RU2787428C1 - Cd73 inhibitor, its production method and its use - Google Patents

Abstract

FIELD: organic chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to the field of organic chemistry and pharmaceutics; it is aimed at compounds, which are CD73 inhibitors. A compound of the formula (IIb) or the formula (IIc), its stereoisomer, or a pharmaceutically acceptable salt are disclosed, where X₁ is CH in the formula (IIb); Y is O in the formula (IIb); where X₁ is N in the formula (IIc); Y is CH₂ in the formula (IIc); each R₁ is independently selected from hydrogen, halogen, C_1-4 alkyl, where C_1-4 alkyl is optionally substituted with one or more halogens; R₄ is hydrogen or C_1-4 alkyl; R₅ is hydrogen, halogen, or C_1-4 alkyl; R₆ and R₇, each independently, are selected from hydrogen or hydroxy; R₈ and R₉, each independently, are selected from hydrogen or hydroxy; R₁₀, R₁₁, and R₁₂ are hydrogen; q is independently selected from 0, 1, 2, or 3; and m is independently selected from 0, 1, or 2. In addition, a method for the production the above-mentioned compounds, a pharmaceutical composition for the treatment of diseases, which are at least partially mediated by CD73, including a compound of the formula (IIb) or the formula (IIc), and the use of the specified compounds for the production of drugs for diseases, which are at least partially mediated by CD73, are disclosed.

EFFECT: group of inventions provides effective treatment of diseases, which are at least partially mediated by CD73.

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20 cl, 1 tbl, 39 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to the field of pharmaceutical synthesis and, in particular, to a CD73 inhibitor, a process for its preparation and its use.

BACKGROUND OF THE INVENTION

CD73, also known as ecto-5'-nucleotidase (eNT), is a protein with a molecular weight of 70 kDa. It is expressed on endothelial cells and certain leukocytes under normal conditions. This protein, anchored to the cell membrane surface via a linked glycosyl phosphatidylinositol (GPI) anchor, plays an important role in the metabolic regulation of adenosine triphosphate (ATP) along with CD39, which is known as ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase), catalyzing the hydrolysis of ATP to form adenosine monophosphate (AMP) and adenosine diphosphate (ADP), while CD73 plays a major role in accelerating the conversion of extracellular monophosphates (eg 5'-AMP) to their corresponding nucleosides (eg adenosine).

Nucleosides produced by CD73, in particular adenosine, are considered endogenous modulators of a variety of physiological functions, including the cardiovascular system, central nervous system, respiratory system, kidney, fat cells, platelets, and the immune system. In the immune system, extracellular adenosine affects a variety of immune cells and is involved in mediating the anti-inflammatory response. In various tissues, adenosine can also contribute to fibrosis.

CD73 expression has been found in cells of many types of cancer, including leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer, and breast cancer. However, CD73 expression has also been found on the surface of immunosuppressive cells (including regulatory T cells (Treg) and myeloid suppressor cells (MDSC). High levels of CD73 expression have also been found to be associated with angiogenesis, invasiveness, resistance to chemotherapy, tumor metastases, as well as a shorter life expectancy for patients with various types of cancer, including breast cancer and melanoma.

Mechanism-based studies have shown that cancer cells can release large amounts of ATP under the influence of chemotherapy and other stresses, and ATP can be rapidly converted to adenosine and accumulated in the tumor microenvironment. Extracellular ATP released due to cell death or intracellular stress can induce an immune response, but adenosine, which is a metabolite of ATP, is an immunosuppressant. Most importantly, in tumors, adenosine, by activating adenosine receptors (such as A2A), is able to suppress the action of tumor-infiltrating effector T-lymphocytes, thereby promoting tumor progression. That is why the accumulation of extracellular adenosine in tumor tissues is an important mechanism for tumor escape from immunological surveillance.

Decreased expression of CD73 by RNA interference or by overexpression of CD73 in tumor cells can inhibit tumor growth and motility; CD73 knockout mice are less prone to graft rejection and spontaneous tumor formation; and deletion of A2A receptors can provoke T-cell tumor rejection. In a mouse model, treatment with an antibody that binds to mouse CD73 is able to slow tumor growth and metastasis of breast cancer.

Therefore, targeting CD73 represents a potential treatment strategy that could increase the efficacy of anticancer therapy and provide a novel therapeutic strategy aimed at inhibiting tumor progression. Moreover, CD73 targeting can be used to treat adenosine-mediated diseases such as enhanced immune response, immune response, and inflammatory responses; and can also be used to treat neurological disorders, neurodegenerative diseases, diseases of the central nervous system (CNS) such as depression, Parkinson's disease, sleep disturbance, fibrosis, and other immune-inflammatory diseases.

Thus, the development of potential CD73-targeting drugs will meet the needs of targeted therapy in the treatment of cancer and other related diseases, as well as provide greater safety and specificity.

DISCLOSURE OF THE INVENTION

As a result of comprehensive and in-depth research, the inventor of the present invention has developed a CD73 inhibitor with the structure shown in formula (I), a method for producing it, and its use. The compounds described in the present invention have a strong inhibitory effect on the enzymatic activity of CD73, can be widely used for the preparation of drugs for the treatment of tumors or malignancies, immune-dependent diseases and disorders, and metabolic diseases that are at least partially mediated by CD73, as well as in particular for the treatment of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma; and also demonstrate the prospects for the development of drugs with a new generation CD73 inhibitor. The present invention has been made on this basis.

The first aspect of the present invention relates to a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:

” представляет собой двойную связь или одинарную связь;where "

” represents a double bond or a single bond;

X ₁ is N or CR ₁₇ ;

X ₂ and X ₃ are each independently N or C;

X ₄ and X ₅ are each independently N or CR ₁₈ ;

Y represents CH ₂ , NH, O or S;

m is selected from 0, 1, 2 or 3 and n is selected from 0, 1, 2 or 3 such that m+n ≤5;

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl , C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -SF ₅ , -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 and -C _{0 -8} -N(R ₂₂ )-C(O)R ₂₁ , or when m≥2, two R ₁ together with a fragment directly attached to them, form a 4-10-membered cycloalkyl, 4-10-membered aryl, 4 -10 membered heterocyclyl or 4-10 membered heteroaryl, the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyla, C _2-10 alkenyl , C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered hete roarila, \u003d 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 and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O )R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -NR ₂₂ R ₂₃ , or R ₂ and R ₃ together with a carbon atom directly attached to them, form a 3-10-membered cycloalkyl or a 3-10-membered heterocyclyl, or one of R ₂ and R ₃ together with R ₁ and a group directly attached to them, forms a 4-10-membered cycloalkyl or 4-10 membered heterocyclyl and the other is selected from the group consisting of hydrogen, deuterium, halogen or C _1-10 alkyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano , nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuter oalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O) NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₄ is selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -C(=NR ₂₂ )R ₂₁ and -C _0-8 -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyla, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O )R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N (R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₅ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl , C _5-10 aryl, 5-10-membered heteroaryl, -SF ₅ , -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 and -C _0-8 -N( R ₂₂ )-C(O)R ₂₁ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyla, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _{0- 8} -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _{0- 8} -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₆ and R ₇ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C( O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _{0- 8} -NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S( O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O )R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₈ and R ₉ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C( O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _{0- 8} -NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S( O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O )R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl , C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ and -C _0-8 -C(O) NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-4 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , - C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C( O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _{0- 8} -NR ₂₂ R ₂₃ , or R ₁₃ and R ₁₄ together with the carbon atom directly attached to them, form a 3-10 membered cycloalkyl or 3-10 membered heterocyclyl the above groups are optionally substituted with one or more additional substituents selected from the group , consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O) NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₁₅ and R ₁₆ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C( O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C( =NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N (R ₂₂ )-C(O)R ₂₁ , or R ₁₅ and R ₁₆ together with the carbon atom directly attached to them, form a 3-10 membered cycloalkyl or 3-10 membered heterocyclyl, the above groups are optionally substituted by one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , - C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _{0- 8} -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

R ₁₇ and R ₁₈ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, -SF ₅ , -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 and -C _{0 -8} -N(R ₂₂ )-C(O)R ₂₁ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyla, C _{2 -10} alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O , -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R _{2 2} )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O)R ₂₁ ;

each R ₁₉ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl and-NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, C _1-10 alkyl, C _1-10 alkoxy, C _{3- 10} cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and - NR ₂₂ R ₂₃ ;

each R ₂₀ is independently selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, and 5-10 membered heteroaryl , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₂ R ₂₃ ;

each R ₂₁ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₂ R ₂₃ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10- membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₂ R ₂₃ ;

R ₂₂ and R ₂₃ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl, the above groups are optionally substituted with one or more additional substituents selected from the group , consisting of deuterium, halogen, hydroxy, C _1-8 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10-membered heterocyclyl, 3-10-membered heterocyclyloxy, C _{5- 10} aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl,

or R ₂₂ and R ₂₃ together with the nitrogen atom directly attached to them, form a 4-10 membered heterocyclyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10- membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl; and each r is independently selected from 0, 1, or 2.

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₁₅ and R ₁₆ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyla, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _{0- 4} -NR ₂₂ R ₂₃ , or R ₁₅ and R ₁₆ together with the carbon atom directly attached to them, form a 3-8 membered cycloalkyl or 3-8 membered heterocyclyl, the above groups are optionally substituted with one or more additional substituents selected from a group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8- membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _0-4 -NR ₂₂ R ₂₃ where R ₂₀ , R ₂₂ and R ₂₃ correspond to those in the compound of the formula (I).

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₁₅ and R ₁₆ is independently selected from the group consisting of hydrogen, deuterium, F, cyano, methyla, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino or dimethylamino, or R ₁₅ and R ₁₆ together with a carbon atom directly attached to them, form a 3-4 membered cycloalkyl or a 4-5 membered heterocyclyl.

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, each R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _{0- 4} -NR ₂₂ R ₂₃ , or R ₁₃ and R ₁₄ together with the carbon atom directly attached to them, form a 3-8 membered cycloalkyl or 3-8 membered heterocyclyl, the above groups are optionally substituted with one or more additional substituents selected from a group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8- membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _0-4 -NR ₂₂ R ₂₃ where R ₂₀ , R ₂₂ and R ₂₃ correspond to those in the compound of the formula (I).

In another preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₁₃ and R ₁₄ is independently selected from the group consisting of hydrogen, deuterium, F, cyano, methyla, 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 to them, form a 3-4 membered cycloalkyl or a 4-5 membered heterocyclyl.

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₁₇ and R ₁₈ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _{1- 4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -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 and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ , the above groups are optionally substituted with one or more additional substituents selected from a group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC(O)R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _{0 -4} -C(O)NR ₂₂ R ₂₃ and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ where R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₆ and R ₇ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyla, C _2-4 alkenyl, C _2-4 alkynyl, -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 and -C _0-4 -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC(O)R ₂₁ , - C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _{0- 4} -C(O)NR ₂₂ R ₂₃ and -C _{0 -4} -N(R ₂₂ )-C(O)R ₂₁ ;

R ₈ and R ₉ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -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 and -C _0-4 -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halo , cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC(O)R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-4 -C(O)NR ₂₂ R ₂₃ and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ where R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -C(O)OR ₂₀ , - C _0-4 -C(O)R ₂₁ and -C _0-4 -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro , azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC(O)R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ ) -C(=NR ₂₃ )R ₂₁ , -C _0-4 -C(O)NR ₂₂ R ₂₃ and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ where R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₂ and R ₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _0-4 -NR ₂₂ R ₂₃ , or R ₂ and R ₃ together with the carbon atom directly attached to them, form a 3-8 membered cycloalkyl or 3-8 membered heterocyclyl or one of R ₂ and R ₃ together with R ₁ and the group directly attached to them form a 4-10 membered cycloalkyl or a 4-10 membered heterocyclyl, and the other is selected from the group consisting of hydrogen, deuterium, F or C _1-4 alkyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalka la, C _3-8 cycloalkyl, 3-8-membered heterocyclyl, -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ and -C _0-4 -NR ₂₂ R ₂₃ where R ₁ , R ₂₀ , R ₂₂ and R ₂₃ correspond to those in the compound of formula (I);

In another preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, each R ₂ and R ₃ is independently selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, methylamino and dimethylamino, or R ₂ and R ₃ together with the carbon atom directly attached to them, form a 3-4-membered cycloalkyl or 4-5 membered heterocyclyl or one of R ₂ and R ₃ together with R ₁ and a group directly attached thereto form a 4-6 membered cycloalkyl or 4-6 membered heterocyclyl and the other is selected from the group consisting of from hydrogen, deuterium or methyl; where R ₁ corresponds to that in the compound of formula (I),

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R ₄ is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-8 cycloalkyl , 3-8-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -C(=NR ₂₂ )R ₂₁ and -C _0-4 -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3- 8} cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , - C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC(O)R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , - C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-4 -C(O)NR ₂₂ R ₂₃ and -C _0-4 -N(R ₂₂ )-C(O) R ₂₁ where R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and r correspond to those in the compound of formula (I).

In a preferred embodiment of the invention, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyla, C _{2- 4} alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -SF ₅ , -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 and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ , or at m≥2 two R ₁ together with the fragment directly attached to them form a 4-8 membered cycloalkyl, 5-8 membered aryl, 4-8 membered heterocyclyl or 5-8 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium , halo, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 - S(O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C(O)OR ₂₀ , -C _0-4 -C(O)R ₂₁ , -C _0-4 -OC (O)R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C(=NR ₂₂ )R ₂₁ , -C _0-4 -N(R ₂₂ )-C(=NR ₂₃ ) R ₂₁ , -C _0-4 -C(O)NR ₂₂ R ₂₃ and -C _0-4 -N(R ₂₂ )-C(O)R ₂₁ , where R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ and r correspond to those in the compound of formula (I).

In another preferred embodiment of the invention, in a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, the compound of formula (I) is a compound whose structure is described by formula (IIa), formula (IIb) or formula (IIc);

,

,

where each X ₁ is independently N or CH; each X ₄ is independently N or CH; each Y is independently CH ₂ or O;

each R ₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, -SF ₅ , -S(O) _r R ₁₉ , -OR ₂₀ , -C(O)OR ₂₀ , -C(O)R ₂₁ , -OC(O)R ₂₁ and -NR ₂₂ R ₂₃ , or when m≥2, the two R ₁ together with the moiety directly attached to them form a 5-6 membered cycloalkyl, 5-6 membered aryl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, the above groups are optionally substituted one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _{3 -6} cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, =O, -S(O) _r R ₁₉ , -OR ₂₀ , -C(O)OR ₂₀ , -C (O)R ₂₁ , -OC(O)R ₂₁ and -NR ₂₂ R ₂₃ ;

R ₂ is selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, hydroxymethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, methylamino, and dimethylamino;

each R ₄ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, or 5-6 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _{1 -4} deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, =O, -S(O) _r R ₁₉ , -OR ₂₀ , -C(O )OR ₂₀ , -C(O)R ₂₁ , -OC(O)R ₂₁ and -NR ₂₂ R ₂₃ ;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -SF ₅ , methylthio, methylsulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxyl, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxyl, amino, dimethylamino, -C(=NR ₂₂ )R ₂₁ , -N( R ₂₂ )-C(=NR ₂₃ )R ₂₁ , aminocarbonyl, dimethylaminocarbonyl and acetylamino, the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _{2- 4} alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, =O, methylthio, methylsulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxyl, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxy a, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl and acetylamino;

R ₆ and R ₇ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, hydroxy, methoxy and acetoxy, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy, and acetoxy ;

R ₈ and R ₉ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, cyclopropyl, hydroxy , methoxy or acetoxy, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy or acetoxy;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, -C(O)OR ₂₀ , -C(O)R ₂₁ and -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5 -6-membered heteroaryl, =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 and -N(R ₂₂ )-C(O)R ₂₁ ;

each R ₁₉ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 -membered heteroaryl and -NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, C _1-4 alkyla, C _1-4 alkoxy, C _{3- 6} cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-6 aryl, C _5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and - NR ₂₂ R ₂₃ ;

each R ₂₀ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, or 5-6 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halo, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _{3- 6} cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-6 aryl, C _5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and -NR ₂₂ R ₂₃ ;

each R ₂₁ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-6 aryl, C _5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and -NR ₂₂ R ₂₃ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6- membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-6 aryl, C _5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and -NR ₂₂ R ₂₃ ;

R ₂₂ and R ₂₃ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino and C _1-4 alkanoyl, the above groups are optionally substituted with one or more additional substituents selected from the group , consisting of deuterium, halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C _{5- 6} aryl, C _5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-4 alkanoyl,

or R ₂₂ and R ₂₃ together with the nitrogen atom directly attached to them, form a 4-6 membered heterocyclyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-6 aryl, C _5-6 aryloxy, 5-6- membered heteroaryl, 5-6 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-4 alkanoyl;

each q is independently selected from 0, 1, 2, or 3;

each m is independently selected from 0, 1, 2, or 3; and

each r is independently selected from 0, 1, or 2.

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, each R ₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, -SF ₅ , -S(O) _r R ₁₉ , -OR ₂₀ , -C(O)OR ₂₀ , -C(O)R ₂₁ , -OC(O)R ₂₁ and -NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -OR ₂₀ , -C(O)OR ₂₀ and -C(O)R ₂₁ ;

each R ₄ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, and 5-6 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3- 6-membered heterocyclyl, =O, -OR ₂₀ , -C(O)OR ₂₀ and -C(O)R ₂₁ ;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -SF ₅ , methylthio, methylsulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxyl, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, acetoxy, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl and acetylamino, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, methoxy , ethoxyl, isopropoxy, hydroxy, -C(O)OH, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl and acetoxy;

R ₆ and R ₇ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy and acetoxy, the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy and acetoxy;

R ₈ and R ₉ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxy, methoxy and acetoxy, the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, hydroxy, methoxy and acetoxy;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, -C(O)OR ₂₀ , -C(O)R ₂₁ and -C(O)NR ₂₂ R ₂₃ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -S(O) _r R ₁₉ , -OR ₂₀ , -C( O)OR ₂₀ , -C(O)R ₂₁ and -OC(O)R ₂₁ ;

each R ₁₉ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl and C _3-6 cycloalkyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

each R ₂₀ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl or C _3-6 cycloalkyl, the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O , cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

each R ₂₁ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl and C _1-4 alkoxy, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

R ₂₂ and R ₂₃ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, or C _1-4 alkanoyl, the above groups optionally substituted with one or several additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl and C _{1- 4} alkanoyl.

In another preferred embodiment of the invention, in a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, the compound of formula (I) is a compound whose structure is described by formula (IIIa1) or formula (IIIa2):

,

,

where each R ₁ is independently selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl ;

each R ₂ is independently selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, ethynyl, cyclopropyl, and hydroxymethyl;

each R ₄ is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _2-4 alkenyl and C _3-6 cycloalkyl;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl;

each R ₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, and hydroxy;

each R ₈ is independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, and hydroxy;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl and isopropyl; and

each m is independently selected from 0, 1, 2, or 3.

In another preferred embodiment of the invention, in a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, the compound of formula (I) is a compound whose structure is described by formula (IIIb):

where X ₁ represents N or CH;

where R ₁ is selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C _3-6 cycloalkyl and 3-6-membered heterocyclyl;

R ₄ is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _2-4 alkenyl and C _3-6 cycloalkyl;

R ₅ is selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl and hydroxy;

R ₉ is selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl and hydroxy;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl and isopropyl; and

m is selected from 0, 1, 2, or 3.

In another preferred embodiment of the invention, in a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, the compound of formula (I) is a compound whose structure is described by formula (IIIc):

where X ₁ represents N or CH;

R ₁ is selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, C _3-6 cycloalkyl, and 3-6 membered heterocyclyl;

R ₄ is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _2-4 alkenyl and C _3-6 cycloalkyl;

R ₅ is selected from the group consisting of hydrogen, deuterium, F, Cl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl;

R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl and hydroxy;

R ₈ is selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl and hydroxy;

R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl and isopropyl; and

m is selected from 0, 1, 2, or 3.

In the most preferred embodiment of the invention, the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt includes, among other things, the following compounds:

.

.

The second aspect of the present invention is a process for the preparation of a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, comprising the following steps:

where Pg is a protecting group for a hydroxyl group, preferably selected from the group consisting of an alkanoyl or silicon protecting group; X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , m and n correspond to those in the compound of formula (I).

The third aspect of the present invention is a pharmaceutical composition containing a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

The fourth aspect of the present invention is the use of the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt for the preparation of medicaments for the treatment of malignant neoplasms or tumors, immune-dependent diseases and disorders, and metabolic diseases that are at least partially mediated by CD73.

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

In another preferred embodiment, the malignancies or tumors are selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma. .

In a preferred embodiment of the invention, immune-dependent diseases and disorders are selected from the group including rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, chronic heart failure, stroke, aortic stenosis, atherosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and allergic contact eczema, systemic scleroderma and multiple sclerosis.

The fifth aspect of the present invention is the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, useful as a drug for the treatment of malignancies or tumors, autoimmune diseases and disorders, and metabolic diseases, which are at least partially mediated by CD73 .

The sixth aspect of the present invention is the above compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, used as a drug for the treatment of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cancer cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head and neck cancer, skin cancer (including melanoma and basalioma), mesothelial cancer, blood cancer (including lymphoma and leukemia), esophageal cancer, cancer breast, muscle tumors, connective tissue tumors, lung cancer (including small cell lung cancer and non-small cell lung cancer), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcomas (including Kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, seminoma, rheumatoid arthritis, renal failure pregnancy, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, chronic heart failure, stroke, aortic stenosis, atherosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and allergic contact eczema, systemic scleroderma and multiple sclerosis.

DETAILED DESCRIPTION OF THE INVENTION

Detailed description: Unless otherwise indicated, the following terms used in the description and claims have the following meanings.

"Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, for example "C _1-10 alkyl" refers to straight alkyl or branched alkyl containing 1 to 10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3- dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethyl pentyl or its various branched isomers, etc. "C _0-8 " means C _0-8 alkyl, "C _0-4 " means C _0-4 alkyl, C ₀ means 0 carbon atoms, "C _1-4 " means C _1-4 alkyl, alkyl is as defined above .

The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, for example "C _3-10 cycloalkyl" refers to cycloalkyl containing from 3 to 10 carbon atoms, which may be monocyclic cycloalkyl and polycyclic cycloalkyl, where

monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like;

and polycyclic cycloalkyl includes spirocyclic, fused and bridged cycloalkanes. "Spirocycloalkyl" refers to a polycyclic group in which a carbon atom (referred to as a spiro atom) is shared between monocyclic rings. These groups may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π electron system. Spirocycloalkyl can be monospirocycloalkyl, bispyrocycloalkyl, or polyspirocycloalkyl according to the number of spiroatoms common to the rings, spirocycloalkyl includes but is not limited to:

.

.

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring has a pair of adjacent carbon atoms with other rings in the system, where one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but neither one of them does not have a fully conjugated π-electron system. Depending on the number of rings, it can be bicyclic, tricyclic, tetracyclic or polycyclic, fused cycloalkyl includes but is not limited to:

.

.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings have two carbon atoms that are not directly bonded, they may contain one or more (preferably 1, 2, or 3) double bonds, but neither ring has fully conjugated π-electron system. Depending on the number of rings it can be bicyclic, tricyclic, tetracyclic or polycyclic, bridged cycloalkyl includes but is not limited to: Depending on the number of rings it can be bicyclic, tricyclic, tetracyclic or polycyclic, fused cycloalkyl includes but is not limited to:

.

.

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where one or more (preferably 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _r (where r is the integer 0, 1, 2) excluding the -OO-, -OS- or -SS- ring portions, and the remaining ring atoms are carbon atoms. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclyl" means a cyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

and polycyclic heterocyclyl includes spirocyclic, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclyl group in which an atom (referred to as a spiro atom) is shared by monocyclic rings, where one or more (preferably 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, or S( O) _r (where r is the integer 0, 1, 2) and the rest of the ring atoms are carbon atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclyl can be monospiroheterocyclyl, bispyroheterocyclyl, or polyspiroheterocyclyl according to the number of spiroatoms common to the rings, spiroheterocyclyl includes but is not limited to:

.

.

"Fused heterocyclyl" refers to a polycyclic heterocyclyl in which each ring shares a pair of adjacent atoms with other rings in the system, wherein one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system in which one or more (preferably 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _r (where r is the integer 0, 1, 2) and the remaining ring atoms are carbon atoms. Depending on the number of rings, it can be bicyclic, tricyclic, tetracyclic or polycyclic, fused heterocyclyl includes but is not limited to:

.

.

"Bridged heterocyclyl" refers to a polycyclic heterocyclyl in which any two rings have two carbon atoms that are not directly bonded to each other, may contain one or more (preferably 1, 2 or 3) double bonds, but none of them have fully conjugated π-electron system, where one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _r (where r is the integer 0, 1, 2 ), and the rest of the ring atoms are carbon atoms. Depending on the number of rings, it can be bicyclic, tricyclic, tetracyclic or polycyclic, bridged heterocyclyl includes but is not limited to:

.

.

The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl, including but not limited to:

.

.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that has a pair of adjacent carbon atoms) group, and a polycyclic group having a conjugated π electron system (i.e., a ring with adjacent pairs of carbon atoms), for example, "C _5-10 aryl" means all-carbon aryl of 5 to 10 carbon atoms, and "5-10 membered aryl" means all-carbon aryl of 5 to 10 carbon atoms, including but not limited to phenyl and naphthyl The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, including but not limited to:

.

.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0- 8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O) _R21 .

"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including a heteroatom selected from nitrogen, oxygen, or S(O)r (where r is the integer 0, 1, 2 ), for example 5-8 membered heteroaryl means a heteroaromatic system containing from 5 to 8 ring atoms, and 5-10 membered heteroaryl means a heteroaromatic system containing from 5 to 10 ring atoms, including, but not limited to, furyl, thiophenyl, pyridyl , pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl group and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, including but not limited to:

.

.

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, _{C2-10 alkenyl} , _{C2-10 alkynyl} , _C1-10 haloalkyl, C1-10 deuteroalkyl, C3-10 cycloalkyl, _3-10 membered heterocyclyl, C5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0- 8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O) _R21 .

"Alkenyl" refers to an alkyl group as defined above containing at least two carbon atoms and at least one carbon-carbon double bond, for example "C _2-10 "means a straight or branched alkenyl containing from 2 to 10 carbon atoms. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

The alkenyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Alkynyl" refers to an alkyl group as defined above containing at least two carbon atoms and at least one carbon-carbon triple bond, for example "C _2-10 alkynyl" means a straight or branched alkynyl having 2 to 10 carbon atoms. Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

The alkynyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Alkoxy" refers to -O-(alkyl) where alkyl is as defined above, eg "C _1-10 alkoxy" means alkyloxy containing from 1 to 10 carbon atoms. Alkoxy includes but is not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"Cycloalkyloxy" refers to -O-(unsubstituted cycloalkyl) where cycloalkyl is as defined above, eg "C3-10 cycloalkyloxy" means cycloalkyloxy having 3 to 10 carbon atoms. Cycloalkyloxy includes, but is not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _{0 -8} -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , - C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )-C(O )R ₂₁ .

"3-10 membered heterocyclyloxy" refers to -O-(unsubstituted 3-10 membered heterocyclyl), where 3-10 membered heterocyclyl is as defined above; The 3-10 membered heterocyclyloxy may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ ) R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ ) -C(O)R ₂₁ .

"C _5-10 aryloxy" refers to -O-(unsubstituted C _5-10 aryl), where C _5-10 aryl is as defined above; C _5-10 aryloxy may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano , nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _{5 -10} aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ )R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ )- C(O)R ₂₁ .

"5-10 membered heteroaryloxy" refers to -O-(unsubstituted 5-10 membered heteroaryl), where 5-10 membered heteroaryl is as defined above; The 5-10 membered heteroaryloxy may be optionally substituted or unsubstituted, and when substituted, the substituent may preferably be one or more of the following groups (preferably 1, 2, 3 or 4) independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C(O)OR ₂₀ , -C _0-8 -C(O)R ₂₁ , -C _0-8 -OC(O)R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C(=NR ₂₂ ) R ₂₁ , -C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ , -C _0-8 -C(O)NR ₂₂ R ₂₃ and -C _0-8 -N(R ₂₂ ) -C(O)R ₂₁ .

"C _1-8 alkanoyl" refers to a monovalent atomic group that results from removal of the hydroxyl from a C _1-8 alkyl acid, and is also commonly referred to as "C _0-7 -C(O)-", e.g. "C ₁ -C (O)-" refers to acetyl; "C ₂ -C(O)-" refers to propionyl; "C ₃ -C(O)-" refers to butyryl or isobutyryl.

"-C _0-8 -S(O) _r R ₁₉ " means that the sulfur atom in -S(O) _r R ₁₉ is bonded to C _0-8 alkyl, where C ₀ alkyl means bond and C _1-8 alkyl corresponds to the above definition.

"-C _0-8 -OR ₂₀ "means that the oxygen atom in -OR ₂₀ is bonded to C _0-8 alkyl, where C ₀ alkyl refers to a bond and C _1-8 alkyl is as defined above.

"-C _0-8 -C(O)OR ₂₀ "means that the carbonyl group in -C(O)OR ₂₀ is bonded to C _0-8 alkyl, where C ₀ alkyla is a bond and C _1-8 alkyl is as above definition.

"-C _0-8 -C(O)R ₂₁ "means that the carbonyl group in -C(O)R ₂₁ is bonded to C _0-8 alkyl, where C ₀ alkyla is a bond and C _1-8 alkyl is as above definition.

"-C _0-8 -OC(O)R ₂₁ " means that the oxygen atom in -OC(O)R ₂₁ is bonded to C _0-8 alkyl, where C ₀ alkyla means a bond and C _1-8 alkyla is as above definition.

"-C _0-8 -NR ₂₂ R ₂₃ "means that the nitrogen atom in -NR ₂₂ R ₂₃ is bonded to C _0-8 alkyl, where C ₀ alkyla is a bond and C _1-8 alkyl is as defined above.

"-C _0-8 -C(=NR ₂₂ )R ₂₁ " means that the carbonyl in -C(=NR ₂₂ )R ₂₁ is bonded to C _0-8 alkyl, where C ₀ alkyla means a bond and C _1-8 alkyla is as defined above.

"-C _0-8 -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ " means that the carbonyl in -N(R ₂₂ )-C(=NR ₂₃ )R ₂₁ is bonded to C _0-8 alkyl, where C ₀ alkyla means a bond, and C _1-8 alkyla corresponds to the above definition.

"-C _0-8 -C(O)NR ₂₂ R ₂₃ "means that the carbonyl in -C(O)NR ₂₂ R ₂₃ is bonded to C _0-8 alkyl, where C ₀ alkyla means a bond and C _1-8 alkyla is as defined above.

"-C _0-8 -N(R ₂₂ )-C(O)R ₂₁ " means that the nitrogen atom in -N(R ₂₂ )-C(O)R ₂₁ is bonded to C _0-8 alkyl, where C ₀ alkyla means a bond, and C _1-8 alkyla corresponds to the above definition.

"C _1-10 haloalkyl" refers to an alkyl group containing from 1 to 10 carbon atoms, in which any hydrogen atoms are optionally substituted by F, Cl, Br, or I, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl , tribromomethyl and the like.

"C _1-10 haloalkoxy" means an alkoxy containing from 1 to 10 carbon atoms, in which any hydrogen atoms are optionally substituted by F, Cl, Br, or I, including, but not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy etc.

"Halogen" refers to F, Cl, Br, or I.

"MeOH" means methanol. "DMF" means N,N-dimethylformamide. "DCE" means 1,2-dichloroethane. "THF" means tetrahydrofuran. "PE" means petroleum ether. "EA"/"EtAc" means ethyl acetate. "DXM" means dichloromethane. "LiOH" means lithium hydroxide. "NaOH" means sodium hydroxide. "NaNO ₂ " means sodium nitrite. "CuI" means copper iodide. "Na ₂ SO ₄ " means sodium sulfate. "UkKs" means acetic acid. "NH ₄ Oac" means ammonium acetate. "Et ₃ N" means triethylamine. "NH ₄ Cl" means ammonium chloride. "TFA" means trifluoroacetic acid. "m-CPBA" means meta-chloroperbenzoic acid. "Pd(PPh ₃ ) ₄ "means tetrakis(triphenylphosphine)palladium. "Pd(PPh ₃ ) ₂ Cl ₂ " means bis(triphenylphosphine) palladium dichloride.

The term "optional" or "optional" means that the described event or circumstance may occur, but does not necessarily occur, including cases where the event or circumstance occurs or does not occur, as well as situations of substitution and non-substitution. For example, "a heterocyclyl group optionally substituted with alkyl" means that an alkyl group may, but need not, be present, and that the description includes cases where the heterocyclyl is substituted or not substituted with alkyl.

The term "substituted" means that one or more hydrogen atoms in the group are independently substituted with the appropriate number of substituents. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art will be able to determine (experimentally or theoretically) a possible or impossible substitution without undue effort. For example, instability is possible if an amino group or a hydroxyl group having a free hydrogen is bonded to a carbon atom having an unsaturated bond (eg, an olefin).

The term "stereoisomer" means an isomer formed as a result of a different spatial arrangement of atoms in molecules, and can be subdivided either into cis-trans isomers and enantiomers, or into enantiomers and diastereomers. Stereoisomers resulting from rotation around a single bond are called conformational stereoisomers and are also sometimes called rotamers. Stereoisomers formed for reasons such as bond lengths, bond angles, the presence of double bonds in molecules and rings are called configurational stereoisomers, which are also divided into two categories. Among them are isomers formed by double bonds or single bonds of ring-forming carbon atoms that cannot rotate freely and are called geometric isomers, also known as cis-trans isomers, which are divided into two configurations: Z and E. For example: cis-2- butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical activity due to the lack of opposite axial symmetry in the molecules are called optical isomers, which are divided into two configurations: R and S. Unless otherwise indicated, in the present invention, "stereoisomer" can be understood as one or more of the above enantiomers, configurational isomers and conformational isomers.

The "pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, and these salts can be prepared by methods known in the art.

"Pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein, or its physiologically/pharmaceutically acceptable salt or prodrug, as well as other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of this pharmaceutical composition is to facilitate the introduction of the drug into the body, improving the absorption of the active substance and thereby facilitating the manifestation of its biological activity.

The following is a detailed description of the present invention in accordance with variants of its implementation, which are not intended to limit the present invention. The present invention is also not limited to the presented embodiments.

The structure of the compound of the present invention is determined using nuclear magnetic resonance (NMR) and/or liquid chromatography in combination with mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR is determined using a Bruker AVANCE-400 nuclear magnetic setup with deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ) as solvents and tetramethylsilane (TMS) as internal standard.

LC/MS determination was performed using an Agilent 6120 mass spectrometer. HPLC determination was performed using an Agilent 1200 DAD high pressure liquid chromatograph (150 x 4.6 mm Sunfire C18 column) and a Waters 2695-2996 high pressure liquid chromatograph ( column Gimini C18 150 × 4.6 mm).

The thin layer chromatography plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC is set to 0.15-0.20 mm, and the specification for thin layer chromatography for separation and isolation is set to 0.4-0.5 mm. Silica gel (Yantai Huanghai silica gel) with a particle size of 200–300 mesh is usually used as a support for column chromatography.

The starting materials in the embodiments of the present invention are known and commercially available or can be synthesized by methods known in the art or in accordance with them.

Unless otherwise indicated, all reactions of the present invention are carried out under dry nitrogen or argon with continuous stirring on a magnetic stirrer, where the solvent is a dry solvent, and the reaction temperature is indicated in degrees Celsius (°C).

I. Preparation of intermediates

Preparation of intermediate 1(R)-1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine

Stage 1: Synthesis of (3-(1-ethoxyvinyl)phenyl)pentafluoro-λ ⁶ -sulfan

(3-bromophenyl)pentafluoro- λ ⁶ -sulfan (1.0 g, 3.53 mmol) was dissolved in N,N-dimethylformamide (20 ml) and then tributyl (1-ethoxyvinyl)tin (1.4 g, 3.89 mmol) and bis(triphenylphosphine)palladium dichloride (248 mg, 0.353 mmol). The reaction solution was heated to 80°C and stirred for 18 hours. After completion of the reaction, the reaction solution was used as it was in the next step.

Stage 2: Synthesis of 1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethan-1-one

A dioxane hydrochloride solution (4N, 2 ml) was added dropwise to the reaction solution, which was then stirred at 0°C for 2 hours. After completion of the reaction, the reaction was stopped with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: ethyl acetate/petroleum ether = 0-10%] to give 1-(3-(pentafluoro- λ ⁶ -sulfanyl )phenyl)ethan-1-one (670 mg, yield: 77%).

Stage 3: Synthesis of (R,Z)-2-methyl-N-(1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethylidene)propane-2-sulfinamide

1-(3-(pentafluoro- 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) and then heated to 70° C. and stirred for 2 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (150 ml), stopped with saturated sodium bicarbonate solution and filtered. 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%] to obtain (R,Z)-2-methyl-N-(1- (3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethylidene)propane-2-sulfinamide (789 mg, yield: 83%). MS, m/z (ESI): 350 [M+H] ⁺ .

Stage 4: Synthesis of (R)-2-methyl-N-((R)-(1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl)propane-2-sulfinamide

(R,Z)-2-methyl-N-(1-(3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethylidene)propane-2-sulfinamide (400 mg, 1.15 mmol) was dissolved in tetrahydrofuran (10 ml , water content: 20%) and cooled to -50 ^° C. Sodium borohydride (130 mg, 3.44 mmol) was added. The reaction solution was stirred at the current temperature for 1 hour, and then stirred again at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with dichloromethane, filtered to remove insoluble matters, dried over anhydrous sodium sulfate, concentrated to dryness, and then separated by column chromatography [eluent: ethyl acetate/petroleum ether=0-80%] to obtain (R)-2- methyl-N-((R)-(1-(3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)propane-2-sulfinamide (300 mg, yield: 74%) MS, m/z (ESI) : 352 [M+H] ⁺ .

Stage 5: Synthesis of (R)-1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine hydrochloride

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

Intermediates 2-4 were prepared according to the method for the synthesis of intermediate 1.

Intermediate number Structural formula chemical name MS [M+H] ⁺ . m/z (ESI) : 2

(S)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-amine 248 3

(R)-1-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine 248 four

(S)-1-(3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethane-1-amine 248

Preparation of intermediate 5 (S)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine

Stage 1: Synthesis of 2-fluoro-N-methoxy-N-methyl-4-(pentafluoro-λ ⁶ -sulfanyl)benzamide

2-fluoro-4-(pentafluoro -λ ⁶ -sulfanyl)benzoic acid (2 g, 7.6 mmol) was dissolved in N-methylpyrrolidone (10 ml) and then O-(7-azabenzotriazole)-1-YL) was added -N,N,N,N-tetramethylaldehyde cationic hexafluorophosphate (4.32 g, 11.3 mmol), methoxymethylamine hydrochloride (1.08 g, 11.3 mmol) and triethylamine (1.53 g, 15.2 mmol) . The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was stopped with water and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. The reaction solution was concentrated to dryness and then separated by column chromatography [eluent: petroleum ether/ethyl acetate (30%)] to obtain 2-fluoro-N-methoxy-N-methyl-4-(pentafluoro- λ ⁶ -sulfanyl)benzamide (1 .8 g, yield: 76%). MS, m/z (ESI): 309.8 [M+H] ⁺ .

Stage 2: Synthesis of 1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethan-1-one

2-fluoro-N-methoxy-N-methyl-4-(pentafluoro- λ ⁶ -sulfanyl)benzamide (1.8 g, 5.8 mmol) was dissolved in tetrahydrofuran (40 ml). A solution of methylmagnesium bromide (12 ml, 12 mmol) was added while cooling in an ice bath. The reaction solution was stirred for 1 hour. After completion of the reaction, the reaction was stopped with a saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. The reaction solution was concentrated to dryness and then separated by column chromatography [eluent: petroleum ether/ethyl acetate (5%)] to obtain 1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-one ( 1.2 g, yield: 78%).

Stage 3: Synthesis of (S,E)-N-(1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-one (700 mg, 2.65 mmol), (S)-2-methylpropane-2-sulfinamide (417 mg, 3 .44 mmol) and tetraethyl titanate (2 ml) were dissolved in tetrahydrofuran (30 ml) and then heated to 50° C. and stirred for 5 hours. After completion of the reaction, the reaction was stopped with saturated sodium carbonate solution, filtered and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (30%)] to give (S,E)-N-(1 -(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, yield: 72%). MS, m/z (ESI): 367 [M+H] ⁺ .

Stage 4: (S)-N-((S)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

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

Stage 5: Synthesis of (S)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine

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

Preparation of intermediate 6 (R)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine

Stage 1: Synthesis of (R,E)-N-(1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-one (500 mg, 1.89 mmol), (R)-2-methylpropane-2-sulfinamide (291 mg, 2 .46 mmol) and tetraethyl titanate (2 ml) were dissolved in tetrahydrofuran (30 ml) and then heated to 50° C. and stirred for 5 hours. After completion of the reaction, the reaction was stopped with saturated sodium carbonate solution, filtered and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness and separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (30%)] to give (R,E)-N-(1 -(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (450 mg, yield: 65%). MS, m/z (ESI): 368 [M+H] ⁺ .

Stage 2: Synthesis of (R)-N-((R)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

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

Stage 3: Synthesis of (R)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethane-1-amine

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

Preparation of intermediate 7 (2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)methylamine hydrochloride

Stage 1: Synthesis of (2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)hydrazine hydrochloride

Pentafluoro(2-fluorophenyl)-λ ⁶ -sulfan (3.0 g, 13.5 mmol) was dissolved in dimethyl sulfoxide (15 ml). Hydrazine hydrate (30 ml) was added. The reaction solution was reacted in a sealed tube at 100° C. for 20 hours. The reaction solution was cooled to room temperature. Added 1 n. aqueous sodium hydroxide solution (150 ml) and saturated water (150 ml). The mixture was extracted with methyl tert-butyl ether (2*100 ml), washed with brine (3*100 ml), dried over anhydrous sodium sulfate and filtered. Dioxane hydrochloride solution (4N, 5 ml, 20 mmol) was added to the filtrate, stirred at room temperature for 20 minutes, and then concentrated to dryness to give (2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)hydrazine hydrochloride ( 3.5 g, yield: 96%). MS, m/z (ESI): 235 [M+H] ⁺ .

Stage 2: Synthesis of 2-(pentafluoro-λ ⁶ -sulfanyl)aniline hydrochloride

(2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)hydrazine hydrochloride was dissolved in methanol (50 ml). Raney nickel was added. The reaction solution was stirred overnight at room temperature in the presence of hydrogen. The reaction solution was filtered. The filter cake was washed with methanol (20 ml). Dioxane hydrochloride solution (4 N, 5 ml, 20 mmol) was added to the filtrate, stirred at room temperature for 20 minutes, and then concentrated to dryness to give 2-(pentafluoro-λ ⁶ -sulfanyl)aniline hydrochloride (3.7 d, crude product), which was used as received in the next step. MS, m/z (ESI): 220 [M+H] ⁺ .

Stage 3: Synthesis of pentafluoro(2-iodophenyl)-λ ⁶ -sulfan

2-(Pentafluoro-λ ⁶ -sulfanyl)aniline hydrochloride (3.7 g, crude product) was dissolved in tetrafluoroboric acid solution (30 ml) and heated until complete dissolution. The reaction solution was cooled to 0° C. (under cooling in an ice bath). A solution of sodium nitrite (2.0 g, 29 mmol, 10 ml of water) was added dropwise with cooling and stirring in an ice bath, after which the reaction solution was constantly stirred for 30 minutes in an ice bath. Potassium iodide solution (7.2 g, 43.4 mmol, 15 ml water) was added slowly, after which the ice bath was removed. The reaction solution was stirred at room temperature for 30 minutes to carry out the reaction. The reaction solution was extracted with ethyl acetate (2*100 ml) and washed with saturated sodium bicarbonate solution and sodium thiosulfate solution (2*100 ml). The organic phase was concentrated and the residue was separated by column chromatography [eluent: petroleum ether/ethyl acetate = 0-5%] to give pentafluoro(2-iodophenyl)-λ ⁶ -sulfane (3.3 g, yield over two steps: 77%).

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).

Stage 4: Synthesis of 2-(pentafluoro-λ ⁶ -sulfanyl)benzonitrile

A mixture (12 ml) of pentafluoro(2-iodophenyl)-λ ⁶ -sulfane (1.85 g, 5.6 mmol) and copper cyanide (2.0 g, 22.4 mmol) in N-methylpyrrolidone was subjected to microwave irradiation at a temperature 100°C for 2.5 hours. Ethyl acetate (100 ml), concentrated aqueous ammonia (15 ml) and water (100 ml) were added to the reaction solution, which was stirred at room temperature for 10 minutes and then partitioned. The organic layer was washed with brine (100 ml) and concentrated, and the residue was separated by column chromatography [eluent: petroleum ether/ethyl acetate = 0-10%] to obtain 2-(pentafluoro-λ ⁶ -sulfanyl)benzonitrile (0.94 g, yield: 73%).

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).

Step 5: Synthesis of (2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)methylamine hydrochloride

2-(pentafluoro-λ ⁶ -sulfanyl)benzonitrile (1.88 g, 8.2 mmol) was dissolved in tetrahydrofuran (5 ml). A solution of borane-tetrahydrofuran complex (1 N, 50 ml, 50 mmol) was added. The reaction solution was refluxed for 20 hours to carry out the reaction. A solution of borane-tetrahydrofuran complex (1 N, 50 ml, 50 mmol) was made up, and the reaction solution was constantly refluxed for 20 hours to carry out the reaction. The reaction solution was cooled to room temperature, methanol (30 ml) and dioxane hydrochloride solution (4 N, 4 ml, 16 mmol) were added slowly, after which the reaction solution was constantly refluxed for 1 hour to carry out the reaction, and then concentrated by the method rotary evaporation. N-pentane (50 ml) was added to the residue, which was stirred at room temperature for half an hour and filtered under vacuum. The filter cake was washed with n-pentane (20 ml) and dried to give 2-(pentafluoro-λ ⁶ -sulfanyl)phenyl)methylamine hydrochloride (2.22 g) which was used as received in the next step. MS, m/z (ESI): 234 [M+H] ⁺ .

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

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

5-fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml). (R)-2-methylpropane-2-sulfinamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol) were added. The reaction solution was heated to reflux for 24 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to 0°C, sodium borohydride (5.04 g, 133.2 mmol) was added in portions and stirred at 0°C for 3 hours. After completion of the reaction of the intermediate, brine was added dropwise to stop the reaction. After filtering 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-methylpropan-2-sulfinamide (2.4 g, yield: 28%), MS m/z (ESI): 256 [M+H] ⁺ .

Stage 2: Synthesis of (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine

(R)-N-((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropan-2-sulfinamide (2.4 g, 9.40 mmol) was dissolved in methanol (10 ml). A solution of methanol hydrochloride (4 M, 10 ml) was added with stirring. The reaction solution was constantly stirred at room temperature for 1 hour. After the reaction system was concentrated, water (10 ml) and ethyl acetate (10 ml) were added, and the aqueous phase was separated and lyophilized to give (R)-5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (1, 6 g, yield: 91%), MS m/z (ESI): 135 [M+H-NH ₃ ] ⁺ .

Intermediates 9-12 were prepared according to the method for the synthesis of intermediate 8.

Intermediate number Structural
formula chemical name MS , m/z (ESI) : nine

(R)-6-fluoro-2,3-dihydro-1H-inden-1-amine 150, [M+HH ₂ ] ⁺ 10

(R)-5,6-difluoro-2,3-dihydro-1H-inden-1-amine 153, [M+H-NH ₃ ] ⁺ eleven

(R)-5-chloro-2,3-dihydro-1H-inden-1-amine 166, [M+HH ₂ ] ⁺ 12

(R)-5-trifluoromethyl-2,3-dihydro-1H-inden-1-amine 185, [M+H-NH ₃ ] ⁺

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

Stage 1: Synthesis of (S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropan-2-sulfinamide

5-fluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 33.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml). (S)-2-methylpropane-2-sulfinamide (8.07 g, 66.6 mmol) and tetraisopropyl titanate (37.86 g, 133.2 mmol) were added. The reaction solution was heated to reflux for 24 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to 0° C. and sodium borohydride (5.04 g, 133.2 mmol) was added in portions. The reaction solution was stirred at 0° C. for 3 hours. After completion of the reaction of the intermediate, brine was added dropwise to stop the reaction. After filtering 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 (S)-N-((S)-5-fluoro-2,3-dihydro -1H-inden-1-yl)-2-methylpropan-2-sulfinamide (2.4 g, yield: 28%), MS m/z (ESI): 256 [M+H] ⁺ .

Stage 2: Synthesis of (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine

(S)-N-((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropan-2-sulfinamide (2.4 g, 9.40 mmol) was dissolved in methanol (10 ml). A solution of methanol hydrochloride (4 M, 10 ml) was added with stirring. The reaction solution was constantly stirred at room temperature for 1 hour. After the reaction system was concentrated, water (10 ml) and ethyl acetate (10 ml) were added, and the aqueous phase was separated and lyophilized to obtain (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (1, 5 g, yield: 85%), MS m/z (ESI): 135 [M+H-NH ₃ ] ⁺ .

Intermediates 14-17 were prepared according to the method for the synthesis of intermediate 13.

Intermediate number Structural
formula chemical name MS , m/z
(ESI) : fourteen

(S)-6-fluoro-2,3-dihydro-1H-inden-1-amine 150, [M+HH ₂ ] ⁺ 15

(S)-5,6-difluoro-2,3-dihydro-1H-inden-1-amine 153,[M+H-NH ₃ ] ⁺ sixteen

(S)-5-chloro-2,3-dihydro-1H-inden-1-amine 166, [M+HH ₂ ] ⁺ 17

(S)-5-trifluoromethyl-2,3-dihydro-1H-inden-1-amine 185,[M+H-NH ₃ ] ⁺

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

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

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

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

(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). Sodium hydride (60%, 355 mg, 8.87 mmol) was added at 0°C. Then, the reaction solution was stirred at 0° C. for 30 minutes, iodomethane (2.52 g, 17.74 mmol) was added, and then the reaction solution was warmed to room temperature and stirred constantly for three hours. The reaction was stopped with water (50 ml), and the reaction solution was extracted with ethyl acetate (50 ml *3). The organic phases were combined, washed with water, dried and concentrated. The crude product was separated by column chromatography [eluent: ethyl acetate/petroleum ether (10/90)] to give tert-butyl (R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (1.3 d, yield: 89%).

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

tert-Butyl (R)-(2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (1.3 g, 5.26 mmol) was dissolved in acetonitrile (10 ml). Added concentrated hydrochloric acid (5 ml). The reaction solution was stirred at room temperature for three hours and then subjected to a pressure reduction to remove most of the acetonitrile. The aqueous phase was lyophilized to give (R)-N-methyl-2,3-dihydro-1H-inden-1-amine (950 mg, yield: 98%), MS m/z (ESI): 148 [M+H] ⁺ .

Intermediate 19 was prepared according to the method for the synthesis of intermediate 18.

Intermediate number
substances Structural formula chemical name MS , m/z (ESI) : nineteen

(S)-N-methyl-2,3-dihydro-1H-inden-1-amine 148, [M+H] ⁺

Preparation of Intermediate 20 yl)-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine

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

To potassium tert-butoxide (10.9 g, 97 mmol) in a solution of methyl tert-butyl ether (400 ml) was added dropwise sec-butyllithium (74.6 ml, 97 mmol) at -70°C in a protective environment nitrogen. After the reaction solution was stirred at -70° C. for 3 hours, lithium bromide (16.82 g, 190 mmol) was added to the tetrahydrofuran (100 ml) solution. The reaction solution was heated to -15°C and stirred for 30 minutes. The temperature of the reaction solution was again lowered to -70℃, and copper bromide-dimethylsulfide complex (9.98 g, 48 mmol) was added to the diisopropyl sulfide (70 ml) solution. The reaction solution was stirred for 10 minutes, and then (3aR,6aR)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4 -on (5 g, 32 mmol). The reaction solution was heated to -30°C and stirred for 30 minutes. After completion of the reaction, a mixed solution (50 ml) of methanol and acetic acid (1:1) was used to stop the reaction, a mixed solution of ammonium chloride and 3% aqueous ammonia (1:1) was poured in. The water layer was removed. The organic layer was washed with a mixed solution of saturated ammonium chloride solution, 3% aqueous ammonia (1:1) and salt water, dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (15%)] to give (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-one (6.8 g, yield: 85% ).

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]dioxol-4-ol

To 2,4-dichloro-7-iodopyrrolo[2,1-f][1,2,4]triazine (13.7 g, 43.8 mmol) in tetrahydrofuran (300 mL) was added N-butyllithium (22 .8 ml, 56.9 mmol) at -70°C under nitrogen protection. After the reaction solution was stirred at -70°C for 2 hours, (3aR,6R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol was added -4-one (10.6 g, 43.8 mmol) in a tetrahydrofuran solution (40 ml), and the reaction solution was constantly stirred at -70° C. for 1 hour. After completion of the reaction, a saturated ammonium chloride solution was used to stop the reaction. The reaction solution was extracted with ethyl acetate, and the organic layer was concentrated, and then separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (15%)] to obtain (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]dioxol-4-ol (12 d, yield: 64%). MS, m/z (ESI): 430 [M+H] ⁺ .

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

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

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

Stage 1: Synthesis of ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

(4-Methoxybenzyl)hydrazine hydrochloride (100.0 g, 0.53 mol) was dissolved in absolute ethanol (1.6 L) and triethylamine (81.0 g, 0.80 mol) was added. The reaction solution was stirred at room temperature for 30 minutes, and ethyl (ethoxymethylene)cyanoacetate (98.0 g, 0.58 mol) was added. The reaction mixture was stirred at reflux overnight and concentrated to remove ethanol. Water (500 ml) was added to the dry residue, which was then extracted with ethyl acetate (2*500 ml). The organic phases were combined, washed with brine (300 ml), dried with anhydrous sodium sulfate and filtered under vacuum. The filtrate was concentrated to give ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (135.0 g, yield: 92%). MS, m/z (ESI): 276 [M+H] ⁺ .

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

Sodium ethoxide (84.0 g, 1.24 mmol) was dissolved in ethanol (600 ml) and cooled to 0° C. (ice bath). Diethylmalonate (198 g, 1.24 mol) was added and the ice bath was removed. The reaction solution was stirred at room temperature for 20 minutes. Ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (85 g, 0.31 mol) was added and the reaction solution was stirred at reflux for 4 days. The reaction solution was concentrated under reduced pressure to remove ethanol. Water (1.5 L) was added to the residue and neutralized with acetic acid to pH -5. The resulting white dry residue was filtered under vacuum, washed with water (500 ml), dried under vacuum to give ethyl 1-(4-methoxybenzyl)-4,6-dioxo-4,5,6,7-tetrahydro-1H-pyrazolo[3 ,4-b]pyridine-5-carboxylate (100.8 g, yield: 95%). MS, m/z (ESI): 344 [M+H] ⁺ .

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

Ethyl 1-(4-methoxybenzyl)-4,6-dioxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (100.8 g, 0.29 mol ) was dissolved in 25% NaOH aqueous solution (700 ml) and reacted at reflux for 15 hours. The reaction solution was cooled to 0℃, diluted with water (1 L), and slowly neutralized with acetic acid to pH -5. The resulting white dry residue was filtered under vacuum and washed with water (1 L). The filter cake was dried under vacuum to give 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (78.0 g, yield: 98%). MS, m/z (ESI): 272 [M+H] ⁺ .

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

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) were stirred at 170° C for 7 hours to carry out the reaction. The reaction solution was cooled to room temperature and diluted with dichloromethane (200 ml). The resulting mixed solution was slowly poured into the water-ice mixture, which was vigorously stirred, and neutralized with concentrated aqueous ammonia to PH -7, extracted with dichloromethane (2*300 ml), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was separated by column chromatography [petroleum ether/ethyl acetate=0-8%] to give 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (18.3 g, yield: 53%). MS, m/z (ESI): 308/310 [M+H] ⁺ .

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

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

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

4,6-dichloro-1H-pyrazolo[3,4-b]pyridine (3.0 g, 16.0 mmol) was dissolved in hexamethyldisilazane (30 ml). Ammonium sulfate (421 mg, 3.2 mmol) was added. The reaction solution was stirred at 150°C for 3.5 hours to carry out the reaction, subjected to rotary evaporation under reduced pressure to remove hexamethyldisilazane. The residue was dissolved in acetonitrile (60 ml) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyltriacetate (5.59 g, 17.6 mmol) was added. The reaction solution was cooled to 0°C (in an ice bath), trimethylsilyl trifluoromethanesulfonate (4.33 ml, 24.0 mmol) was slowly added dropwise, after which the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate (150 ml) was added to the residue, and it was washed with saturated sodium bicarbonate solution (150 ml) to partition. The aqueous phase was extracted with ethyl acetate (2*100 ml). The organic phases were combined, dried over anhydrous sodium sulfate and filtered under vacuum. The filtrate was concentrated, and the residue was subjected to column chromatography [eluent: petroleum ether/ethyl acetate = 0-15%] to obtain (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, yield: 70%). MS, m/z (ESI): 446/448 [M+H] ⁺ .

Preparation of intermediate 22 (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4 -diyl diacetate

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

4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 13.2 mmol) was dissolved in hexamethyldisilamine (15 ml). Ammonium sulfate (20 mg, 0.15 mmol) was added in a catalytic amount. Then the reaction solution was heated to reflux (at 135°C) for 3 hours. Then, the reaction solution was centrifuged until dry. Acetonitrile (30 ml) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyltriacetate (5.06g, 15.9mmol) were added. The reaction solution was cooled to 0°C. Trimethylsilyl trifluoromethanesulfonate (2.7 ml) was added. Then, the reaction solution was warmed to room temperature and stirred for 24 hours. After completion of the reaction, brine was used to stop the reaction. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give (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, yield: 84%). MS, m/z (ESI): 447 [M+H] ⁺ .

II. Getting Compounds as Examples

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

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

(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate (200mg, 0.55 mmol) and R)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-amine (140 mg, 0.46 mmol) was dissolved in tetrahydrofuran (5 ml). Then N,N-diisopropylethylamine (217 mg, 1.68 mmol) was added. The reaction solution was heated to 60℃ and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate, which was used as received in the next step. MS, m/z (ESI): 658 [M+H] ⁺ .

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

((2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino )-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate (0.30 g, 0.45 mmol) was dissolved in methanol (5 mL) An excess of dry sodium methoxide was added to carry out the reaction at room temperature for 3 hours.Then, 1/1000 aqueous formic acid solution (200 ml) was added to stop the reaction.The resulting reaction solution was lyophilized and then separated by reverse phase column chromatography [column C ₁₈ , eluent: water-water /acetonitrile (0-100)] to give (2R,3R,4S,5R)-2-(6-chloro-4-(((R)-1-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl) ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (120 mg, yield: 49%) MS, m/z ( ESI): 532 [M+H] ⁺ .

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

(2R,3R,4S,5R)-2-(6-chloro-4-(( (R)- 1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3 ,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (60 mg, 0.12 mmol) was dissolved in trimethyl phosphate (2.5 ml). Methylenephosphonium bischloride (112 mg, 0.48 mmol) in a trimethyl phosphate solution (0.5 ml) was added dropwise at 0° C., after which the temperature was maintained for 3 hours to carry out the reaction. A small amount of ice was added to stop the reaction. Then, the reaction solution was separated by reversed-phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (5:1)] to obtain (((((2R,3S,4R,5R)-5-(6-chloro- 4-(((R)-1-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran -2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (30 mg, yield: 18%). MS, m/z (ESI): 690 [M+H] ⁺ .

¹ H NMR (400 MHz, D ₂ O) 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 of examples 2-4 were obtained in accordance with the synthesis method of example 1:

Number Structural formula Name [M+H] ⁺ 2

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H -pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 690 3

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl) amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 708 four

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)ethyl) amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 708

Compound data obtained by NMR spectroscopy obtained in the above examples:

Number NMR 2 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 8.32 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 6.02 (d, J=4.3 Hz, 1H), 5.44 (q, J= 6.9 Hz, 1H), 4.51 (t, J=4, 1 Hz, 1H), 4.28 (t, J=4.8 Hz, 1H), 4.09 (dp, J=13.2, 5.0 Hz, 1H), 3.91 (dt, J= 12.9, 6.2 Hz, 2H), 2.21 (t, J=20.1 Hz, 2H), 1.56 (d, J=7.0 Hz, 3H). 3 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 8.33 (s, 1H), 7.90 (d, J=10.8 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.66 - 7.64 (m, 1H), 6.00 (s, 1H), 5.56 - 5.54 (m, 1H), 4.56 - 4.53 (m, 1H), 4.28 - 4.26 (m, 1H), 4.04 - 4.02 (m, 2H), 3.83 - 3.80 (m, 1H), 2.08 (t , J=18.6 Hz, 2H), 1.56 (d, J=5.2 Hz, 3H). four ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 8.40 (s, 1H), 7.97 (d, J=10.4 Hz, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.73 - 7.69 (m, 1H), 6.09 (d, J=4.4 Hz, 1H), 5.63 - 5.63 (m, 1H), 4.58-4.56(m, 1H), 4.34-4.33(m, 1H), 4.14-4.12(m, 2H), 3.97-3.96(m, 1H ), 2.24 (t, J=20.0 Hz, 2H), 1.64 (d, J=7.6 Hz, 3H).

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

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

(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-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethan-1-amine (600 mg, 1.98 mmol) were dissolved in N- methylpyrrolidone (15 ml) followed by the addition of N,N-diisopropylethylamine (608 mg, 4.95 mmol). The reaction solution was heated to 90℃ and stirred for 40 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, concentrated and separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (40%)] to give (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4 -(((S)-1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3 ,4-diyl diacetate (360 mg, yield: 32%). MS, m/z (ESI): 675 [M+H] ⁺ .

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

(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(((S)-1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl) ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)tetrahydrofuran-3,4-diyl diacetate (0.32 g, 0.48 mmol) was dissolved in methanol (20 ml). Potassium carbonate (0.19 g, 1.44 mmol) was added to carry out the reaction at room temperature for 1 hour. Then 1/1000 aqueous formic acid solution (200 ml) was added to stop the reaction. The resulting reaction solution was lyophilized and then separated by reverse-phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (0-70%)] to obtain (2R,3R,4S,5R)-2-(6-chloro- 4-(((S)-1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-5 -(hydroxymethyl)tetrahydrofuran-3,4-diol (240 mg, yield: 91%). MS, m/z (ESI): 549 [M+H] ⁺ .

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

(2R,3R,4S,5R)-2-(6-chloro-4-(((S)1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H- pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (240 mg, 0.44 mmol) was dissolved in trimethyl phosphate (3 ml). Methylenephosphonium bischloride (436 mg, 1.75 mmol) in a trimethyl phosphate solution (0.5 ml) was added dropwise at 0° C., after which the temperature was maintained for 3 hours to carry out the reaction. A small amount of ice was added to stop the reaction. Then, the reaction solution was separated by reversed-phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (5:1)] to obtain (((((2R,3S,4R,5R)-5-(6-chloro- 4-(((S)-1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3 ,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (90 mg, yield: 29%). MS, m/z (ESI): 707 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 8.38 (s, 1H), 7.96 (dd, J=10.4, 1.6 Hz, 1H), 7.76 ( dd, J=8.4, 1.6Hz, 1H), 7.62 (t, J=8.0Hz, 1H), 6.08 (d, J=4.4Hz, 1H), 6, 03 (s, 1H), 5.15 - 5.13 (m, 1H), 4.53 (t, J=4.8 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).

Compounds of examples 6-22 were obtained in accordance with the synthetic method of example 5:

Number Structural formula Name [M+H] ⁺ 6

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H -pyrazolo[3,4-d]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 689 7

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H -pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 689 8

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H -pyrazolo[3,4-d]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 689 nine

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(3-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl)amino)-1H -pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 689 10

(((((2R,3S,4R,5R)-5-(6-chloro-4-((2-(pentafluoro- λ ⁶ -sulfanyl)phenylmethyl)amino)-1H-pyrazolo[3,4-b] pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 675 eleven

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1-(2-fluoro-4-(pentafluoro- λ ⁶ -sulfanyl)phenyl)ethyl) amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 707 12

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-1H-pyrazolo[ 3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 575 13

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-1H-pyrazolo[ 3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 575 fourteen

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H -pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 589 15

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H -pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 589 sixteen

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)amino)- 1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 593 17

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-6-fluoro-2,3-dihydro-1H-inden-1-yl)amino)- 1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 593 eighteen

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-5-chloro-2,3-dihydro-1H-inden-1-yl)amino)- 1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 609 nineteen

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino )-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 643 20

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino )-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 643 21

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino )-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 611 22

(((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl)amino )-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 611

Compound data obtained by NMR spectroscopy obtained in the above examples:

Number NMR 6 ¹ H NMR (400 MHz, D ₂ O) δ 8.21 (s, 1H), 7.76 – 7.65 (m, 2H), 7.54 – 7.43 (m, 2H), 6.16 (d, J=5.5Hz, 1H), 6.04 (d, J=8.0Hz, 1H), 4.88 – 4.83 (m, 2H), 4.49 (t, J= 4.7 Hz, 1H), 4.22 (q, J=4.5 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 2.06 (t, J=19, 9 Hz, 2H), 1.53 (t, J=6.2 Hz, 3H). 7 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.23 (s, 1H), 7.80 (d, 2H), 7.58 (d, J=8.4 Hz, 2H), 6.28 (d, J=3.9Hz, 1H), 6.02 (s, 1H), 4.99 – 4.89 (m, 1H), 4.74 (t, J=4.6Hz, 1H) , 4.58 (t, J=4.9 Hz, 1H), 4.18 (d, J=6.0 Hz, 2H), 4.15 – 4.03 (m, 1H), 2.30 ( td, J=20.3, 3.1 Hz, 2H), 1.63 (d, J=6.8 Hz, 3H). 8 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.25 (s, 1H), 7.88 (t, J=1.9 Hz, 1H), 7.72 (d, J=8.3 Hz , 1H), 7.66 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.28 (d, J=4.0 Hz, 1H ), 6.03 (s, 1H), 4.96 – 4.88 (m, 1H), 4.78 – 4.73 (m, 1H), 4.64 – 4.55 (m, 1H), 4.20 (q, J=5.2 Hz, 1H), 4.14 – 4.01 (m, 2H), 2.21 (t, J=19.0 Hz, 2H), 1.64 (d , J=6.8 Hz, 3H). nine ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.24 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.28 (d, J=3.5 Hz, 1H), 6.07 (s , 1H), 4.70 (s, 1H), 4.56 (s, 1H), 4.29 (s, 1H), 4.20 (s, 2H), 2.68 (s, 1H), 2 .42 (t, J=21.0 Hz, 2H), 1.64 (d, J=6.8 Hz, 3H). 10 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.06 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.53 (d, J=7.8 Hz , 1H), 7.46 (t, J=7.5 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 6.22 (d, J=3.6 Hz, 1H ), 5.91 (s, 1H), 4.80 (s, 2H), 4.63 (t, J=4.6 Hz, 1H), 4.49 (t, J=5.3 Hz, 1H ), 4.20-4.02 (m, 3H), 2.29 (s, J = 20.8 Hz, 2H). eleven ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 8.38 (s, 1H), 7.96 (d, J=10.4, 1H), 7.75 (d, J=8 .4 Hz, 1H), 7.64 - 7.60 (m, 1H), 6.07 (d, J=4.4 Hz, 1H), 6.03 - 6.00 (m, 1H), 5 .14 (s, 1H), 4.58 - 4.57 (m, 1H), 4.27 - 4.25 (m, 1H), 3.98 (d, J=4.4 Hz, 1H), 3.88 - 3.87 (m, 1H), 3.76 -3.74 (m, 1H), 1.93 (t, J=19.2 Hz, 2H), 1.58 (d, J= 6.4 Hz, 3H). 12 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.35-7.15 (m, 4H), 6.49 (s, 1H), 6.31 (d, J = 3.8 Hz, 1H), 5.30 (s, 1H), 4.72 (t, J=4.6 Hz, 1H), 4.57 (t, J=5.0 Hz, 1H) , 4.28 – 4.17 (m, 2H), 4.16 – 4.07 (m, 1H), 3.15 – 3.03 (m, 1H), 3.03 – 2.90 (m, 1H), 2.73 - 2.57 (m, 1H), 2.35 (t, J=20.6 Hz, 2H), 2.04 (dq, J=15.0, 7.8 Hz, 1H ). 13 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.39 – 7.09 (m, 4H), 6.49 (s, 1H), 6.31 (d, J = 3.7Hz, 1H), 5.30(s, 1H), 4.71(s, 1H), 4.57(s, 1H), 4.31-4.38(m, 2H), 4.18-4.08 (m, 1H), 3.15 - 3.03 (m, 1H), 3.03 - 2.87 (m, 1H), 2.73 - 2.57 (m, 1H ), 2.38 (t, J=20.6 Hz, 2H), 2.03 (m, 1H). fourteen ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.24 (s, 1H), 7.39 – 7.12 (m, 4H), 6.50 (s, 1H), 6.36 (s, 1H), 5.91 (s, 1H), 4.76 (s, 1H), 4.63 (s, 1H), 4.21 (s, 1H), 4.08 (s, 2H), 3, 14 - 3.01 (m, 2H), 2.94 (s, 3H), 2.65 (s, 1H), 2.26 - 2.04 (m, 3H). 15 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.24 (s, 1H), 7.35-7.13 (m, 4H), 6.50 (s, 1H), 6.36 (d, J=3.8Hz, 1H), 5.91(t, J=7.8Hz, 1H), 4.74(t, J=5.3Hz, 1H), 4.63(t, J= 5.3 Hz, 1H), 4.25 - 4.15 (m, 1H), 4.15 - 4.01 (m, 2H), 3.17 - 2.97 (m, 2H), 2.94 (s, 3H), 2.70 – 2.58 (m, 1H), 2.23 – 2.05 (m, 3H). sixteen ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.31 (dd, J=8.4, 5.2 Hz, 1H), 7.02 (dd, J= 9.0, 2.3 Hz, 1H), 6.94 (td, J=8.8, 2.4 Hz, 1H), 6.49 (s, 1H), 6.32 (d, J=3 .7 Hz, 1H), 5.28 (t, J=6.1 Hz, 1H), 4.71 (t, J=4.5 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 4.32 - 4.17 (m, 2H), 4.14 (dt, J=11.0, 6.2 Hz, 1H), 3.09 (ddd, J=16.3, 8.7, 4.4 Hz, 1H), 2.96 (dt, J=16.1, 7.9 Hz, 1H), 2.75 – 2.62 (m, 1H), 2.39 (t , J=20.8 Hz, 2H), 2.15 – 2.01 (m, 1H). 17 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.19 (s, 1H), 7.28 (dd, J=8.3, 5.1 Hz, 1H), 7.00 (ddd, J= 17.9, 8.9, 2.4 Hz, 2H), 6.50 (s, 1H), 6.33 (d, J=3.7 Hz, 1H), 5.32 (t, J=7 .3 Hz, 1H), 4.71 (dd, J=5.2, 3.8 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 4.30 (ddd, J = 11.0, 7.3, 3.8 Hz, 1H), 4.25 - 4.08 (m, 2H), 3.05 (ddd, J=16.1, 8.7, 3.9 Hz , 1H), 2.93 (dt, J=15.9, 8.0 Hz, 1H), 2.70 (dtd, J=11.9, 7.6, 4.0 Hz, 1H), 2, 42 (t, J=21.0 Hz, 2H), 2.07 (dq, J=12.9, 8.0 Hz, 1H). eighteen ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.31 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 6.49 (s, 1H), 6.31 (d, J=3.7 Hz, 1H), 5.29 (t, J=7.0 Hz , 1H), 4.74–4.67 (m, 1H), 4.57 (t, J=5.2 Hz, 1H), 4.32–4.08 (m, 3H), 3.13 – 3.01 (m, 1H), 3.02 - 2.89 (m, 1H), 2.74 - 2.61 (m, 1H), 2.38 (t, J=20.8 Hz, 2H) , 2.13–1.99 (m, 1H). nineteen ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.60 (s, 1H), 7.51 (q, J=8.3 Hz, 2H), 6.52 (s, 1H), 6.32 (d, J=3.5 Hz, 1H), 5.39 (s, 1H), 4.58 (s, 1H), 4.21 (s, 2H), 4 .11 (s, 1H), 3.16 – 3.09 (m, 1H), 3.09 – 2.97 (m, 2H), 2.31 (t, J=19.5 Hz, 2H), 2.10 (dd, J=12.8, 7.9 Hz, 1H). 20 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 6.52 (s, 1H), 6.32 (d, J=3.9Hz, 1H), 5.39 (t, J=7.2Hz , 1H), 4.76 – 4.69 (m, 1H), 4.57 (t, J=5.1 Hz, 1H), 4.30 – 4.18 (m, 2H), 4.18 – 4.09 (m, 1H), 3.22 – 3.10 (m, 1H), 3.10 – 2.97 (m, 1H), 2.80 – 2.67 (m, 1H), 2, 40 (t, J=20.8 Hz, 2H), 2.15 - 2.01 (m, 1H). 21 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.15 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.78 (t, J=9.5 Hz , 1H), 6.45 (s, 1H), 6.31 (d, J=3.8 Hz, 1H), 5.43 (s, 1H), 4.72 (t, J=4.7 Hz , 1H), 4.57 (t, J=4.9 Hz, 1H), 4.28 – 4.17 (m, 2H), 4.17 – 4.07 (m, 1H), 3.18 ( td, J=15.0, 13.8, 6.7 Hz, 1H), 2.98 (dq, J=15.7, 5.6 Hz, 1H), 2.66 – 2.59 (m, 1H), 2.36 (t, J=20.4 Hz, 2H), 2.17 (ddt, J=12.5, 8.0, 4.0 Hz, 1H). 22 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.17 (s, 1H), 7.19 (t, J=8.9 Hz, 2H), 6.48 (s, 1H), 6.32 (d, J=3.8 Hz, 1H), 5.30 (t, J=7.2 Hz, 1H), 4.73 (t, J=4.6 Hz, 1H), 4.58 (t , J=5.1Hz, 1H), 4.23 (dp, J=12.6, 4.5Hz, 2H), 4.13 (dt, J=10.3, 4.9Hz, 1H) , 3.06 (ddd, J=13.5, 8.7, 4.2 Hz, 1H), 2.94 (dt, J=16.0, 7.9 Hz, 1H), 2.70 (dtd , J=12.2, 7.6, 4.2 Hz, 1H), 2.36 (t, J=20.7 Hz, 2H), 2.14 – 2.00 (m, 1H).

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)phosphoryl)methyl)phosphonic acid

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

(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 ml) . Potassium carbonate (0.44 g, 3.18 mmol), tetrakistriphenylphosphine palladium (0.37 g, 0.32 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborocyclohexane were added (0.40 g, 3.18 mmol) in the presence of nitrogen. The reaction solution was sealed and subjected to microwave irradiation at 130°C for 3 hours. Ethyl acetate (30 ml) was added to the reaction solution, which was then washed with water and brine, dried over sodium sulfate, filtered, concentrated and then separated by reverse phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (0- 100%)] to give (2R,3R,4S,5R)-2-(4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)- 6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (255 mg, yield: 53%). MS, m/z (ESI): 433 [M+H] ⁺ .

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)phosphoryl)methyl)phosphonic acid

(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). Methylenephosphonium bischloride (515 mg, 2.06 mmol) in a trimethyl phosphate solution (2.0 ml) was added dropwise at 0° C., after which the temperature was maintained for 3 hours to carry out the reaction. A small amount of ice was added to stop the reaction, and the reaction solution was stirred at the current temperature for 10 minutes. Saturated sodium bicarbonate solution was added to adjust the pH ≥ 8, the reaction solution was stirred at room temperature for 5 hours, and then separated by reverse phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (5:1)] with obtaining (((((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)phosphoryl)methyl)phosphonic acid (136.5 mg, yield: 35 %). MS, m/z (ESI): 591 [M+H] ⁺ .

¹ H NMR (400 MHz, D ₂ O) 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=5.6Hz, 1H), 4.62(t, J=5.0Hz, 1H), 4.33(q, J=4.9Hz, 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 was obtained in accordance with the synthetic method of example 23:

Number Structural formula Name [M+H] ⁺ 24

(((((2R,3S,4R,5R)-5-(4-(((R)-5-fluoro-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)phosphoryl)methyl)phosphonic acid 573

Compound data obtained by NMR spectroscopy obtained in the above examples:

Number NMR [M+H] ⁺ 24 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.33 (s, 1H), 7.34 (t, J=6.8 Hz, 1H), 7.06 (d, J=9.0 Hz , 1H), 6.97 (t, J=8.6 Hz, 1H), 6.70 (s, 1H), 6.17 (s, 1H), 5.51 (s, 1H), 4.59 - 4.52 (m, 1H), 4.25 (d, J= 4.6 Hz, 1H), 4.18 - 4.00 (m, 2H), 3.20 - 3.08 (m, 1H ), 3.00 (dt, J= 16.0, 7.6 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.66 (s, 3H), 2.25 - 2, 06(m, 3H). 573

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)phosphoryl)methyl)phosphonic acid

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

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

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)cyclopent-3-ene-1,2-diol

7-((3aR,4R,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-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) was dissolved in 90% acetic acid (40 ml), heated to 60℃ and stirred for 16 hours. After completion of the reaction, the reaction solution was concentrated, and then separated by column chromatography [eluent: dichloromethane-dichloromethane/methanol (10%)] to obtain (1R,2S,5R)-5-(tert-butoxymethyl)-3-(2-chloro- 4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclopent-3-ene -1,2-diol (600 mg, yield: 97%). MS, m/z (ESI): 469 [M+H] ⁺ .

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)cyclopentan-1,2-diol

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

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)cyclopentan-1,2-diol

(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)cyclopentan-1,2-diol (500 mg, 1.06 mmol) was dissolved in acetonitrile (4 ml). A solution of dioxane hydrochloride (4 ml, 1 N) was added to carry out the reaction at room temperature for 1 hour. Then, the reaction solution was concentrated and then separated by reversed-phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (0-50%)] to obtain (1R,2S,3S,5R)-3-(2-chloro- 4-(((R)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl )cyclopentane-1,2-diol (200 mg, yield: 46%). MS, m/z (ESI): 415 [M+H] ⁺ .

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)phosphoryl)methyl)phosphonic acid

(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)cyclopentan-1,2-diol (200 mg, 0.48 mmol) was dissolved in trimethyl phosphate (3 ml). Methylenephosphonium bischloride (481 mg, 1.93 mmol) in a trimethyl phosphate solution (0.5 ml) was added dropwise at 0° C., after which the temperature was maintained for 3 hours to carry out the reaction. A small amount of ice was added to stop the reaction. Then, the reaction solution was separated by reverse phase column chromatography [column C ₁₈ , eluent: water-water/acetonitrile (5:1)] to obtain (((((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)phosphoryl)methyl)phosphonic acid (65 mg, yield: 24%). MS, m/z (ESI): 573 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) 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 compounds of examples 26-39 were obtained in accordance with the synthetic method of example 25:

Number Structural formula Name [M+H] ⁺ 26

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo[2,1 -f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 573 27

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 591 28

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-5-fluoro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 591 29

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-6-fluoro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 591 thirty

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-6-fluoro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 591 31

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 609 32

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 609 33

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 609 34

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 609 35

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 641 36

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 641 37

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((S)-5-chloro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 607 38

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-5-chloro-2,3-dihydro-1H-inden-1-yl)amino)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 607 39

(((((1R,2R,3S,4S)-4-(2-chloro-4-(((R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid 641

Compound data obtained by NMR spectroscopy obtained in the above examples:

Number NMR 26 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 7.29 - 7.14 (m, 4H), 6.78 - 6.77 (m, 1H), 6.60 - 6.59 (m, 1H), 5.68 (t, J=7.2 Hz, 1H), 4.20 - 4.14 (m, 1H), 4.04 - 4.02 (m, 1H), 3, 88 - 3.81 (m, 2H), 3.73 - 3.70 (m, 1H), 3.61 - 3.54 (m, 1H), 3.01 - 2.96 (m, 1H), 2.90 - 2.81 (m, 1H), 2.57 - 2.52 (m, 1H), 2.37 - 2.29 (m, 1H), 2.06 (t, J=7.2 Hz, 2H), 1.37 -1.36 (m, 1H), 1.22 -1.19 (m, 1H) 27 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.29 (dd, J=8.3, 5.3 Hz, 1H), 7.02 (d, J=9.1 Hz, 1H), 6 .97 - 6.86 (m, 2H), 6.57 (d, J=4.5 Hz, 1H), 5.91 (t, J=7.5 Hz, 1H), 4.24 - 4, 18 (m, 1H), 4.15 (t, J=5.7 Hz, 2H), 4.07 (t, J=5.0 Hz, 1H), 3.77 – 3.66 (m, 1H ), 3.18 – 3.06 (m, 1H), 3.02 – 2.89 (m, 1H), 2.74 – 2.61 (m, 1H), 2.51 – 2.36 (m , 4H), 2.18 – 2.04 (m, 1H), 1.67 – 1.55 (m, 1H). 28 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 7.28 - 7.25 (m, 1H), 7.14 - 7.12 (m, 1H), 7.01 - 6.98 (m, 2H), 6.54 (d, J=4.0 Hz, 1H), 5.80 - 5.78 (m, 1H), 4.00 - 3.91 (m, 3H), 3, 80 - 3.78 (m, 1H), 3.55 - 3.52 (m, 1H), 3.02 - 3.01 (m, 1H), 2.92 - 2.88 (m, 1H), 2.57 -2.53 (m, 2H), 2.23 - 2.14 (m, 3H), 2.09 -2.04 (m, 1H), 1.30 -1.23 (m, 1H ). 29 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.25 (dd, J=8.3, 5.0 Hz, 1H), 7.04 – 6.90 (m, 2H), 6.88 ( d, J=4.5 Hz, 1H), 6.56 (d, J=4.5 Hz, 1H), 5.91 (t, J= 7.7 Hz, 1H), 4.19 (dd, J \u003d 7.4, 5.4 Hz, 1H), 4.13 (t, J \u003d 5.7 Hz, 2H), 4.05 (t, J \u003d 4.9 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.10 – 3.00 (m, 1H), 2.96 – 2.84 (m, 1H), 2.72 – 2.61 (m, 1H), 2, 48 - 2.34 (m, 4H), 2.15 - 2.03 (m, 1H), 1.65 - 1.50 (m, 1H). thirty ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.25 (dd, J=8.2, 5.1 Hz, 1H), 7.02 – 6.91 (m, 2H), 6.88 ( d, J=4.5 Hz, 1H), 6.56 (d, J=4.6 Hz, 1H), 5.91 (t, J=7.7 Hz, 1H), 4.21 (dd, J=7.4, 5.4Hz, 1H), 4.15(t, J=5.7Hz, 2H), 4.05(t, J=5.0Hz, 1H), 3.70( dt, J=9.4, 7.4Hz, 1H), 3.05 (ddd, J=15.9, 8.9, 3.6Hz, 1H), 2.90 (dt, J=15, 8, 8.2 Hz, 1H), 2.62 - 2.70 (m, 1H), 2.55 - 2.28 (m, 4H), 2.09 (dq, J=12.9, 8, 4 Hz, 1H), 1.65 - 1.53 (m, 1H). 31 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.05 (t, J=8.9 Hz, 2H), 6.76 (d, J=4.5 Hz, 1H), 6.47 (d , J=4.5 Hz, 1H), 5.77 (t, J=7.7 Hz, 1H), 4.07 (dd, J=7.4, 5.4 Hz, 1H), 4.03 - 3.89 (m, 3H), 3.60 (q, J=8.1 Hz, 1H), 3.04 - 2.91 (m, 1H), 2.87 - 2.73 (m, 1H ), 2.62 – 2.49 (m, 1H), 2.34 – 2.22 (m, 2H), 2.21 (t, J=20.2 Hz, 2H), 2.07 – 1, 92 (m, 1H), 1.52 - 1.40 (m, 1H). 32 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ7.37 - 7.25 (m, 2H), 6.97 (d, J=3.6 Hz, 1H), 6.55 (d , J=4.4 Hz, 1H), 5.77 - 5.75 (m, 1H), 3.99 - 3.90 (m, 4H), 3.56 - 3.50 (m, 1H), 3.03 - 2.98 (m, 1H), 2.88 - 2.82 (m, 1H), 2.52 - 2.50 (m, 2H), 2.22 - 2.17 (m, 3H ), 2.12 -2.07 (m, 1H), 1.29 -1.22 (m, 1H). 33 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 6.89 (d, J=8.5 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.74 (td , J=9.5, 2.1 Hz, 1H), 6.53 (d, J=4.5 Hz, 1H), 6.15 – 5.93 (m, 1H), 4.19 (dd, J=7.3, 5.5 Hz, 1H), 4.14 (t, J=5.6 Hz, 2H), 4.05 (t, J=5.0 Hz, 1H), 3.79 – 3.62 (m, 1H), 3.18 (ddd, J=15.6, 8.8, 5.8 Hz, 1H), 3.03 – 2.87 (m, 1H), 2.65 ( dtd, J=13.8, 8.3, 5.5 Hz, 1H), 2.55 – 2.31 (m, 4H), 2.13 (ddt, J=14.2, 8.9, 5 .9 Hz, 1H), 1.63 - 1.47 (m, 1H). 34 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 6.89 (d, J=8.4 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.74 (td , J=9.5, 2.1 Hz, 1H), 6.53 (d, J=4.5 Hz, 1H), 6.04 (t, J=6.7 Hz, 1H), 4.19 (dd, J=7.4, 5.3Hz, 1H), 4.14 (t, J=5.7Hz, 2H), 4.05 (t, J=5.0Hz, 1H), 3 .73 – 3.63 (m, 1H), 3.23 – 3.12 (m, 1H), 3.01 – 2.89 (m, 1H), 2.72 – 2.59 (m, 1H) , 2.43 (t, J=20.6 Hz, 2H), 2.42-2.33 (m, 2H), 2.18 - 2.07 (m, 1H), 1.63 - 1.50 (m, 1H). 35 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.55 (s, 1H), 7.54 (d, J= 11.6 Hz, 1H), 7.46 (d, J=7.9 Hz , 1H), 6.89 (d, J=4.6Hz, 1H), 6.58 (d, J=4.5Hz, 1H), 5.97 (t, J=7.7Hz, 1H ), 4.20 (dd, J=7.4, 5.4Hz, 1H), 4.15 (t, J=5.7Hz, 2H), 4.05 (t, J=4.9Hz , 1H), 3.72 (q, J=8.1 Hz, 1H), 3.22 – 3.12 (m, 1H), 3.01 (dt, J=16.5, 8.3 Hz, 1H), 2.69 (dtd, J=12.1, 8.0, 3.7 Hz, 1H), 2.48 – 2.28 (m, 4H), 2.12 (dq, J=13, 0, 8.4 Hz, 1H), 1.64 - 1.52 (m, 1H). 36 ¹ H NMR (400 MHz, DMSO- d ₆ +D ₂ O) δ 7.68 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.06 (d, J=4.0 Hz, 1H), 6.64 (d, J=4.0 Hz, 1H), 5.95 - 5.91 (m, 1H), 4.06 - 4.03 (m, 1H), 3.95 - 3.93 (m, 2H), 3.89 - 3.86 (m, 1H), 3.60 - 3.58 ( m, 1H), 3.21 - 3.15 (m, 1H), 3.09 - 3.02 (m, 1H), 2.68 - 2.63 (m, 1H), 2.32 - 2, 12(m, 5H), 1.37-1.29(m, 1H). 37 ¹ H NMR (400 MHz, D ₂ O) δ 7.30 (s, 1H), 7.19 (q, J=8.2 Hz, 2H), 6.79 (d, J=4.7 Hz, 1H), 6.62 (d, J=3.9Hz, 1H), 5.67 (t, J=7.8Hz, 1H), 4.18 (t, J=7.3Hz, 1H) , 4.10 – 4.06 (m, 1H), 3.96 – 3.87 (m, 1H), 3.84 – 3.76 (m, 1H), 3.63 – 3.55 (m, 1H), 3.41-3.26 (m, 1H), 3.03 – 2.94 (m, 1H), 2.91 – 2.82 (m, 1H), 2.64 – 2.54 ( m, 1H), 2.37 - 2.29 (m, 2H), 1.93 (t, J=19.7 Hz, 3H). 38 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.27 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.18 (dd, J=8.1, 1.9 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H), 6.57 (d, J=4.6 Hz, 1H), 5.90 (t, J=7, 7 Hz, 1H), 4.18 (dd, J=7.4, 5.3 Hz, 1H), 4.12 - 4.01 (m, 3H), 3.70 (q, J=8.1 Hz, 1H), 3.15 – 3.03 (m, 1H), 2.99 – 2.87 (m, 1H), 2.69 – 2.59 (m, 1H), 2.43 – 2, 36 (m, 2H), 2.36 - 2.24 (m, 2H), 2.14 - 2.02 (m, 1H), 1.62 - 1.50 (m, 1H). 39 ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.57 (s, 1H), 7.51-7.41 (m, 2H), 6.87 (d, J=4.5 Hz, 1H) , 6.56 (d, J=4.5Hz, 1H), 6.00 (t, J=8.0Hz, 1H), 4.20 (dd, J=7.4, 5.4Hz, 1H), 4.14 (t, J=5.7 Hz, 2H), 4.05 (t, J=5.0 Hz, 1H), 3.75 – 3.65 (m, 1H), 3, 20 - 3.11 (m, 1H), 3.07 - 2.96 (m, 1H), 2.74 - 2.65 (m, 1H), 2.49 - 2.34 (m, 4H), 2.18 - 2.06 (m, 1H), 1.63 - 1.51 (m, 1H).

Evaluation during biological analysis

I. In vitro enzymatic activity against CD73

In the present invention, in order to characterize the inhibitory activity of compounds against CD73, a malachite green test was performed using soluble CD73 synthesized in vitro. The specific experimental procedure was as follows:

1. In this experiment, the enzymatic reaction was carried out in 384-well plates, CD73 (R&D systems #5795-EN-010) at a concentration of 36 ng/ml, compounds at various concentrations, and AMP at a concentration of 50 μmol were incubated at 25°C for 30 minutes in a 40 µl reaction system (consisting of 25 mM Tris buffer pH 7.5, 5 mM MgCl ₂ and 0.005% Tween-20);

2. Then, 10 µl of malachite green solution (Sigma) was added to each well to stop the reaction;

3. Determine the concentration of the resulting inorganic phosphate in accordance with the instructions of the reagent manufacturer;

4. Based on the concentration of the product, the enzymatic activity of CD73 was calculated, and then the IC ₅₀ values were determined by the method of non-linear regression analysis of percent inhibition at different concentrations of the compounds of the present invention. The results of the examples of the present invention are shown in Table 1.

II. Inhibition of CD73 enzymatic activity on the cell surface (experiment using CellTiter-Glo (CTG) assay)

In the present invention, MDA-MB-231 human breast cancer cells, which endogenously express CD73, were used to evaluate the ability of a compound to inhibit the enzymatic activity of CD73, which is expressed on the cell surface. The cells used in the experiment were taken from the cell bank of the Chinese Academy of Sciences. The specific experimental procedure was as follows:

1. Before testing, MDA-MB231 cells were seeded in a 96-well plate, 20,000 cells per well;

2. Cells were cultured in RPMI1640 medium with 10% fetal bovine serum (Gibco, 10099-141) and incubated in a 5% CO ₂ atmosphere at 37°C overnight (cells were washed three times with serum-free RPMI medium before testing) ;

3. 50 μl of serum-free medium containing compounds at various concentrations was added to the cells, and then the cells were incubated for 15 minutes;

4. 25 µl of AMP 1.2 mM was added to incubate at 37°C for 2 hours, then 25 µl of conditioned medium was collected from the cells and mixed with 25 µl of ATP 100 mM, followed by CTG (Promega, #G7573) the concentration of AMP in the samples was determined.

5. Then, the reduction ratio of the AMP substrate level in the conditioned cell culture medium collected after the reaction was quantified to evaluate the inhibitory effect of the examples of the present invention and the positive compounds on the CD73 enzymatic activity on the cell surface;

6. Finally, using a four-parameter non-linear logistic model curve fitted in Graphpad Prism, the compound concentration at which half-maximal inhibition of enzymatic activity (IC50) occurs was determined. The results of the examples of the present invention are shown in Table 1.

Table 1 Results of biological analysis

Number
example Enzymatic activity, IC ₅₀ (nm) Cellular activity, IC ₅₀ (nm) Number
example Enzymatic activity, IC ₅₀ (nm) Cellular activity, IC ₅₀ (nm) Example 1 6.8 0.373 Example 21 0.21 0.21 Example 2 20.6 0.73 Example 22 0.26 0.151 Example 3 1.6 0.722 Example 23 0.89 0.245 Example 4 23.4 0.9 Example 24 1.26 0.256 Example 5 36.5 0.49 Example 25 5.5 0.55 Example 6 2.4 0.302 Example 26 NT 3.182 Example 7 15.1 1.61 Example 27 82.6 2.54 Example 8 2.0 0.59 Example 28 3.95 0.252 Example 9 4.8 1.45 Example 29 15.0 0.71 Example 10 3.1 0.21 Example 30 3.4 0.19 Example 11 31.6 0.99 Example 31 48.6 0.95 Example 12 0.26 0.26 Example 32 4.08 0.27 Example 13 0.42 0.13 Example 33 27.9 2.4 Example 14 0.16 0.45 Example 34 1.01 0.22 Example 15 0.97 0.121 Example 35 354.2 5.73 Example 16 0.34 0.176 Example 36 21.7 0.63 Example 17 0.32 0.14 Example 37 >1000 59.97 Example 18 1.67 0.24 Example 38 7.8 0.266 Example 19 11.81 0.54 Example 39 63.0 0.743 Example 20 0.71 0.27 WO2017120508 Example 127 3.37 0.508 Note "NI" - not studied, that is, the object has not yet been discovered.

From the activity data of certain examples, it can be seen that the compounds described in the present invention have a strong inhibitory effect on the enzymatic and cellular activities of CD73.

All documents mentioned in the present invention are incorporated by reference, as well as each document is cited separately by reference. In addition, it should be understood that specialists in this field, having read the above ideas of the present invention, may make various modifications or changes, and these equivalent forms are also included in the scope of the claims.

Claims (55)

1. A compound of formula (IIb) or formula (IIc), a stereoisomer thereof, or a pharmaceutically acceptable salt of formula

where X ₁ represents CH in the formula (IIb); Y is O in formula (IIb); where X ₁ represents N in the formula (IIc); Y is CH ₂ in formula (IIc); each R ₁ is independently selected from hydrogen, halogen, C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more halogens; R ₄ is hydrogen or C _1-4 alkyl; R ₅ is hydrogen, halogen or C _1-4 alkyl; R ₆ and R ₇ are each independently selected from hydrogen or hydroxy; R ₈ and R ₉ are each independently selected from hydrogen or hydroxy; R ₁₀ , R ₁₁ and R ₁₂ is hydrogen; q is independently selected from 0, 1, 2, or 3; and m is independently selected from 0, 1, or 2. 2. The compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound of formula (IIb) is a compound whose structure is described by formula (IIIb)

where X ₁ represents CH; each R ₁ is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, isopropyl, difluoromethyl or trifluoromethyl; R ₄ is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R ₅ is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl or isopropyl; R ₇ is selected from hydrogen or hydroxy; R ₉ is selected from hydrogen or hydroxy; R ₁₀ , R ₁₁ and R ₁₂ are hydrogen; and m is selected from 0, 1 or 2. 3. The compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound of formula (IIc) is a compound whose structure is described by formula (IIIc)

where X ₁ represents N; each R ₁ is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, isopropyl, difluoromethyl or trifluoromethyl; R ₄ is selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl; R ₅ is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl or isopropyl; R ₆ is selected from hydrogen or hydroxy; R ₈ is selected from hydrogen or hydroxy; R ₁₀ , R ₁₁ and R ₁₂ are hydrogen; and m is selected from 0, 1, 2, or 3. 4. The compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-3 where the compound is selected from the following compounds:

5. A process for the preparation of a compound of formula (IIb) or formula (IIc) of its stereoisomer or pharmaceutically acceptable salt according to claim 1, comprising the following steps:

where Pg is a protecting group for a hydroxyl group selected from the group consisting of an alkanoyl or silicon protecting group; X ₁ , Y, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , m and q correspond to those in paragraph 1. 6. Pharmaceutical composition for the treatment of diseases that are at least partially mediated by CD73, comprising a compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-4, as well as a pharmaceutically acceptable carrier. 7. The use of a compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-4 for the preparation of medicaments for the treatment of cancers or tumors, immune-dependent diseases and disorders, and metabolic diseases that are at least partially mediated by CD73. 8. Use according to claim 7, wherein the malignant neoplasms or tumors are selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head and neck cancer, skin cancer, mesothelial cancer, blood cancer, esophageal cancer, breast cancer, muscle tissue tumor, connective tissue tumor, lung cancer, adrenal gland cancer, thyroid cancer, cancer kidney, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma and seminoma. 9. Use according to claim 8, wherein the malignant neoplasm or tumor is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma. 10. Use according to claim 8, wherein the malignant neoplasm or tumor is skin cancer, wherein the skin cancer is melanoma or basal cell carcinoma. 11. Use according to claim 8, wherein the cancer or tumor is blood cancer, where the blood cancer is lymphoma or leukemia. 12. Use according to claim 8, wherein the malignant neoplasm or tumor is lung cancer, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer. 13. Use according to claim 8, wherein the malignant neoplasm or tumor is a sarcoma, wherein the sarcoma is Kaposi's sarcoma. 14. The use according to claim 7, where the immune-dependent diseases and disorders are selected from the group including rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, chronic heart failure , stroke, aortic stenosis, atherosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and allergic contact eczema, systemic scleroderma and multiple sclerosis. 15. The use of a compound of formula (IIb) or formula (IIc), its stereoisomer or pharmaceutically acceptable salt according to any one of paragraphs. 1-4 as drugs for the treatment of cancers or tumors, autoimmune diseases and disorders, and metabolic diseases that are at least partially mediated by CD73. 16. Use according to claim 15, wherein the cancer or tumor, autoimmune disease and disorder, and metabolic disease, which are at least partially mediated by CD73, is selected from prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cancer stomach, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head and neck cancer, skin cancer, mesothelial cancer, blood cancer, esophageal cancer, breast cancer, muscle tumors , connective tissue tumors, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma, seminoma, rheumatoid arthritis, renal failure , lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, chronic heart failure, stroke, aortic stenosis, atherosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and allergic contact eczema, systemic scleroderma, and multiple sclerosis. 17. Use according to claim 16 wherein the skin cancer is melanoma or basal cell carcinoma. 18. Use according to claim 16 wherein the blood cancer is lymphoma or leukemia. 19. The use of claim 16 wherein the lung cancer is small cell lung cancer or non-small cell lung cancer. 20. Use according to claim 16 wherein the sarcoma is Kaposi's sarcoma.