects. Most importantly, intratumoral adenosine inhibits infiltrating effector T lymphocytes by activating adenosine receptors (such as A2A) and promotes tumor progression. Thus, the accumulation of extracellular adenosine in key tissues is an important mechanism of tumor immune evasion.

[0006] Reducing CD73 expression by RNA inhibition or overexpressing CD73 in tumor cells can modulate tumor growth and migration. CD73 knockout mice are less likely to develop organ transplant rejection and spontaneous tumors. Deletion of the A2A receptor gene by genetic means can induce T cell-dependent tumor rejection. Antibody therapy capable of binding to CD73 in mice can inhibit mammary tumor growth and migration in mouse models.

[0007] Thus, targeting CD73 represents a potential therapeutic strategy to enhance the efficacy of antitumor therapy and provide a new therapeutic strategy to further inhibit tumor progression. Targeting CD73 may also be useful for the treatment of other adenosine-mediated diseases, such as depression, Parkinson's disease, and sleep disorders, by enhancing the immune response, enhancing immune effects, and enhancing inflammatory responses. The present invention can be used to treat neurological disorders such as fibrosis and other immune-mediated inflammatory diseases, neurodegenerative and central nervous diseases.

[0008] Therefore, research and development of suitable drug candidates that target CD73 could satisfy the demand for drugs that target cancer and other diseases, and offer the advantages of good safety and strong specificity.

[0009] [Summary of the Invention] The inventors of the present application, through extensive and in-depth research, have discovered for the first time that CD73 having the structure of the following formula (I): The present invention has developed a CD73 inhibitor, its preparation method and application. The series of compounds according to the present invention have a strong inhibitory effect on CD73 enzyme activity and can be widely used for the preparation of drugs for the treatment of cancer, tumor, immune-related disease and disorder, metabolic disease, particularly melanoma, colon cancer, pancreatic adenocarcinoma, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma, which are at least partially mediated by CD73, and are expected to be developed as a new generation of CD73 inhibitors. Based on this, the present invention has been completed.

[0010] In a first aspect of the present invention, there is provided a compound of general formula (I), a stereoisomer, a prodrug or a pharma- ceutically acceptable salt thereof:

[0011] [ka]

[0012] Here,

[0013] [ka] " is a double bond or a single bond,

[0014] X1 is N or CR 17 and X2 and X3 are each independently N or C; X4 and X5 are each independently N or CR 18 and Y is CH, NH, O or S; m is 0, 1, 2 or 3 and n is 0, 1, 2 or 3, with the proviso that m+n does not exceed 5; R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C5-10 Aryl groups, 5-10 membered heteroaryl groups, -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(R2 2)-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 or, when m≧2, two R1's together with the moiety to which they are directly connected form a 4-10 membered cycloalkyl group, a 4-10 membered aryl group, a 4-10 membered heterocyclic group, or a 4-10 membered heteroaryl group, which may optionally be selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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)R21 , -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 is further substituted with one or more substituents selected from R2 and R3 each independently represent hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 R2 and R3 together with the carbon atom directly connected thereto form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclic group, or either R2 or R3 and R1 together with the group directly connected thereto form a 4- to 10-membered cycloalkyl group or a 4- to 10-membered heterocyclic group, and the other is hydrogen, deuterium, halogen or C 1-10 alkyl groups, which may optionally be deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from R4 is hydrogen, deuterium, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 23or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from R5 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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(R22 )-C(O)R 21 is further substituted with one or more substituents selected from R6 and R7 each independently represent hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 the above groups are optionally selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from R8 and R9 each independently represent hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 the above groups are optionally selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =O, -C 0-8 -S(O) r R 19 , -C 0-8 -OR20 , -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 is further substituted with one or more substituents selected from R 10 , R 11 , R 12 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -C 0-8 -C(O)OR 20 , -C 0-8 -C(O)R 21 or -C 0-8 -C(O)NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-10 Cycloal alkyl group, 3-10 membered heterocyclic group, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from R 13 , R 14 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 and R 14together with the carbon atom directly attached thereto form a 3-10 membered cycloalkyl group or a 3-10 membered heterocyclic group, which may optionally be substituted with deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from R 15 , R 16 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -C 0-8 -S(O) r R19 , -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 or R 15 and R 16 together with the carbon atom directly attached thereto form a 3-10 membered cycloalkyl group or a 3-10 membered heterocyclic group, which may optionally be substituted with deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 )R21 , -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 is further substituted with one or more substituents selected from R 17 , R 18 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -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 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-1 0 Alkenyl group, C 2-10Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from Each R 19 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl group, 5-10 membered heteroaryl group or -NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Aryl group, C 5-10Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 20 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 aryl or 5-10 membered heteroaryl groups, which may optionally be deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Aryl group, C 5-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 21 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Aryl group, C 5-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group or -NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Aryl group, C 5-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 22 , R 23 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl group, 5- to 10-membered heteroaryl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group, monoalkylamino group, dialkylamino group or C 1-10 alkanoyl groups, which may optionally be deuterium, halogen, hydroxyl groups, C 1-8 Alkyl group, C 1-10 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Aryl group, C 5-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, monoalkylamino group, dialkylamino group or C 1-10 is further substituted with one or more substituents selected from an alkanoyl group; Or R 22 , R 23 together with the nitrogen atom directly attached thereto form a 4-10 membered heterocyclic group, said group optionally containing deuterium, halogen, hydroxyl group, C 1-10 Alkyl group , C 1-10 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkyloxy group, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C5-10 Aryl group, C 5-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, monoalkylamino group, dialkylamino group or C 1-10 alkanoyl groups, and each r is independently 0, 1, or 2.

[0015] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 15 , R 16 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 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 and R 16 together with the carbon atom directly attached thereto form a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, which may optionally contain deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 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 wherein R 20 , R 22 , R 23 is as in the compound of formula (I), Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, and dimethylamino, or R 15 and R 16 together with the carbon atom directly attached thereto form a 3- or 4-membered cycloalkyl group or a 4- or 5-membered heterocyclic group.

[0016] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 13 , R 14 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 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 and R 14 together with the carbon atom directly attached thereto form a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, which may optionally contain deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 , -C 0-4 -C(O)OR 20 or -C0-4 -NR 22 R 23 wherein R 20 , R 22 , R 23 is as for compounds of formula (I), More preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 13 , R 14 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, and dimethylamino, or R 13 and R 14 together with the carbon atom directly attached thereto form a 3- or 4-membered cycloalkyl group or a 4- or 5-membered heterocyclic group.

[0017] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 17 , R 18 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, -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 , -C0-4 -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 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 wherein R 19 , R 20 , R 21 , R 22 , R 23, r is as for compounds of formula (I).

[0018] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, R6 and R7 are each independently hydrogen, deuterium, halogen, a cyano group, a nitro group, an azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl 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 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 )R21 , -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 is further substituted with one or more substituents selected from R8 and R9 each independently represent hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl 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 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 wherein R 19 , R 20 , R 21 , R 22 , R 23 , r is as for compounds of formula (I).

[0019] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R 10 , R 11 , R 12 are hydrogen, heavy water, Basic, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, -C 0-4 -C(O)OR 20 , -C 0-4 -C(O)R 21 or -C 0-4 -C(O)NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 wherein R 19 , R 20 , R 21 , R 22 , R 23 , r is as for compounds of formula (I).

[0020] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, R2 and R3 are each independently hydrogen, deuterium, halogen, a cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, -C 0-4 -OR 20 , -C 0-4 -C(O)OR 20 or -C 0-4 -NR 22 R 23or R2 and R3 together with the carbon atom directly connected thereto form a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, or either R2 or R3 and R1 together with the group directly connected thereto form a 4-10 membered cycloalkyl group or a 4-10 membered heterocyclic group, and the other is hydrogen, deuterium, fluorine or C 1-4 alkyl groups, which may optionally be deuterium, halogen, cyano, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 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 wherein R, R 20 , R 22 , R 23 is as for the compound of formula (I).

[0021] More preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyano, methyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, methylamino or dimethylamino; or R2 and R3 together with the carbon atom directly connected thereto form a 3-4 membered cycloalkyl group or a 4-5 membered heterocyclic group; or R2 and R3 together with the group directly connected thereto form a 4-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, and the other is selected from hydrogen, deuterium or a methyl group, where R1 is as in the compound of formula (I).

[0022] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, -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 23 or the above groups are optionally selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 )R21 , -C 0-4 -C(O)NR 22 R 23 or -C 0-4 -N(R 22 )-C(O)R 21 wherein R 19 , R 20 , R 21 , R 22 , R 23 , r is as for compounds of formula (I).

[0023] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, R1 is independently hydrogen, deuterium, halogen, 、 Cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, -C 0-4 -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 21or, when m≧2, two R1 therein together with the moiety to which they are directly linked form a 4-8 membered cycloalkyl group, a 5-8 membered aryl group, a 4-8 membered heterocyclic group, or a 5-8 membered heteroaryl group, which may optionally be selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 5-8 Aryl groups, 5-8 membered heteroaryl groups, =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 wherein R 19 , R 20 , R 21 , R 22 , R 23 , r is as for compounds of formula (I).

[0024] Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, the compound of formula (I) has the structure of the following compound of formula (IIa), compound of formula (IIb) or compound of formula (IIc):

[0025] [ka] wherein each X1 is independently N or CH, each X4 is independently N or CH, and each Y is independently CH2 or O;

[0026] Each R1 is independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, or C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, -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 or, when m≧2, two R1 therein together with the moiety to which they are directly linked form a 5-6 membered cycloalkyl group, a 5-6 membered aryl group, a 5-6 membered heterocyclic group, or a 5-6 membered heteroaryl group, which groups may optionally be selected from the group consisting of deuterium, halogen, cyano, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, =O, -S(O) r R 19 , -OR 20 , -C(O)OR 20 , -C(O)R 21 , -OC(O)R 21 or -NR22 R 23 is further substituted with one or more substituents selected from R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyano, methyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, methylamino, and dimethylamino groups; Each R4 is independently hydrogen, deuterium, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 aryl or 5-6 membered heteroaryl groups, which may optionally be deuterium, halogen, cyano, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, =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 is further substituted with one or more substituents selected from Each R5 is independently hydrogen, deuterium, a halogen, a cyano group, or C 1-4 Alkyl group, C 3-6Cycloalkyl groups, 3- to 6-membered heterocyclic groups, phenyl groups, 5- to 6-membered heteroaryl groups, -SF5, methylthio groups, methylsulfonyl groups, isopropylsulfonyl groups, aminosulfonyl groups, methoxy groups, ethoxy groups, isopropoxy groups, hydroxy groups, -C(O)OH, methoxycarbonyl groups, ethoxycarbonyl groups, formyl groups, acetyl groups, acetoxy groups, amino groups, dimethylamino groups, -C(=NR 22 )R 21 , -N(R 22 )-C(=NR 23 )R 21 , aminocarbonyl, dimethylaminocarbonyl or acetylamino, the above groups being optionally selected from deuterium, halogen, cyano, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 further substituted with one or more substituents selected from a cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a 5- to 6-membered heteroaryl group, =O, a methylthio group, a methylsulfonyl group, an isopropylsulfonyl group, an aminosulfonyl group, a methoxy group, an ethoxy group, an isopropoxy group, a hydroxy group, -C(O)OH, a methoxycarbonyl group, an ethoxycarbonyl group, a formyl group, an acetyl group, an acetoxy group, an amino group, a dimethylamino group, an aminocarbonyl group, a dimethylaminocarbonyl group, or an acetylamino group; each R6, R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, hydroxy, methoxy, or acetoxy, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy, or acetoxy; each R8, R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, cyclopropyl, hydroxy, methoxy, or acetoxy, or any of the above groups optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy, or acetoxy; Each R 10 , R 11 , R 12 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, -C(O)OR 20 , -C(O)R 21 or -C(O)NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, =O, -S(O) r R 19 , -OR 20 , -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 is further substituted with one or more substituents selected from Each R 19are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-6 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl group, 5-6 membered heteroaryl group or -NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, hydroxyl, carbonyl, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6 Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 20 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 aryl or 5-6 membered heteroaryl groups, which may optionally be deuterium, halogen, hydroxyl, Si group, carbonyl group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6 Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 21 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 1-4 Alkoxy group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6 Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group or -NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6 Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group or -NR 22 R 23 is further substituted with one or more substituents selected from Each R 22 , R 23 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl group, 5-6 membered heteroaryl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group, monoalkylamino group, dialkylamino group or C 1-4 alkanoyl groups, which may optionally be deuterium, halogen, hydroxyl groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group, amino group, monoalkylamino group, dialkylamino group or C 1-4 is further substituted with one or more substituents selected from an alkanoyl group; Or R 22 , R 23 together with the nitrogen atom directly attached thereto form a 4-6 membered heterocyclic group, said group optionally containing deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 5-6 Aryl group, C 5-6 Aryloxy group, 5-6 membered heteroaryl group, 5-6 membered heteroaryloxy group, amino group, monoalkylamino group, dialkylamino group or C 1-4 is further substituted with one or more substituents selected from an alkanoyl group; each q is independently 0, 1, 2 or 3; each m is independently 0, 1, 2, or 3; Each r is independently 0, 1, or 2.

[0027] More preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt thereof, each R is independently hydrogen, deuterium, halogen, a cyano group, a nitro group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, -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 or the above groups are optionally selected from deuterium, halogen, cyano group, C 1-4Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, -OR 20 , -C(O)OR 20 Or -C(O)R 21 is further substituted with one or more substituents selected from the group Each R4 is independently hydrogen, deuterium, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 aryl or 5-6 membered heteroaryl groups, which may optionally be deuterium, halogen, cyano, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group , C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, =O, -OR 20 , -C(O)OR 20 Or -C(O)R 21 is further substituted with one or more substituents selected from Each R5 is independently hydrogen, deuterium, a halogen, a cyano group, or C 1-4 Alkyl group, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a 5- to 6-membered heteroaryl group, -SF5, a methylthio group, a methylsulfonyl group, an isopropylsulfonyl group, an aminosulfonyl group, a methoxy group, an ethoxy group, an isopropoxy group, a hydroxy group, -C(O)OH, a methoxycarbonyl group, an ethoxycarbonyl group, a formyl group, an acetyl group, an acetoxy group, an amino group, a dimethylamino group, an aminocarbonyl group, a dimethylaminocarbonyl group or an acetylamino group, the above groups being optionally deuterium, a halogen, a cyano group, a C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6further substituted with one or more substituents selected from a cycloalkyl group, a 3-6 membered heterocyclic group, =O, a methoxy group, an ethoxy group, an isopropoxy group, a hydroxy group, -C(O)OH, a methoxycarbonyl group, an ethoxycarbonyl group, a formyl group, an acetyl group, or an acetoxy group; each R6, R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, or acetoxy, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy, or acetoxy; Each R8, R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxy, methoxy, or acetoxy, or any of the above groups is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy, or acetoxy; Each R 10 , R 11 , R 12 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 5-6 Aryl groups, 5-6 membered heteroaryl groups, -C(O)OR 20 , -C(O)R 21 or -C(O)NR 22 R 23 or the above groups are optionally selected from deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 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 is further substituted with one or more substituents selected from Each R 19 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group or C 3-6 cycloalkyl groups, which may optionally be deuterium, halogen, hydroxyl, carbonyl, C 1-4 Alkyl group, C 1-4 Alkoxy group or C 3-6 is further substituted with one or more substituents selected from a cycloalkyl group; Each R 20 are independently hydrogen, deuterium, and C 1-4 Alkyl group or C 3-6 cycloalkyl groups, which may optionally be deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group or C 3-6 is further substituted with one or more substituents selected from a cycloalkyl group; Each R 21 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group or C 1-4 alkoxy groups, which may optionally be deuterium, halogen, hydroxyl groups, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group or C 3-6 is further substituted with one or more substituents selected from a cycloalkyl group; Each R 22 , R 23 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group or C 1-4 alkanoyl groups, which may optionally be deuterium, halogen, hydroxyl groups, C 1-4Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, a 3- to 6-membered heterocyclic group or C 1-4 is further substituted with one or more substituents selected from an alkanoyl group; Even more preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, the compound of formula (I) has a structure of the following formula (IIIa1) compound or formula (IIIa2) compound:

[0028] [ka]

[0029] Here, each R1 is independently hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C 3-6 selected from a cycloalkyl group or a 3- to 6-membered heterocyclic group; each R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, allyl, ethynyl, cyclopropyl, or hydroxymethyl; Each R4 is independently hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, an isopropyl group, or C 2-4 Alkenyl group or C 3-6 cycloalkyl groups, Each R5 is independently hydrogen, deuterium, fluorine, chlorine, a cyano group, an azido group, a methyl group, an ethyl group, a propyl group, an isopropyl group, 2-6 Alkenyl group, C 2-6 Alkynyl group or C 3-6 cycloalkyl groups, each R6 is independently selected from hydrogen, deuterium, a halogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxy group; each R8 is independently selected from hydrogen, deuterium, a halogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxy group; Each R 10 , R 11 , R 12 are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; Each m is independently 0, 1, 2, or 3.

[0030] Even more preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, the compound of formula (I) has the structure of the compound of formula (IIIb) below.

[0031] [ka] where X1 is N or CH;

[0032] Here, R1 is hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C 3-6 selected from a cycloalkyl group or a 3- to 6-membered heterocyclic group; R4 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, C 2-4 Alkenyl group or C 3-6 cycloalkyl groups, R5 is hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, ethyl, propyl, isopropyl, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 3-6 cycloalkyl groups, R7 is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, or hydroxyl; R9 is selected from hydrogen, deuterium, a halogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxy group.

[0033] R 10 , R 11 , R 12 are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; m is 0, 1, 2 or 3.

[0034] Even more preferably, in the compound of formula (I), its stereoisomer, prodrug or pharma- ceutically acceptable salt, the compound of formula (I) has the structure of the compound of formula (IIIc) below.

[0035] [ka] where X1 is N or CH;

[0036] R1 is hydrogen, deuterium, fluorine, chlorine, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a dideuteromethyl group, Trideuteromethyl group, C 3-6 selected from a cycloalkyl group or a 3- to 6-membered heterocyclic group; R4 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, C 2-4 Alkenyl group or C 3-6 cycloalkyl groups, R5 is hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, ethyl, propyl, isopropyl, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 3-6 cycloalkyl groups, R6 is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, or hydroxyl; R8 is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, or hydroxyl; R 10 , R 11 , R 12are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; m is 0, 1, 2 or 3.

[0037] Most preferably, the compounds of formula (I) above, their stereoisomers, prodrugs or pharma- ceutically acceptable salts include, but are not limited to, the following compounds:

[0038] [ka] TIFF0007627966000008.tif239169TIFF0007627966000009.tif246169TIFF0007627966000010.tif173169A second aspect of the present invention provides a method for preparing the compound of formula (I), its stereoisomer, prodrug or a pharma- ceutically acceptable salt thereof, comprising the steps as shown below:

[0039] [ka] where Pg is a hydroxy protecting group, preferably an alkanoyl group or a silyl protecting group, and 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 defined for compounds of formula (I).

[0040] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) above, a stereoisomer, a prodrug or a pharma- ceutically acceptable salt thereof, and a pharmaceutical carrier. In a fourth aspect, the present invention provides an application of the compound of formula (I), its stereoisomer, prodrug or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer or tumor, immune-related disease and disorder, metabolic disease, which are at least partially mediated by CD73.

[0041] Preferably, the cancer or tumor is selected from prostate cancer, colon cancer, rectal cancer, pancreatic adenocarcinoma, 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 endometrial cancer, white blood cell cancer (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 gland cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma.

[0042] More preferably, the cancer or tumor is selected from melanoma, colon cancer, pancreatic adenocarcinoma, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma. Preferably, the immune-related disease and disorder is selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis.

[0043] In a fifth aspect of the present invention, there is provided a compound of formula (I), its stereoisomer, prodrug or a pharma- ceutically acceptable salt thereof for use as a medicament for the treatment of cancer or tumors, autoimmune diseases and disorders, metabolic diseases mediated at least in part by CD73.

[0044] In a sixth aspect of the present invention, there is provided a compound of formula (I), its stereoisomers, prodrugs or and its pharmacologic agents, such as pharmacologic agents that inhibit the production of steroids and / or anti-inflammatory drugs, such as steroids and anti-inflammatory drugs, and / or steroids and / or ... In addition, the present invention provides a drug for use as a drug for the treatment of inflammatory bowel disease, including bronchitis, choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma, rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

[0045] [Embodiment of the invention] DETAILED DESCRIPTION: Unless stated to the contrary, the terms used in the following specification and claims shall have the following meanings.

[0046] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group having a straight or branched chain. For example, "C 1-10The term "alkyl group" refers to a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 10 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-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-dimethyl Examples of aryl groups include, but are not limited to, butyl, 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, and various branched isomers thereof. 0-8 " is C 0-8 The alkyl group is represented by "C 0-4 " is C 0-4 The alkyl group is represented by C0, which means that it has 0 carbon atoms. 1-4 " is C 1-4 This refers to an alkyl group, and the definition of the alkyl group is as described above.

[0047] The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0048] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 Cycloalkyl groups are those containing 3 to 10 carbon atoms. Cycloalkyl groups are classified into monocyclic and polycyclic cycloalkyl groups, and among them, Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0049] Polycyclic cycloalkyl groups include spiro, fused and bridged ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share a carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups, spirocycloalkyl groups include, but are not limited to:

[0050] [ka]

[0051] "Fused cycloalkyl groups" refer to all-carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of which may contain one or more double bonds (preferably one, two or three), but no ring has a completely conjugated pi-electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic, and fused cycloalkyl groups include, but are not limited to, the following:

[0052] [ka]

[0053] "Bridged cycloalkyl groups" refer to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected, and these groups may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated pi-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic, and bridged cycloalkyl groups include, but are not limited to, the following:

[0054] [ka]

[0055] The cycloalkyl group may be fused to an aryl, heteroaryl, or heterocyclic ring, where the ring connected to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like.

[0056] Cycloalkyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0057] A "heterocyclic group" refers to a saturated or partially saturated monocyclic or polycyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are nitrogen, oxygen or heteroatoms selected from S(O)r (where r is an integer 0, 1 or 2), the group does not contain an -OO-, -OS- or -SS- ring moiety, and the remaining ring atoms are carbon. For example, a "5- to 10-membered heterocyclic group" refers to a ring group containing 5 to 10 ring atoms, and a "3- to 10-membered heterocyclic group" refers to a ring group containing 3 to 10 ring atoms.

[0058] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, homopiperazyl groups, and the like. Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups. A "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings, one or more (preferably 1, 2, 3 or 4) of which are nitrogen, oxygen or heteroatoms selected from S(O)r, where r is an integer 0, 1 or 2, and the remaining ring atoms are carbon. These groups may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spiro heterocyclic groups are classified as monospiro heterocyclic groups, dispiroheterocyclic groups or polyspiro heterocyclic groups. Spiro heterocyclic groups include, but are not limited to:

[0059] [ka]

[0060] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more (preferably 1, 2, 3 or 4) of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated pi-electron system, one or more (preferably 1, 2, 3 or 4) of which ring atoms are nitrogen, oxygen or a heteroatom selected from S(O)r, where r is an integer 0, 1 or 2, and the remaining ring atoms are carbon. Depending on the number of constituent rings, fused heterocyclic groups can be bicyclic, tricyclic, tetracyclic or polycyclic, and fused heterocyclic groups include, but are not limited to, the following:

[0061] [ka]

[0062] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and which may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably 1, 2, 3 or 4) of the ring atoms are nitrogen, oxygen or S(O). r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of rings, bridged heterocyclic groups may be bicyclic, tricyclic, tetracyclic or polycyclic, and bridged heterocyclic groups include, but are not limited to, the following:

[0063] [ka]

[0064] The ring of the heterocyclic group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to, the following:

[0065] [ka]

[0066] Heterocyclic groups may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0067] An "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, e.g., a "C5-10 aryl group" refers to an all-carbon aryl group containing 5 to 10 carbons, and a "5-10 membered aryl group" refers to an all-carbon aryl group containing 5 to 10 carbons, including, but not limited to, phenyl and naphthyl. The ring of the aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including, but not limited to, the following:

[0068] [ka]

[0069] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0070] The term "heteroaryl group" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen or S(O)r, where r is an integer 0, 1 or 2. For example, a 5-8 membered heteroaryl group refers to a heteroaromatic system containing 5 to 8 ring atoms, and a 5-10 membered heteroaryl group refers to a heteroaromatic system containing 5 to 10 ring atoms, including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The ring of the heteroaryl group may be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including, but not limited to, the following:

[0071] [ka]

[0072] Heteroaryl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, or the like. , C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0073] An "alkenyl group" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as, for example, C 2-10 The alkenyl group refers to a straight-chain or branched-chain alkenyl group containing 2 to 10 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0074] The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0075] An "alkynyl group" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as, for example, C 2-10 The alkynyl group refers to a straight or branched chain alkynyl group containing 2 to 10 carbons, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0076] The alkynyl group may be substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0077] The term "alkoxy group" refers to -O-(alkyl group), the alkyl group being as defined above. For example, "C 1-10 The term "alkoxy group" refers to an alkoxy group containing 1 to 10 carbons, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0078] The alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0079] The term "cycloalkyloxy group" refers to -O- (unsubstituted cycloalkyl group), where the cycloalkyl group is as defined above. For example, a "C3-10 cycloalkyloxy group" refers to a cycloalkyloxy group containing 3 to 10 carbon atoms, including, but not limited to, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0080] The cycloalkyloxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0081] The term "3- to 10-membered heterocyclic oxy group" refers to -O- (an unsubstituted 3- to 10-membered heterocyclic group), the definition of which is as described above. The 3- to 10-membered heterocyclic oxy group may be optionally substituted or unsubstituted, but in the case of a substituted group, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0082] "C 5-10 "Aryloxy group" means -O-(unsubstituted C 5-10 Aryl group), but its C 5-10 The definition of the aryl group is as above. 5-10 The aryloxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocycles group, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0083] The term "5- to 10-membered heteroaryloxy group" refers to -O- (an unsubstituted 5- to 10-membered heterocyclic group), the definition of which is as set forth above. The 5- to 10-membered heteroaryloxy group may be optionally substituted or unsubstituted, but when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, =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 It is preferred that the group is one or more (preferably 1, 2, 3 or 4) groups selected from the following:

[0084] "C 1-8 "Alkanoyl group" means C 1-8 This refers to the monovalent atomic group remaining after removing the hydroxyl group from an alkyl acid. 0-7 For example, "C1-C(O)-" refers to an acetyl group, "C2-C(O)-" refers to a propionyl group, and "C3-C(O)-" refers to a butyryl group or an isobutyryl group.

[0085] "-C 0-8 -S(O) r R 19 " -S(O) r R 19 The sulfur atom in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0086] "-C 0-8 -OR 20 " -OR 20 The oxygen atom in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0087] "-C 0-8 -C(O)OR 20 "What is C(O)OR? 20 In the oxo group, C 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8The alkyl group is as defined above.

[0088] "-C 0-8 -C(O)R 21 "What is -C(O)R 21 In the oxo group, C 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0089] "-C 0-8 -OC(O)R 21 "What is OC(O)R? 21 The oxygen atom in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0090] "-C 0-8 -NR 22 R 23 " -NR 22 R 23 The nitrogen atom in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0091] "-C 0-8 -C(=NR 22 )R 21 " is -C(=NR 22 )R 21 The carbonyl group in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0092] "-C 0-8 -N(R 22 )-C(=NR 23 )R 21 " is -N(R 22 )-C(=NR 23 )R 21 The carbonyl group in 0-8It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0093] "-C 0-8 -C(O)NR 22 R 23 " is -C(O)NR 22 R 23 The carbonyl group in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0094] "-C 0-8 -N(R 22 )-C(O)R 21 " is -N(R 22 )-C(O)R 21 The nitrogen atom in 0-8 It refers to a bond connected to an alkyl group, and the C0 alkyl group is a bond. 1-8 The alkyl group is as defined above.

[0095] "Halogen-substituted C 1-10 The term "alkyl group" refers to an alkyl group having 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom, and includes, but is not limited to, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, and the like.

[0096] "Halogen-substituted C 1-10 The term "alkoxy group" refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogen in an alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom. Examples of the alkoxy group include, but are not limited to, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, and a tribromomethoxy group.

[0097] "Halogen" refers to fluorine, chlorine, bromine or iodine. "MeOH" refers to ethanol. "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 lithium 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-chloroperbenzoic acid. "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium. "Pd(PPh3)2Cl2" refers to bis(triphenylphosphine)palladium dichloride.

[0098] "Optional" or "optionally" means that the event or circumstance described below may be present, but does not necessarily occur, and the description includes when the event or circumstance occurs or does not occur, and includes substituted or unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be present, but is not necessarily present, and the description includes when the heterocyclic group is substituted with an alkyl group and when the heterocyclic group is not substituted with an alkyl group.

[0099] "Substituted" means that one or more heterohydrogen atoms in a group are replaced independently of one another by the corresponding number of substituents. Of course, the substituents are only those in which they are chemically possible. A person skilled in the art can easily determine (experimentally or theoretically) whether a substitution is possible or not. For example, an amino group or a hydroxy group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (e.g., an olefin).

[0100] The English name for "stereoisomer" is stereoisomer, which refers to isomers due to differences in the way atoms are arranged in a molecule in space. They are divided into cis-trans isomers and enantiomers, and also into enantiomers and enantiomers. Stereoisomers due to the rotation of a single bond are called configurational stereoisomers, sometimes called rotamers. Stereoisomers due to bond length, bond angle, double bonds in a molecule, rings, etc. are called configurational stereoisomers, and configurational isomers are divided into two types. Among them, isomers due to double bonds that cannot rotate freely or single bonds of ring carbon atoms are called geometric isomers or cis-trans isomers, and are divided into Z and E configurations. For example, cis-2-butylene and trans-2-butylene are paired geometric isomers, and stereoisomers that have different optical rotatory properties due to the lack of antiaxial symmetry in the molecule are called optical isomers and are divided into R and S configurations. Unless otherwise specified, the "stereoisomer" described in the present invention may be understood to be one or more of the above-mentioned enantiomers, configurational isomers, and configurational isomers.

[0101] In the present invention, "pharmaceutically acceptable salts" refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0102] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical salts or prodrugs thereof, and other chemical components, and other components, such as physiologically / pharmaceutical carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and to exert a biological activity by contributing to the absorption of the active ingredient.

[0103] The present invention will be described in more detail and comprehensively below with reference to examples. However, the present invention is not limited to the examples, and the present invention is not limited to the contents of the examples. The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (HNMR) and / or liquid phase mass spectrometry (LC-MS). NMR chemical shifts are in parts per million (ppm). The NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with the solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0104] Liquid phase mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid phase chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high pressure liquid phase chromatograph (Gimini C18 150 × 4.6 mm column).

[0105] The silica gel plates used for thin-layer chromatography are Yantai Yellow Sea HSGF254 or Qingdao GF254. The specifications used for TLC are 0.15 mm to 0.20 mm, and the specifications used for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm. Column chromatography is usually performed with Yantai Yellow Sea silica gel 200 ~300 mesh silica gel was used as the support.

[0106] The starting materials in the examples of the present invention are either known commercially or can be synthesized by methods known in the art. Unless otherwise stated, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius (° C.).

[0107] 1. Manufacturing of intermediates Intermediate 1 (R)-1-(3-(perfluoro-λ 6 Preparation of (-sulfanyl)phenyl)ethan-1-amine

[0108] [ka]

[0109] Step 1: (3-(1-ethoxyvinyl)phenyl)perfluoro-λ 6 -Synthesis of sulfane

[0110] [ka]

[0111] (3-Bromophenyl)perfluoro-λ 6 Dissolve 1.0 g (3.53 mmol) of 1-sulfane in N,N-dimethylformamide (20 mL), add tributyl(1-ethoxyvinyl)tin (1.4 g, 3.89 mmol) and bis(triphenylphosphine)palladium dichloride (248 mg, 0.353 mmol), heat to 80°C, and stir for 18 hours. After the reaction, use directly in the next step.

[0112] Step 2: 1-(3-(perfluoro-λ 6 Synthesis of (sulfanyl)phenyl)ethan-1-one

[0113] [ka]

[0114] Add dioxane hydrochloride solution (4N, 2 mL) dropwise to the above reaction solution and stir at 0°C for 2 hours. After the reaction, quench the reaction solution with saturated sodium bicarbonate solution and extract twice with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: ethyl acetate / petroleum ether = 0-10%]. 6 -sulfanyl)phenyl)ethan-1-one (670 mg, 77% yield) was obtained.

[0115] Step 3: (R,Z)-2-Methyl-N-(1-(3-(perfluoro-λ 6 Synthesis of (Sulfanyl)phenyl)ethylene)propane-2-sulfenamide

[0116] [ka]

[0117] 1-(3-(perfluoro-λ 6 -sulfanyl)phenyl)ethan-1-one (670 mg, 2.72 mmol), (R)-(+)-Tert-butylsulfinamide (396 mg, 3.27 mmol), and tetraethyl titanate (3.76 g, 5.44 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 70 °C, and stirred for 2 h. After the reaction, the reaction solution was diluted with ethyl acetate (150 mL), quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: ethyl acetate / petroleum ether = 0-30%]. (R,Z)-2-methyl-N-(1-(3-(perfluoro-λ)-2-methyl-1,2-dihydro-2,4-dihydro-1,2 ... 6 -sulfanyl)phenyl)ethylene)propane-2-sulfenamide (789 mg, 83% yield). MS m / z (ESI): 350 [M+H] + .

[0118] Step 4: (R)-2-Methyl-N-((R)-1-(3-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethyl)propane-2-sulfenamide

[0119] [ka]

[0120] (R,Z)-2-Methyl-N-(1-(3-(perfluoro-λ 6 Dissolve 400 mg (1.15 mmol) of 1-sulfanylphenylethylenepropane-2-sulfenamide in 10 mL of tetrahydrofuran (20% water) and add 10 mL of 10 mL of 1-methyl-2-propanediol. o Cool to 30°C, add sodium borohydride (130 mg, 3.44 mmol), and stir for 1 hour while keeping warm, then stir at room temperature for another 1 hour. After the reaction, the reaction solution is diluted with dichloromethane, insoluble matter is filtered, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: ethyl acetate / petroleum ether = 0~80%]. (R,Z)-2-methyl-N-((R)-1-(3-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)propane-2-sulfenamide (300 mg, 74% yield). MS m / z (ESI): 352 [M+H] + .

[0121] Step 5: (R)-1-(3-(perfluoro-λ 6 -Sulfanyl)phenyl)ethane Synthesis of 1-amine hydrochloride

[0122] [ka]

[0123] (R,Z)-2-Methyl-N-((R)-1-(3-(perfluoro-λ 6 -Sulfanyl)phenyl)ethyl)propane-2-sulfenamide (300 mg, 0.85 (R)-1-(3-(perfluoro-λ)-2-(2-(1,2-difluorophenyl)- ... 6The hydrochloride salt of (-sulfanyl)phenyl)ethan-1-amine (270 mg) was obtained and used directly in the next reaction. MS m / z (ESI): 248 [M+H] + .

[0124] The preparation of intermediates 2-4 is based on intermediate 1.

[0125] [Table 1]

[0126] Intermediate 5 (S)-1-(2-fluoro-4-(perfluoro-λ 6 Preparation of (-sulfanyl)phenyl)ethan-1-amine

[0127] [ka]

[0128] Step 1: 2-Fluoro-N-methoxy-N-methyl-4-(perfluoro-lambda 6 Synthesis of (sulfanyl)benzamide

[0129] [ka]

[0130] 2-Fluoro-4-(perfluoro-16-sulfanyl)benzoic acid (2 g, 7.6 mmol) was dissolved in N-methylpyrrolidone (10 mL) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethylaldehyde hexafluorophosphate (4.32 g, 11.3 mmol), methoxymethylamine hydrochloride were added. (1.08 g, 11.3 mmol) and triethylamine (1.53 g, 15.2 mmol) are added and stirred at room temperature for 16 hours. After the reaction, the mixture is quenched with water and extracted twice with ethyl acetate. The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (30%)]. 2-Fluoro-N-methoxy-N-methyl-4-(perfluoro-λ 6 -sulfanyl)benzamide (1.8 g, 76% yield). MS m / z (ESI): 309.8 [M+H] + .

[0131] Step 2: 1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (sulfanyl)phenyl)ethan-1-one

[0132] [ka]

[0133] 2-Fluoro-N-methoxy-N-methyl-4-(perfluoro-lambda 6 -sulfanyl)benzamide (1.8 g, 5.8 mmol) was dissolved in tetrahydrofuran (40 mL), methylmagnesium bromide solution (12 mL, 12 mmol) was added in an ice bath, and the mixture was stirred for 1 hour. After the reaction, the mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the reaction solution was concentrated to dryness and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (5%)]. 1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethan-1-one (1.2 g, 78% yield) was obtained.

[0134] Step 3: (S,E)-N-(1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide

[0135] [ka]

[0136] 1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethan-1-one (700 mg, 2.65 mmol), (S)-2-methylpropane-2-sulfenamide (417 mg, 3.44 mmol), and tetraethyl titanate (2 mL) were dissolved in tetrahydrofuran (30 mL), heated to 50°C, and stirred for 5 hours. After the reaction, the reaction solution was quenched with saturated sodium carbonate solution, filtered, and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (30%)]. (S,E)-N-(1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide (700 mg, 72% yield). MS m / z (ESI): 367 [M+H] + .

[0137] Step 4: (S)-N-((S)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide

[0138] [ka]

[0139] (S,E)-N-(1-(2-fluoro-4-(perfluoro-λ 6 -Sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide (700 mg, Dissolve (1.91 mmol) in tetrahydrofuran (20 mL), cool to -50°C, add sodium borohydride (195 mg, 5.73 mmol), and stir for 30 minutes while keeping warm. After the reaction, quench the reaction solution with saturated saline, extract twice with ethyl acetate, combine the organic phases, wash with saturated saline, dry over anhydrous sodium sulfate, concentrate to dryness, and separate by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (60%)]. (S)-N-((S)-1-(2-fluoro-4-(perfluoro-λ6-sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (700 mg, 99% yield) is obtained. MS m / z (ESI): 370 [M+H] + .

[0140] Step 5: (S)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethan-1-amine

[0141] [ka]

[0142] (S)-N-((S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (700 mg, 1.89 mmol) in dioxane hydrochloride solution (2N, 30 mL) and stir at room temperature for 4 hours. After the reaction, the reaction solution is concentrated to dryness and (S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethan-1-amine (600 mg, 95% yield). MS m / z (ESI): 266 [M+H] + .

[0143] Intermediate 6 (R)-1-(2-fluoro-4-(perfluoro-λ 6 Preparation of (-sulfanyl)phenyl)ethan-1-amine

[0144] [ka]

[0145] Step 1: (R,E)-N-(1-(2-fluoro-4-(perfluoro-λ) 6 Synthesis of (-sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide

[0146] [ka]

[0147] 1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethan-1-one (500 mg, 1.89 mmol), (R)-2-methylpropane-2-sulfenamide (291 mg, 2.46 mmol), and tetraethyl titanate (2 mL) were dissolved in tetrahydrofuran (30 mL), heated to 50°C, and stirred for 5 hours. After the reaction, the reaction solution was quenched with saturated sodium carbonate solution, filtered, and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (30%)]. (R,E)-N-(1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide (450 mg, 65% yield). MS m / z (ESI): 368 [M+H] + .

[0148] Step 2: (R)-N-((R)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide

[0149] [ka]

[0150] (R,E)-N-(1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide (450 mg, (R)-N-((R)-1-(2-fluoro-4-(perfluoro-λ)-2-methyl-1,3-dihydro-1,4-dihydro-1,5-trifluoro-1,6-dihydro-1,7-trifluoro-1,8-trifluoro-1,9-trifluoro-1,9-trifluoro-1,1-dihydro-1,3-dihydro-1,5 ...3-dihydro-1,5-trifluoro-1,9-trifluoro-1,1-dihydro-1,3-dihydro-1,3-dihydro-1,5-trifluoro-1,9-trifluoro-1,1-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3- 6 -sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (380 mg, 84% yield). MS m / z (ESI): 370 [M+H] + .

[0151] Step 3: (R)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethan-1-amine

[0152] [ka]

[0153] (R)-N-((R)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (380 mg, 1.03 mmol) in dioxane hydrochloride solution (2N, 30 mL) and stir at room temperature for 4 hours. After the reaction, the reaction solution is concentrated to dryness and (R)-1-(2-fluoro-4-(perfluoro-λ 6-sulfanyl)phenyl)ethan-1-amine (300 mg, 96% yield). MS m / z (ESI): 266 [M+H] + .

[0154] Intermediate 7 (2-(perfluoro-λ 6 Preparation of (-sulfanyl)phenyl)methylamine hydrochloride

[0155] [ka]

[0156] Step 1: (2-(perfluoro-λ 6 Synthesis of (sulfanyl)phenyl)hydrazine hydrochloride

[0157] [ka]

[0158] Perfluoro(2-fluorophenyl)-λ 6 Dissolve 2-sulfane (3.0 g, 13.5 mmol) in dimethyl sulfoxide (15 mL), add hydrazine hydrate (30 mL), seal the tube, and react at 100 °C for 20 hours. Cool the reaction solution to room temperature, add 1N sodium hydroxide aqueous solution (150 mL) and saturated water (150 mL), extract with methyl tert-butyl ether (2 * 100 mL), wash with saturated saline (3 * 100 mL), dry with anhydrous sodium sulfate, and filter. Add dioxane hydrochloride solution (4 N, 5 mL, 20 mmol) to the filtrate, stir at room temperature for 20 minutes, and concentrate to dryness to obtain (2-(perfluoro-λ)-2-(4- ... 6 -sulfanyl)phenyl)hydrazine hydrochloride (3.5 g, 96% yield). MS m / z (ESI): 235 [M+H] + .

[0159] Step 2: 2-(perfluoro-λ 6 Synthesis of (sulfanyl)aniline hydrochloride

[0160] [ka]

[0161] (2-(perfluoro-λ 6 Dissolve 2-(perfluoro-λ-sulfanyl)phenyl)hydrazine hydrochloride in methanol (50 mL), add Raney nickel, and stir the reaction mixture overnight at room temperature under hydrogen gas atmosphere. Filter, wash the filter cake with methanol (20 mL), add dioxane hydrochloride solution (4 N, 5 mL, 20 mmol) to the filtrate, stir at room temperature for 20 minutes, and concentrate to dryness to obtain 2-(perfluoro-λ-sulfanyl)phenylhydrazine hydrochloride. 6 -sulfanyl)aniline hydrochloride (3.7 g crude) was obtained and used directly in the next reaction. MS m / z (ESI): 220 [M+H] + .

[0162] Step 3: Perfluoro(2-iodophenyl)-λ 6 -Synthesis of sulfane

[0163] [ka]

[0164] 2-(perfluoro-λ 6 Dissolve 1-sulfanyl)aniline hydrochloride (3.7 g crude) in tetrafluoroborate solution (30 mL) and warm until completely dissolved. Cool the reaction solution to 0°C (ice bath), add sodium nitrite solution (2.0 g, 29 mmol, 10 mL water) dropwise while stirring in the ice bath, and after addition, stir in the ice bath for 30 minutes. Slowly add potassium iodide solution (7.2 g, 43.4 mmol, 15 mL water), remove the ice bath after addition, and react at room temperature with stirring for 30 minutes. Extract the reaction solution with ethyl acetate (2 * 100 mL), and add saturated sodium bicarbonate solution and sodium thiosulfate solution (2 *100 mL). Concentrate the organic phase and separate the residue by column chromatography [eluent: petroleum ether / ethyl acetate = 0-5%]. Perfluoro(2-iodophenyl)-λ6 -sulfane (3.3 g, 77% yield for two steps) was obtained.

[0165] 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).

[0166] Step 4: 2-(perfluoro-λ 6 Synthesis of (sulfanyl)benzonitrile

[0167] [ka]

[0168] Perfluoro(2-iodophenyl)-λ 6 A mixture of sulfane (1.85 g, 5.6 mmol) and copper cyanide (2.0 g, 22.4 mmol) in N-methylpyrrolidone (12 mL) was heated at 100 The mixture was reacted at ℃ for 2.5 hours. Ethyl acetate (100mL), concentrated ammonia (15mL), and water (100mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and separated. The organic layer was washed with saturated saline (100 mL), concentrated, and the residue was separated by column chromatography [eluent: petroleum ether / ethyl acetate = 0-10%]. 2-(perfluoro-λ 6 -sulfanyl)benzonitrile (0.94 g, 73% yield).

[0169] 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (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).

[0170] Step 5: (2-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)methylamine hydrochloride

[0171] [ka]

[0172] 2-(perfluoro-λ 6 -sulfanyl)benzonitrile (1.88 g, 8.2 mmol) was dissolved in tetrahydrofuran (5 mL), borane tetrahydrofuran complex solution (1 N, 50 mL, 50 mmol) was added, and the reaction mixture was refluxed for 20 hours. An additional borane tetrahydrofuran complex solution (1 N, 50 mL, 50 mmol) was added, and the reaction 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 reaction mixture was refluxed for another hour, concentrated, and rotary evaporated. The residue was added to n-pentane (50 mL), stirred at room temperature for 30 minutes, suction filtered, and the filter cake was washed with n-pentane (20 mL), dried, and purified to give (2-(perfluoro-λ 6 -sulfanyl)phenyl)methylamine hydrochloride (2.22 g) was obtained and used directly in the next reaction. MS m / z (ESI): 234 [M+H] + .

[0173] Intermediate 8 Preparation of (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0174] [ka]

[0175] Step 1: Synthesis of (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide

[0176] [ka]

[0177] Dissolve 5-fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) in anhydrous tetrahydrofuran (100 mL), add (R)-2-methylpropane-2-sulfenamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol), and heat the reaction solution to reflux in a chlorine gas atmosphere for 24 h. After the reaction, cool to 0 °C, add sodium borohydride (5.04 g, 133.2 mmol) in batches, and react at 0 °C for 3 hours. After the intermediate has completely reacted, dropwise add saturated saline to quench the reaction. Filter the reaction system. The filtrate was concentrated and the crude product was separated by silica gel column chromatography [eluent: petroleum ether / ethyl acetate=70 / 30] to obtain (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (2.4 g, yield: 28%). MS m / z (ESI): 256 [M+H] + .

[0178] Step 2: Synthesis of (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0179] [ka]

[0180] (R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (2.4 g, 9.40 mmol) was dissolved in methanol (10 mL), and a solution of hydrochloric acid in methanol (4 M, 10 mL) was added while stirring, and the mixture was stirred at room temperature for another hour. After concentrating the reaction system, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was separated and lyophilized to obtain (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (1.6 g, yield: 91%). MS m / z (ESI): 135 [M+H-NH3] + .

[0181] The preparation of intermediates 9-12 is based on the preparation of intermediate 8.

[0182] [Table 2]

[0183] Intermediate 13 (S)-5-Fluoro-2,3-dihydro-1H-inden-1-amine Manufacturing

[0184] [ka]

[0185] Step 1: Synthesis of (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide

[0186] [ka]

[0187] Dissolve 5-fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) in anhydrous tetrahydrofuran (100 mL), add (S)-2-methylpropane-2-sulfenamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol), and heat the reaction mixture to reflux under chlorine gas for 24 h. After the reaction, cool to 0 °C, add sodium borohydride (5.04 g, 133.2 mmol) in batches, and react at 0 °C for 3 h. After the intermediate is completely reacted, dropwise add saturated saline to quench the reaction. After filtering the reaction system, concentrate the filtrate, and separate the crude product by silica gel column chromatography [eluent: petroleum ether / ethyl acetate (70 / 30)]. (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (2.4 g, yield: 28%) is obtained. MS m / z (ESI): 256 [M+H] +。

[0188] Step 2: Synthesis of (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine

[0189] [ka]

[0190] Dissolve (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (2.4 g, 9.40 mmol) in methanol (10 mL), add hydrochloric acid in methanol (4 M, 10 mL) while stirring, and stir at room temperature for another hour. After concentrating the reaction system, add water (10 mL) and acetic acid. Ethyl acetate (10 mL) is added, the aqueous phase is 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] + .

[0191] For the preparation of intermediates 14-17, refer to intermediate 13.

[0192] [Table 3]

[0193] Preparation of Intermediate 18 (R)-N-Methyl-2,3-dihydro-1H-inden-1-amine

[0194] [ka]

[0195] Step 1: Synthesis of (R)-N-Boc-2,3-dihydro-1H-inden-1-amine

[0196] [ka]

[0197] (R)-2,3-Dihydro-1H-inden-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 Add 10 mmol) and stir at room temperature overnight. After the reaction, concentrate the reaction mixture and separate the crude product by column chromatography [eluent: ethyl acetate / petroleum ether (5 / 95)] to obtain (R)-N-Boc-2,3-dihydro-1H-inden-1-amine (1.38 g, 100% yield).

[0198] Step 2: Synthesis of tert-butyl (R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate

[0199] [ka]

[0200] (R)-N-Boc-2,3-dihydro-1H-inden-1-amine (1.38 g, 5.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL), and sodium hydride (60%, 355 mg, 8.87 mmol) was added at 0°C. After stirring at 0°C for 30 minutes, iodomethane (2.52 g, 17.74 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for another 3 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with water, dried, concentrated, and the crude product was separated by column chromatography [eluent: ethyl acetate / petroleum ether (10 / 90)]. Tert-butyl (R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (1.3 g, 89% yield) was obtained.

[0201] Step 3: Synthesis of (R)-N-methyl-2,3-dihydro-1H-inden-1-amine

[0202] [ka]

[0203] Tert-butyl (R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (1.3 g, 5.26 mmol) was dissolved in acetonitrile (10 mL), concentrated hydrochloric acid (5 mL) was added, and the mixture was stirred at room temperature for 3 hours. Most of the acetonitrile was then removed under reduced pressure, and the aqueous phase was lyophilized to give (R)-N-methyl-2,3-dihydro-1H-inden-1-amine (950 mg, 98% yield). MS m / z (ESI): 148 [M+H] + .

[0204] The preparation of intermediate 19 is based on intermediate 18.

[0205] [Table 4]

[0206] Preparation of Intermediate 20 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine

[0207] [ka]

[0208] Step 1: Synthesis of (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-one

[0209] [ka]

[0210] Under nitrogen protection, add s-butyllithium (74.6 mL, 97 mmol) dropwise to a solution of potassium tert-butoxide (10.9 g, 97 mmol) in methyl tert-butyl ether (400 mL) at -70°C. After stirring at -70°C for 3 hours, add a solution of lithium bromide (16.82 g, 190 mmol) in tetrahydrofuran (100 mL). Raise the reaction temperature to -15°C and stir for 30 minutes. The temperature of the reaction mixture was further lowered to -70°C, and a solution of copper bromide dimethylsulfide complex (9.98 g, 48 mmol) in diisopropyl sulfide (70 mL) was added. After stirring for 10 minutes, a solution of (3aR,6aR)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-4-one (5 g, 32 mmol) in tetrahydrofuran (50 mL) was added, and the temperature of the reaction mixture was lowered to -30°C. o C and stir for 30 minutes. After the reaction, quench with a mixed solution (50 mL) of methanol and acetic acid (1:1), add a mixed solution of ammonium chloride and 3% aqueous ammonia (1:1), remove the aqueous layer, and extract the organic layer with ammonium chloride. The mixture is washed with a mixture of saturated hexane and 3% aqueous ammonia (1:1) and with saline, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (15%)] to obtain (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-one (6.8 g, 85% yield). 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-cyclopenta[d][1,3]dioxazol-4-ol

[0211] [ka]

[0212] Under nitrogen protection, s-butyllithium (22.8 mL, 56.9 mmol) was added to -70 o C: 2,4-dichloro-7-iodopyrrolo[2,1-f][1,2,4]triazine (13.7 g, 43.8 mmol) in tetrahydrofuran (300 mL). After stirring at -70°C for 2 hours, add (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-one (10.6 g, 43.8 mmol) in tetrahydrofuran (40 mL) and stir at -70°C for 1 hour. After the reaction, quench with saturated ammonium chloride solution, extract with ethyl acetate, concentrate the organic layer, and separate by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (15%)]. (3aR,6R,6aR)-6-(tert-butoxymethyl)-4-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-ol (12 g, 64% yield). MS m / z (ESI): 430 [M+H] + .

[0213] Step 3: Synthesis of 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine

[0214] [ka]

[0215] Burgess reagent (14.3 g, 56 mmol) was added to a solution of (3aR,6R,6aR)-6-(tert-butoxymethyl)-4-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-ol (12 g, 28 mmol) in tetrahydrofuran (200 mL), and the resulting mixture was cooled to 50° C. oThe mixture was heated to 30° C. and stirred for 4 hours. After the reaction, the mixture was concentrated to dryness and separated by column chromatography [petroleum ether to petroleum ether / ethyl acetate (15%)]. 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (7 g, 61% yield) was obtained. MS m / z (ESI): 412 [M+H] + .

[0216] 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-diyl diacetate

[0217] [ka]

[0218] Step 1: Synthesis of ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

[0219] [ka]

[0220] Dissolve (4-methoxybenzyl)hydrazine hydrochloride (100.0 g, 0.53 mol) in absolute ethanol (1.6 L) and add triethylamine (81.0 g, 0.80 mol). Stir the reaction mixture at room temperature for 30 minutes, add ethyl (ethoxymethylene)cyanoacetate (98.0 g, 0.58 mol). Stir the reaction mixture at reflux overnight and concentrate to remove ethanol. Add water (500 mL) to the solid residue, extract with ethyl acetate (2*500 mL), combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, suction filter, and concentrate the filtrate to give ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (135.0 g, 92% yield). MS m / z (ESI): 276 [M+H] + .

[0221] Step 2: Ethyl 1-(4-methoxybenzyl)-4,6-oxo-4,5,6,7- Synthesis of ethyl tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0222] [ka]

[0223] Sodium ethoxide (84.0 g, 1.24 mmol) was dissolved in ethanol (600 Dissolve in 1 mL of ethyl 1-(4-methoxybenzyl)-4,5-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and cool to 0 °C (ice bath). Add diethyl malonate (198 g, 1.24 mol), remove ice bath, and stir at room temperature for 20 min. Add ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (85 g, 0.31 mol) and stir the reaction mixture at reflux for 4 days. Concentrate under reduced pressure to remove ethanol, add water (1.5 L) to the residue, neutralize with acetic acid to pH ~5, and filter the white solid with suction, wash with water (500 mL), and dry in vacuo to give ethyl 1-(4-methoxybenzyl)-4,6-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (100.8 g, 95% yield). MS m / z (ESI): 344 [M+H] + .

[0224] Step 3: Synthesis of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol

[0225] [ka]

[0226] Ethyl 1-(4-methoxybenzyl)-4,6-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (100.8 g, 0.29 mol) was dissolved in 25% aqueous NaOH (700 mL) and refluxed for 15 h. The reaction was cooled to 0°C, diluted with water (1 L), and slowly neutralized with acetic acid to pH ~5. The white solid was suction filtered, washed with water (1 L), and the filter cake was dried in vacuum to give 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (78.0 g, 98% yield). MS m / z (ESI): 272 [M+H] + .

[0227] Step 4: Synthesis of 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine

[0228] [ka]

[0229] 1-(4-Methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (30.0 g, 110 mmol) and phenylphosphonyl dichloride (62.7 mL, 442 mmol) are reacted at 170°C for 7 hours. The reaction is cooled to room temperature, diluted with dichloromethane (200 mL), the mixture is poured slowly into a vigorously stirred ice-water mixture, neutralized with concentrated ammonia water to pH ~7, extracted with dichloromethane (2*300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is separated by column chromatography [petroleum ether / ethyl acetate = 0~8%]. 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (18.3 g, yield 53%) is obtained. MS m / z (ESI): 308 / 310 [M+H] + .

[0230] Step 5: Synthesis of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine

[0231] [ka]

[0232] Dissolve 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (28.0 g, 90.9 mmol) in trifluoroacetic acid (84 mL), stir at 60°C and react for 17 hours. Concentrate the reaction, dilute the residue with ethyl acetate (500 mL), wash with saturated sodium bicarbonate solution (200 mL), dry the organic phase over anhydrous sodium sulfate and suction filter. Concentrate the filtrate and separate the residue by column chromatography [eluent: petroleum ether / ethyl acetate = 0~8%]. Obtain 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine (15.3 g, 90% yield). MS m / z (ESI): 188 / 190 [M+H] + .

[0233] 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-diyl diacetate

[0234] [ka]

[0235] Dissolve 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine (3.0 g, 16.0 mmol) in hexamethyldisilazane (30 mL), add ammonium sulfate (421 mg, 3.2 mmol), and stir at 150 °C for 3.5 hours to react. Remove hexamethyldisilazane by vacuum and rotary evaporation. Dissolve the residue in acetonitrile (60 mL) and add (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (5.59 g, 17.6 mmol). Cool the reaction solution to 0 °C (ice bath), add trimethylsilicone trifluoromethanesulfonate (4.33 mL, 24.0 mmol), slowly warm to room temperature after dropwise addition, and stir overnight. The reaction mixture is concentrated under reduced pressure, and the residue is added with ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution (150 mL), and separated. The aqueous phase is extracted with ethyl acetate (2*100 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and filtered under suction. The filtrate is concentrated, and the residue is separated by column chromatography [eluent: petroleum ether / ethyl acetate = 0~15%]. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate (4.98 g, 70% yield) is obtained. MS m / z (ESI): 446 / 448 [M+H] + .

[0236] 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-diyl diacetate

[0237] [ka]

[0238] 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-diyl diacetate

[0239] [ka]

[0240] Dissolve 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 13.2 mmol) in hexamethyldisilazane (15 mL), add catalytic amount of ammonium sulfate (20 mg, 0.15 mmol), heat to reflux (135 °C) and continue for 3 hours, centrifuge the reaction solution, add acetonitrile (30 mL) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (5.06 g, 15.9 mmol), cool to 0 °C, add trimethylsilyl trifluoromethanesulfonate (2.7 mL), warm to room temperature and stir for 24 hours. After the reaction, the mixture was quenched with saturated saline and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated, followed by 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-diyl diacetate (5.0 g, 84%). MS m / z (ESI): 447 [M+H] + .

[0241] II. Preparation of the Compounds of Specific Examples Example 1 (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0242] [ka]

[0243] Step 1: (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 Synthesis of -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate

[0244] [ka]

[0245] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate (200 mg, 0.55 mmol) and (R)-1-(4-(perfluoro-λ 6 Dissolve N,N-diisopropylethylamine (217 mg, 1.68 mmol) in tetrahydrofuran (5 mL), add N,N-diisopropylethylamine (217 mg, 1.68 mmol), heat to 60°C, and stir for 2 hours. After the reaction, concentrate to dryness and obtain ((2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate is obtained and used directly in the next step reaction. MS m / z (ESI): 658 [M+H] + .

[0246] Step 2: (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

[0247] [ka]

[0248] ((2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 Dissolve (0.30 g, 0.45 mmol) of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate in methanol (5 mL), add excess sodium methoxide solid, and react at room temperature for 3 hours. Then, add 1 / 1000 solution of formic acid (200 mL) to quench the reaction. After lyophilization, separate the product by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (0 to 100)]. (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (120 mg, 49% yield). MS m / z (ESI): 532 [M+H] + .

[0249] Step 3: (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 Synthesis of -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0250] [ka]

[0251] (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 Dissolve (60 mg, 0.12 mmol) of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol in trimethyl phosphate (2.5 mL), add dropwise a solution of methylenebis(phosphonic acid dichloride) (112 mg, 0.48 mmol) in trimethyl phosphate (0.5 mL) at 0°C, and react for 3 hours while keeping warm. Quench the reaction with a small amount of ice and separate by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (5:1)]. (((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid (30 mg, 18% yield). MS m / z (ESI): 690 [M+H] + .

[0252] 1H NMR (400 MHz, D2O) δ 8.14 (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 = 20.1 Hz, 2H), 1.73-1.30 (m, 3H). Compounds in Examples 2 to 4 are prepared according to the synthesis method in Example 1.

[0253] [Table 5]

[0254] The nuclear magnetic resonance data of the example compounds obtained by the above synthesis are as follows.

[0255] [Table 6]

[0256] Example 5 (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0257] [ka]

[0258] Step 1: (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6Synthesis of -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate

[0259] [ka]

[0260] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate (730 mg, 1.65 mmol) and (S)-1-(2-fluoro-4-(perfluoro-λ 6 Dissolve N,N-diisopropylethylamine (608 mg, 4.95 mmol) in N-methylpyrrolidone (15 mL), add N,N-diisopropylethylamine (608 mg, 4.95 mmol), heat to 90°C, and stir for 40 hours. After the reaction, dilute with water, extract with ethyl acetate, combine the organic phase, concentrate, and then separate by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (40%)]. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate (360 mg, 32% yield). MS m / z (ESI): 675 [M+H] + .

[0261] Step 2: (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

[0262] [ka]

[0263] (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 Dissolve (0.32 g, 0.48 mmol) of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate in methanol (20 mL), add potassium carbonate (0.19 g, 1.44 mmol), and react at room temperature for 1 hour. Then, add 1 / 1000 solution of formic acid (200 mL) to quench the reaction. After lyophilization, the product is separated by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (0 to 100)]. (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)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 ] + .

[0264] Step 3: (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 Synthesis of -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0265] [ka]

[0266] (2R,3R,4S,5R)-2-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 Dissolve (240 mg, 0.44 mmol) of (-sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol in trimethyl phosphate (3 mL), add dropwise a solution of methylenebis(phosphonic acid dichloride) (436 mg, 1.75 mmol) in trimethyl phosphate (0.5 mL) at 0°C, and react for 1 hour while keeping warm. Quench the reaction with a small amount of ice and separate by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (5:1)]. (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(perfluoro-λ 6 -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid (90 mg, 29% yield). MS m / z (ESI): 707 [M+H] + .

[0267] 1 H NMR (400 MHz, DMSO-d6+D2O) δ 8.38 (s, 1H), 7.96 (dd, J=10.4, 1.6 Hz, 1H), 7.76 (dd, J=8.4,1.6 Hz,1H), 7.62 (t, J=8.0 Hz, 1H), 6.08 (d, J=4.4 Hz, 1H), 6.03 (s, 1H), 5.15 - 5.13 (m, 1H), 4.53 (t, J=4.8 Hz, 1H), 4.26 (t, J=4.0 Hz, 1H), 4.04 - 4.02 (m, 2H), 3.86-3.83 (m, 1H), 2.12 (t, J= 20.0 Hz, 2H), 1.59 (d, J=6.8 Hz, 3H). The preparation of compounds in Examples 6 to 22 is carried out according to the synthesis method in Example 5.

[0268] [Table 7] TIFF0007627966000081.tif251170TIFF0007627966000082.tif252170

[0269] The nuclear magnetic resonance data of the example compounds obtained by the above synthesis are as follows.

[0270] [Table 8] TIFF0007627966000084.tif251169TIFF0007627966000085.tif251169TIFF0007627966000086.tif29169

[0271] Example 23 Preparation of ((((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)phosphorus)methyl)phosphonic acid

[0272] [ka]

[0273] 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

[0274] [ka]

[0275] (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) was dissolved in dioxane / water (8 mL / 2 The mixture was dissolved in 1 mL of ethyl acetate, and potassium carbonate (0.44 g, 3.18 mmol), tetrakis(triphenylphosphine)palladium (0.37 g, 0.32 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.40 g, 3.18 mmol) were added under nitrogen. After sealing, the mixture was reacted in a microwave at 130°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction solution, which was washed successively with water and saturated saline, dried over sodium sulfate, filtered, concentrated, and separated by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (0 to 100%). (2R,3R,4S,5R)-2-(4-(((R)-5,7-difluoro-2,3-dihydro-1H-indene -1-yl)amino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (255 mg, Yield: 53%). MS m / z (ESI): 433 [M+H] + .

[0276] Step 2: Synthesis of ((((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)phosphorus)methyl)phosphonic acid

[0277] [ka]

[0278] (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), and a solution of methylenebis(phosphonic acid dichloride) (515 mg, 2.06 mmol) in trimethyl phosphate (2.0 mL) was added at 0°C, and the mixture was reacted for 1 hour while keeping warm. The reaction was quenched with a small amount of ice, and the mixture was stirred while keeping warm for 10 minutes. The pH was adjusted to ≥8 with saturated sodium bicarbonate solution, and the mixture was stirred at room temperature for 5 hours. Then, the mixture was separated by reverse phase column chromatography [C 18 column, eluent: water to water / acetonitrile (5:1)]. (((((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)phosphorus)methyl)phosphonic acid (136.5 mg, 35% yield). MS m / z (ESI): 591 [M+H] + .

[0279] 1 H NMR (400 MHz, D2O) δ 8.15 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.83 (t, J=9.8 Hz, 1H), 6.48 (d, J=3.0 Hz, 1H), 6.39 (d, J=5.4 Hz, 1H), 5.51 (s, 1H), 4.93 (t, J=5.6 Hz, 1H), 4.62 (t, J=5.0 Hz, 1H), 4.33 (q, J=4.9 Hz, 1H), 4.07 (hept, J=5.4 Hz, 2H), 3.24 - 3.11 (m, 1H), 3.04 - 2.93 (m, 1H), 2.64 (dq, J=15.4, 8.1, 7.4 Hz, 1H), 2.53 (s, 3H), 2.25 - 2.15 (m, 1H), 2.05 (t, J=19.6 Hz, 2H). The compound of Example 24 is prepared according to the synthesis method of Example 23.

[0280] [Table 9]

[0281] The nuclear magnetic resonance data of the example compounds obtained by the above synthesis are as follows.

[0282] [Table 10]

[0283] Example 25 Preparation of ((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0284] [ka]

[0285] Step 1: 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2, Synthesis of 2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0286] [ka]

[0287] 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[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-inden-1-amine (326 mg, 2.42 mmol) were dissolved in 1,4-dioxane (20 mL), N,N-diisopropylethylamine (446 mg, 3.63 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined and concentrated, followed by separation by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (20%)]. 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (670 mg, 91% yield). MS m / z (ESI): 509 [M+H] + .

[0288] 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]triazin-7-yl)cyclopenten-3-ene-1,2-diol

[0289] [ka]

[0290] 7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxazol-6-yl)-2-chloro-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (670 mg, 1.31 mmol) is dissolved in 90% acetic acid (40 mL), heated to 60°C, and stirred for 16 hours. After the reaction, the mixture is concentrated and separated by column chromatography [eluent: dichloromethane to dichloromethane / methanol (10%)]. (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)cyclopenten-3-ene-1,2-diol (600 mg, 97% yield). MS m / z (ESI): 469 [M+H] + .

[0291] 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

[0292] [ka]

[0293] (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)cyclopenten-3-ene-1,2-diol (600 mg, 1.28 mmol) and Crabtree's catalyst (100 mg). Dissolve in dichloromethane (100 mL) and hydrogenate at room temperature and stir for 16 hours. After the reaction, concentrate and separate by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (50%)]. (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)cyclopentene-1,2-diol (500 mg, 83% yield) is obtained. MS m / z (ESI): 471 [M+H] + .

[0294] Step 4: Synthesis of (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

[0295] [ka]

[0296] (1S,2R,3R,5S)-3-(tert-butoxymethyl)-5-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2 Dissolve [1,2,4]triazin-7-yl)cyclopentene-1,2-diol (500 mg, 1.06 mmol) in acetonitrile (4 mL), add dioxane hydrochloride solution (4 mL, 1N), and react at room temperature for 1 hour. After concentration, separate the product by reverse phase column chromatography [C 18column, eluent: water to water / acetonitrile (0 to 50%)]. (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)cyclopentene-1,2-diol (200 mg, 46% yield). MS m / z (ESI): 415 [M+H] + .

[0297] Step 5: Synthesis of ((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid

[0298] [ka]

[0299] (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)cyclopentene-1,2-diol (200 mg, 0.48 mmol) in trimethyl phosphate (3 mL), and a solution of methylenebis(phosphonic acid dichloride) (481 mg, 1.93 mmol) in trimethyl phosphate (0.5 mL) was added at 0°C. The mixture was then incubated for 1 hour and quenched with a small amount of ice. The mixture was then separated by reverse phase column chromatography [C 18 Column, eluent: water to water / acetonitrile (5:1)]. (((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphorus)methyl)phosphonic acid (65 mg, yield 24%). MS m / z (ESI): 573 [M+H] + .

[0300] 1 H NMR (400 MHz, DMSO-d6+D2O) δ 7.31 - 7.17 (m, 4H), 6.99 (d, J=4.4 Hz, 1H), 6.54 (d, J=4.4 Hz, 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). The preparation of Examples 26-39 compounds is based on the synthesis method of Example 25.

[0301] [Table 11] TIFF0007627966000099.tif226170TIFF0007627966000100.tif173170

[0302] The nuclear magnetic resonance data of the example compounds obtained by the above synthesis are as follows.

[0303] [Table 12] TIFF0007627966000102.tif251169TIFF0007627966000103.tif236169

[0304] Biological measurements and evaluation 1. Evaluation of CD73 enzyme activity in vitro In the present invention, the inhibitory activity of compounds against CD73 is measured using malachite green of in vitro synthesized soluble CD73. The experimental procedure is as follows:

[0305] 1. The enzyme reaction in this experiment was performed in a 384-well plate, and 36ng / mL CD73 (R&D systems #5795-EN-010), different concentrations of compounds, and 50μM AMP were incubated in 40μL reaction system (25mM Tris pH 7.5, 5mM MgCl2, 0.005% Tween-20) at 25℃ for 30 minutes.

[0306] 2. The reaction is then stopped by adding 10 μL of malachite green solution (Sigma) to each well. 3. Measure the concentration of generated inorganic phosphate according to the instructions provided by the reagent manufacturer.

[0307] 4. Calculate the CD73 enzyme activity based on the concentration of the product, and then analyze the inhibition percentage of the compounds of the present invention at different concentrations by nonlinear regression to obtain the IC 50 The experimental results of the compounds described in the examples of the present invention are shown in Table 1.

[0308] 2. Evaluation of cell surface CD73 enzyme activity (Cell Titer Glo (CTG) experiment) The present invention evaluates the inhibitory effect of compounds on the activity of CD73 enzyme expressed on the cell surface in human breast cancer cells MDA-MB-231, which endogenously express CD73. The cells used are from the Cell Bank of the Chinese Academy of Sciences. The experimental process is as follows:

[0309] 1. Before measurement, 20,000 MDA-MB231 cells were seeded into a 96-well plate. 2. RPMI1640, 10% fetal bovine serum (Gibco, 10099-141) was placed in a 37°C, 5% CO2 culture box and cultured overnight (at the time of measurement, the cells were washed three times with serum-free RPMI medium).

[0310] 3. 50 μl of serum-free medium containing compounds diluted at different concentrations was added to the cells and incubated for 15 minutes. 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 with 25 μL of 100 μM ATP, then measure the AMP concentration of the sample by the CTG (Promega, #G7573) method.

[0311] 5. Next, the rate of decrease in the substrate AMP level in the cell culture supernatant after the reaction is quantitatively measured to evaluate the inhibitory effect of the compounds of the present invention and positive compounds on the cell surface CD73 enzyme activity.

[0312] 6. Finally, the half inhibitory concentration (IC) of the compound that caused maximum enzyme activity inhibition was calculated using four-parameter curve fitting in Graphpad Prism. 50 The experimental results of the compounds described in the examples of the present invention are shown in Table 1.

[0313] [Table 13]

[0314] The activity data of the compounds in the specific examples suggests that the compounds in the series of the present invention have strong inhibitory effects on CD73 enzymatic and cellular activities. All documents related to the present invention are incorporated herein by reference as if each document were incorporated individually. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. A compound of formula (IIIb), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Here, X １ is CH, Each R １ is hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C ３－６ selected from cycloalkyl groups and 3- to 6-membered heterocyclic groups; R ４ is hydrogen, deuterium, methyl group, ethyl group, propyl group, isopropyl group, C ２－４ Alkenyl group and C ３－６ cycloalkyl groups, R ５ is hydrogen, deuterium, fluorine, chlorine, cyano group, azide group, methyl group, ethyl group, propyl group, isopropyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group and C ３－６ cycloalkyl groups, R ７ is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl and hydroxyl; R ９ is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl and hydroxyl; R １０ , R １１ , R １２ are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; m is 0, 1, 2 or 3; The compound of formula (IIIb), its stereoisomer or a pharma- ceutically acceptable salt thereof.

2. The compound is selected from the following compounds:

2. A compound of formula (IIIb) according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 【change】

3. A process for preparing a compound of formula (IIIb) according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, comprising the steps of: The method includes the following steps: 【Chemistry 3】 where Pg is a hydroxy protecting group, an alkanoyl group or a silyl protecting group; １ , R １ , R ４ , R ５ , R ７ , R ９ , R １０ , R １１ , R １２ 2. A process for preparing a compound of formula (IIIb) as defined in claim 1, its stereoisomers or its pharma- ceutically acceptable salts, characterized in that: m is as defined in claim 1.

4. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising a compound of formula (IIIb) as defined in claim 1 or 2, its stereoisomer or a pharma- ceutically acceptable salt thereof and a pharmaceutical carrier.

5. Use of a compound of formula (IIIb) as defined in claim 1 or 2, its stereoisomer or a pharma- ceutically acceptable salt thereof, in the manufacture of a drug for the treatment of cancer or tumor, immune-related disease and disorder, or metabolic disease, at least in part mediated by CD73.

6. The cancer or tumor is selected from prostate cancer, colon cancer, rectal cancer, pancreatic adenocarcinoma, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma, and testicular seminoma.

6. The use according to claim 5.

7. The skin cancer is selected from melanoma and basal cell carcinoma, the white blood cell cancer is selected from lymphoma and leukemia; the lung cancer is selected from small cell lung cancer and non-small cell lung cancer; The sarcoma is characterized in that it is Kaposi's sarcoma.

7. The use according to claim 6.

8. The cancer or tumor is selected from melanoma, colon cancer, pancreatic adenocarcinoma, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.

6. The use according to claim 5.

9. The immune-related disease and disorder is selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

6. The use according to claim 5.

10. A compound of formula (IIIb) as claimed in claim 1 or 2, its stereoisomer or a pharma- ceutically acceptable salt thereof, for use as a medicament for the treatment of cancer or tumor, autoimmune diseases and disorders, or metabolic diseases, at least in part mediated by CD73.

11. Prostate cancer, colon cancer, rectal cancer, pancreatic adenocarcinoma, stomach cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal gland cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma, rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, A compound of formula (IIIb) as claimed in claim 1 or 2, its stereoisomer or a pharma- ceutically acceptable salt thereof, for use as a medicament for the treatment of allergies, fibrosis, anemic fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis.

12. The skin cancer is selected from melanoma and basal cell carcinoma, the white blood cell cancer is selected from lymphoma and leukemia; the lung cancer is selected from small cell lung cancer and non-small cell lung cancer; The sarcoma is characterized in that it is Kaposi's sarcoma.

12. A compound of formula (IIIb) according to claim 11, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

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