CN111094317A - Phosphonic acid derivative with CD73 inhibitory activity, and preparation method and application thereof - Google Patents

Abstract

The invention relates to a phosphonic acid derivative with a structure shown as a formula (I) and CD73 inhibitory activity, and a preparation method and application thereof. The series of compounds of the invention can be widely applied to the preparation of medicines for treating cancers or tumors, autoimmune diseases and disorders and metabolic diseases which are at least partially mediated by CD73, in particular to the treatment of melanoma, colon cancer, pancreatic cancer,The medicine for treating breast cancer, prostatic cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma is expected to be developed into a new generation of CD73 inhibitor medicine.

Description

Phosphonic acid derivative with CD73 inhibitory activity, and preparation method and application thereof Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a phosphonic acid derivative with CD73 inhibitory activity, and a preparation method and application thereof.

Background

CD73, also known as extracellular-5' -nucleotidase (eNT), is a 70kDa protein molecule. Under normal conditions, it is expressed on vascular endothelial cells and a part of blood cells. It is anchored to the cell membrane surface by Glycosylphosphatidylinositol (GPI), and together with CD39, regulates the metabolism of Adenosine Triphosphate (ATP). Of these, CD39 (also known as the extracellular nucleoside diphosphate hydrolase-NTPDase 1) catalyzes the production of Adenosine Monophosphate (AMP) from ATP, producing only a small amount of Adenosine Diphosphate (ADP) while the primary function of CD73 is to catalyze the conversion of extracellular nucleotides (such as 5' AMP) to their corresponding nucleosides (such as adenosine)

The nucleosides catalyzed by CD73, particularly adenosine, are thought to be internal regulatory molecules for a wide variety of different physiological functions. Adenosine regulates the cardiovascular system, the central nervous system, the respiratory system, the kidneys, adipocytes, platelets and the immune system. In the immune system, extracellular adenosine can act on a wide variety of different immune cells and mediate anti-inflammatory responses. In many tissues, adenosine also promotes the process of fibrosis.

Expression of CD73 is found in many tumor cells, including leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer, and breast cancer. Meanwhile, expression of CD73 was also found on the surface of immunosuppressive cells including regulatory T cell tregs and myeloid suppressor cells MDSCs. High expression of CD73 has also been found to be associated with angiogenesis, infiltration, resistance to chemotherapy, tumor metastasis and shorter survival in cancer patients in a variety of tumors including breast cancer and melanoma.

Mechanism-based studies have shown that malignant cells, under chemotherapy and other stressful conditions, release large amounts of ATP and are rapidly converted to adenosine, which accumulates in the tumor microenvironment. The release of extracellular ATP due to cell death or intracellular pressure activates the immune response. Adenosine, a metabolite of ATP, has immunosuppressive activity. It is important that adenosine in tumors inhibit infiltrating T-effector lymphocytes by activating adenosine receptors (such as A2A), thereby promoting tumor development. The accumulation of extracellular adenosine in tumor tissue is therefore an important mechanism for tumor immune escape.

The use of interfering RNA to reduce CD73 expression or to overexpress CD73 in tumor cells can modulate tumor growth and migration. CD73 knockout mice are less prone to organ transplant rejection and spontaneous tumor deletion of the A2A receptor gene by genetic means can induce T cell dependent tumor rejection. In contrast, treatment with an antibody that binds mouse CD73 inhibited breast tumor growth and migration in a mouse model.

Therefore, targeting CD73 represents a potential therapeutic strategy that could enhance the efficacy of anti-tumor immunotherapy and provide a new therapeutic strategy to limit the further development of tumors. Also, targeting CD73 may be used to treat other diseases mediated by adenosine, such as enhancing immune response, enhancing immune efficacy, enhancing inflammatory response and treating diseases including neurological disorders, neurodegeneration and central nervous system disorders, such as depression, parkinson's disease, sleep disorders, fibrosis and other immunoinflammatory diseases.

Therefore, the development of a CD 73-targeted drug candidate as a good drug candidate would satisfy the need for a targeted drug in the treatment of cancer and other related diseases, with the advantages of good safety and strong specificity.

Disclosure of Invention

The present invention aims to provide a compound having a CD73 inhibitory activity.

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

wherein the content of the first and second substances,

X₁、X₂each independently is selected from N or CH;

X₃、X₄each independently is selected from N or C;

X₅、X₆each independently selected from O, S, C (R)₁₀) N or N (R)₁₁)；

Y₁Selected from-O-, -S-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆)-；

Y₂、Y₃Each independently selected from-O-, -S-or-C (R)₁₇R₁₈)-；

Z is selected from-O-, -S-or-NH-;

R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃The above-mentionedThe radicals are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₃、R₄each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、 -C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₅、R₆each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Or, R₅And R₆Together with the carbon atom to which they are directly attached form a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₇、R₈、R₉each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃or-C_0-8-C(O)NR₂₄R₂₅Or, R₇And R₈Or R₉Together with the group to which they are directly attached form a 6-to 10-membered heterocyclic group, R₈And R₉And the directly attached groups thereof together form a 4-10 membered heterocyclic group, said groups optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₀、R₁₂、R₁₃、R₁₄、R₁₅、R₁₇、R₁₈Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₁、R₁₆Each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_3-10Cycloalkyl radical C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、 -C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₉、R₂₀Each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_3-10Cycloalkyl radical C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkenyl group, 3-to 10-membered heterocyclic group, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Or, R₁₉、R₂₀Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₂₁Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

each R₂₂Selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-to 10-membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxyRadical, carbonyl group, cyano group, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

each R₂₃Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

each R₂₄、R₂₅Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C_1-8Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

or, R₂₄、R₂₅Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

each r is independently 0,1 or 2.

For compounds of formula (I) or pharmaceutically acceptable salts thereof, the configuration of each chiral carbon is independently R-or S-form.

As a preferred embodiment, R in said compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof₅、R₆Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Or, R₅And R₆Together with the carbon atom to which they are directly attached form a 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Is substituted by a substituent of (A), R₂₂、R₂₄、R₂₅And r is as described for compounds of formula (I); preferably, R₅、R₆Each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino or dimethylamino, or, R₅And R₆And the carbon atoms to which they are directly attached form a 3-4 membered cycloalkyl group, a 4-5 membered heterocyclyl group.

As a further preferred embodiment, the followingR in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₃、R₄Each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl or C_2-4Alkynyl, said group being optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Is substituted by a substituent of (A), R₂₂、R₂₄、R₂₅And r is as described for compounds of formula (I); preferably, R₃、R₄Each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl.

As a further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof is Y₂、Y₃Each independently selected from-C (R)₁₇R₁₈) -; each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, halogen, cyano, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-O-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -O-R₂₂or-O-C (O) R₂₃Is substituted by a substituent of (A), R₂₂、R₂₃As described for compounds of formula (I); preferably, each R is₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy, optionally further substituted by one or more groups selected from deuterium, fluorine, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxySubstituted by a substituent.

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₁Selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅and r is as described for compounds of formula (I).

As a still further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof is X₃、X₄Each independently selected from N or C, and X₃、X₄Comprises at least one N; y is₁Selected from-O-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆)-；Y₂、Y₃Each independently selected from-C (R)₁₇R₁₈)-；

R₁Selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

R₃、R₄each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl;

R₅、R₆each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;

each R₁₂、R₁₃、R₁₄、R₁₅Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₆Each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、 -C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxyacyl or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅and r is as described for compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the structure as shown in formula (iia) or formula (iib):

wherein, X₁、X₂Each independently is selected from N or CH; x₅、X₆Each independently selected from C (R)₁₀) Or N; y is₁Selected from-O-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆) -; z is selected from-O-or-NH-;

R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more substituents selected from deuterium, halogen,Cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

R₃、R₄each independently selected from hydrogen, deuterium, cyano, methyl, vinyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

R₅、R₆each independently selected from hydrogen, deuterium, methyl, cyclopropyl, trifluoromethyl or trideuterium methyl;

each R₁₂、R₁₃、R₁₄、R₁₅Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent(s);

each R₁₆Each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or-C_0-4-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxyacyl or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

R₇、R₈、R₉、R₁₀、R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅and r is as described for compounds of formula (I).

As a still further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof is X₅Is selected from C (R)₁₀) Or N; x₆Is selected from CH;

R₁₀each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent(s);

R₂₂、R₂₃、R₂₄、R₂₅as described for compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the following structure:

wherein, X₁、X₂Each independently is selected from N or CH; x₅Is selected from C (R)₁₀) Or N; y is₁Is selected from-O-or-C (R)₁₂R₁₃)-；

R₁Is selected from C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_5-8Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or-NR₁₉R₂₀Optionally, said group is further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;

R₂selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy, methoxy, amino, methylamino or dimethylamino, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;

R₃selected from hydrogen, deuterium, cyano, methyl, ethenyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

R₁₂、R₁₃each independently selected from hydrogen, deuterium, fluoro, chloro, methyl, vinyl, cyclopropyl, hydroxy, trifluoromethyl or cyclopropylmethyl;

R₁₇、R₁₈each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, trifluoromethyl, trideuteromethyl, trifluoromethoxy, trideuteromethoxy, cyclopropylmethyl, methoxymethyl, ethoxyacyl or acetoxy;

R₁₀selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy, methoxy, amino, methylamino or dimethylamino, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;

R₁₉、R₂₀each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-10Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl radical, C_4-10Cycloalkenyl group, 3-to 10-membered heterocyclic group, C_5-10Aryl, 5-10 membered heteroaryl, hydroxy, acetyl or-C (O) NH₂Or, R₁₉、R₂₀Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl, vinyl, trifluoromethyl, cyclopropyl, cyclopentyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy.

As a most preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

as a further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the following structure:

wherein, X₅、X₆One is selected from C (R)₁₀) And the other is selected from O or S;

R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy radical5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent(s);

R₃、R₄each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl;

R₅、R₆each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;

each R₁₀Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅and r is as described for compounds of formula (I).

As a still further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof is X₅、X₆One is selected from C (R)₁₀) And the other is selected from O;

R₃、R₄each independently selected from hydrogen or deuterium；

R₅、R₆Each independently selected from hydrogen, deuterium, methyl or cyclopropyl;

each R₁₀Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4An alkyl group;

each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, methyl or hydroxy, said groups being optionally further substituted by one or more substituents selected from deuterium or fluoro.

As a most preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as defined above, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein Pg is hydrogen, a hydroxyl protecting group, a mercapto protecting group or an amino protecting group, preferably hydrogen, tert-butyloxycarbonyl or p-toluenesulfonyl; x₁、X₂、X₃、X₄、X₅、X₆、Y₁、Y₂、Y₃、Z、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉As described for compounds of formula (I).

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described above, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention provides a use of a compound of formula (I), a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a cancer or tumor mediated at least in part by CD73, immune-related diseases and disorders, and metabolic diseases.

Preferably, the cancer or tumor is 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 cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma.

As a further preferred embodiment, the cancer 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.

As a preferred embodiment, the immune-related diseases and disorders are selected from the group consisting of rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infections, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

In a fifth aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition as described above for use as a medicament for the treatment of cancer or tumors, autoimmune diseases and disorders, metabolic diseases, mediated at least in part by CD 73.

In a sixth aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, for use as a medicament for treating prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma, rheumatoid arthritis, choriocarcinoma, epidermal basal cell carcinoma, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, Renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infections, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

In a seventh aspect, the present invention provides a method of treating cancer or tumors, immune-related diseases and disorders, metabolic disorders mediated at least in part by CD73, comprising administering to a patient a compound of formula (I) as described above, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.

Preferably, the cancer or tumor is 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 cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma; the immune-related and metabolic disorders are selected from the group consisting of rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.

In an eighth aspect, the present invention provides the use of a compound according to the first aspect as a CD73 inhibitor.

Detailed Description

The present inventors have extensively and intensively studied and, for the first time, developed a phosphonic acid derivative having CD73 inhibitory activity, having the following structure (i), a preparation method thereof, and pharmaceutical applications thereof. The series of compounds have strong inhibition effect on the enzyme activity of CD73, can be widely applied to the preparation of medicaments for treating at least part of CD 73-mediated cancers or tumors, immune-related diseases and disorders and metabolic diseases, in particular to medicaments for treating melanoma, colon cancer, pancreatic cancer, breast cancer, prostatic cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma, and are expected to be developed into a new-generation CD73 inhibitor medicament. On the basis of this, the present invention has been completed.

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group, e.g., "C_1-10Alkyl "refers to straight chain alkyl groups and branched chain-containing alkyl groups comprising 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-methylpentyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, 2-dimethylpentyl, 2, 4-dimethylhexyl, 2-, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.

Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C_3-10Cycloalkyl "refers to cycloalkyl groups comprising 3 to 10 carbon atoms, divided into monocyclic cycloalkyl, polycyclic cycloalkyl groups, wherein:

monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multi-spirocycloalkyl depending on the number of spiro atoms shared between rings, including but not limited to:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, including, but not limited to:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups may be included, including but not limited to:

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

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyanoNitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer 0,1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. For example, "4-10 membered heterocyclyl" refers to a cyclic group containing 4 to 10 ring atoms, and "3-6 membered heterocyclyl" refers to a cyclic group containing 3 to 6 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0,1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Spiroheterocyclyl groups include, but are not limited to:

"fused heterocyclic" refers to each ring and body in the systemOther rings in the system share an adjacent pair of atoms in a polycyclic heterocyclic group, one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)_r(wherein r is an integer of 0,1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, but not limited to:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0,1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, depending on the number of constituent rings, including but not limited to:

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

the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, e.g., "C_5-10Aryl "refers to an all-carbon aryl group having 5 to 10 carbons, and" 5-10 membered aryl "refers to an all-carbon aryl group having 5 to 10 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0,1, 2), e.g., 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、 -C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., C_2-10Alkenyl means a straight or branched chain alkenyl group having 2 to 10 carbons. Including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, a substituted aryl, a substituted heteroaryl, and a substituted heteroaryl,Halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., C_2-10Alkynyl refers to straight or branched chain alkynyl groups containing 2-10 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above, e.g., "C_1-10Alkoxy "refers to an alkyloxy group having 1 to 10 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

Alkoxy groups may be optionally substituted or unsubstitutedWhen substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"Cycloalkoxy" means and-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C_3-10Cycloalkoxy "refers to cycloalkyloxy groups containing 3-10 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

"Heterocyclyloxy" means and-O-heterocyclyl, wherein heterocyclyl is as defined above, e.g. "C_3-10Heterocyclooxy "refers to heterocyclyloxy having 3-10 carbons, including but not limited to azetidinyloxy, oxacycloxyButoxy, azacyclopentyloxy, nitrogen, oxacyclohexyloxy, and the like.

The heterocyclyloxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s).

“C_1-10Alkanoyl "means C_1-10The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C_0-9-C (O) - ", e.g." C₁-c (o) — "means acetyl; "C₂-c (o) — "refers to propionyl; "C₃-C (O) -means butyryl or isobutyryl.

“-C_0-8-S(O)_rR₂₁"means-S (O)_rR₂₁With sulfur atoms bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-O-R₂₂"means-O-R₂₂In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(O)OR₂₂"means-C (O) OR₂₂Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(O)R₂₃"means-C (O) R₂₃Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-O-C(O)R₂₃"means-O-C (O) R₂₃In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-NR₂₄R₂₅"means-NR₂₄R₂₅In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(O)NR₂₄R₂₅"means-C (O) NR₂₄R₂₅Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-N(R₂₄)-C(O)R₂₃"means-N (R)₂₄)-C(O)R₂₃In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

"halogen substituted C_1-10Alkyl "refers to a 1-10 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C_1-8Alkoxy "a 1-8 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

The LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade (deg.C).

Synthesis of intermediate

1. Preparation of (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

The first step is as follows: synthesis of 2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

2, 4-dichloro pyrrolo [2, 1-f)][1,2,4]Triazine (1.51g,8.0mmol) was dissolved in 1, 4-dioxane (20mL), N-diisopropylethylamine (2.08g,16.1mmol) was added at room temperature, N-methylcyclopentylamine (1.44g,66 wt%, 9.6mmol) was added, the reaction was stirred at room temperature for 1 hour, and then concentrated, ethyl acetate was added, and the mixture was washed once with water, a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated common salt solution in this order, dried over sodium sulfate, and concentrated to give 2-chloro-N-cyclopentyl-N-methylpyrrolido [2,1-f ]][1,2,4]Triazin-4-amine (1.97g, 96% yield). MS M/z (ESI) 251.2 [ M + H ]]⁺。

¹H NMR(400MHz,CDCl₃)δ7.52(dd,J＝2.7,1.5Hz,1H),6.78(dd,J＝4.6,1.6Hz,1H),6.58(dd,J＝4.6,2.7Hz,1H),3.28(s,3H),2.09–1.92(m,2H),1.87–1.57(m,7H)。

The second step is that: synthesis of 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

2-chloro-N-cyclopentyl-N-methyl pyrrolo [2, 1-f)][1,2,4]Dissolving triazine-4-amine (2.66g,10.6mmol) in dichloromethane (20mL), adding N-bromosuccinimide (1.89g,10.6mmol) at-10 deg.C, stirring at constant temperature for 10 min, heating to room temperature for reaction for 15.5 h, adding N, N-dimethylformamide (0.5mL), stirring for 10 min, washing with saturated sodium bicarbonate three times, washing with saturated saline once, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/dichloromethane (2.5:1) ]]To obtain 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f][1,2,4]Triazin-4-amine (2.90g, 82% yield). MS M/z (ESI):329.2 and 331.2[ M + H ]]⁺。

¹H NMR(400MHz,CDCl₃)δ6.82(d,J＝4.8Hz,1H),6.63(d,J＝4.8Hz,1H),3.27(s,3H),2.05–1.92(m,2H),1.85–1.59(m,7H)。

The third step: synthesis of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-ol

Reacting 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ]][1,2,4]Dissolving triazine-4-amine (2.90g,8.8mmol) in 2-methyltetrahydrofuran (20mL), dropwise adding n-butyllithium (4.95mL,2.5M,12.4mmol) under nitrogen at-78 deg.C, reacting under stirring at the temperature for 1 hour, dropwise adding a solution of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (3.68g,8.8mmol) in 2-methyltetrahydrofuran (5mL) at the temperature, reacting under stirring for 1 hour, quenching with saturated ammonium chloride solution, extracting with ethyl acetate twice after raising to room temperature, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: stone column chromatographyOil Ether-Petroleum Ether/Ethyl acetate (2.5:1)]To obtain (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-ol (3.80g, 64% yield). MS M/z (ESI) 651.6[ M + H-H₂O]⁺,oxonium。

The fourth step: synthesis of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

Reacting (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-ol (3.80g,5.7mmol), triethylsilane (9.07mL,56.8mmol) were dissolved in dichloromethane/acetonitrile mixed solution (30mL,1:1), boron trifluoride diethyl etherate (3.50mL,28.4mmol) was added dropwise at-20 ℃, after stirring at constant temperature for 1 hour, saturated sodium bicarbonate was added to quench the reaction, the reaction was warmed to room temperature, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated [ eluent: petroleum ether-petroleum ether/ethyl acetate (2.5:1) ]]To give 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-N-methylpyrrolido [2, 1-f)][1,2,4]Triazin-4-amine (2.35g, 63% yield). MS M/z (ESI) 653.5[ M + H ]]⁺。

¹H NMR(400MHz,CDCl₃)δ7.41–7.35(m,2H),7.28–7.15(m,13H),6.67–6.57(m,2H),5.58(d,J＝2.5Hz,1H),4.86–4.72(m,2H),4.62–4.46(m,2H),4.44–4.20(m,3H),4.12(dd,J＝4.8,2.6Hz,1H),4.00(dd,J＝7.8,4.7Hz,1H),3.80(dd,J＝10.8,3.1Hz,1H),3.63(dd,J＝10.8,4.2Hz,1H),3.19(s,3H),1.97–1.88(m,2H),1.77–1.50(m,7H)。

The fifth step: synthesis of (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

Reacting 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-N-methylpyrrolo [2, 1-f)][1,2,4]Triazin-4-amine (0.70g,1.1mmol), chlorobenzene (0.12g,1.1mmol) dissolved in tetrahydrofuran solution (10mL), added palladium hydroxide (0.14g,15 wt%), hydrogen replaced three times, stirred at room temperature and normal pressure for reaction for 13 hours, filtered, concentrated, and separated by column chromatography [ eluent: dichloromethane to dichloromethane/methanol (9:1)]To obtain (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (0.33g, 80% yield). MS M/z (ESI) 383.4[ M + H]⁺。

¹H NMR(400MHz,CDCl₃)δ6.77(d,J＝4.7Hz,1H),6.64(d,J＝4.6Hz,1H),5.07(d,J＝8.0Hz,1H),4.71(dd,J＝8.1,5.5Hz,1H),4.35(dd,J＝5.6,2.2Hz,1H),4.20(q,J＝2.4Hz,1H),3.90(dd,J＝12.1,2.5Hz,1H),3.73(dd,J＝12.2,2.5Hz,1H),3.27(s,3H),1.97(d,J＝11.9Hz,2H),1.66(s,7H)。

Preparation of intermediates 2-4 reference was made to the synthesis of intermediate 1 to give:

5. preparation of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

The first step is as follows: synthesis of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-ol

Reacting 7-bromo-2-chloro-N-cyclopentyl pyrrolo [2,1-f][1,2,4]Triazine-4-amine (2.20g,6.97mmol) was dissolved in 2-methyltetrahydrofuran (20mL), n-butyllithium (6.41mL,2.5M,16.0mmol) was added dropwise at-78 ℃ under nitrogen, stirring under constant temperature for 1 hour, at this temperature, trimethylchlorosilane (752mg,6.97mmol) was added dropwise, the reaction was stirred while maintaining the temperature for 1 hour, a solution of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (3.47g,8.3mmol) in 2-methyltetrahydrofuran (5mL) was added dropwise at this temperature, the reaction was stirred while maintaining the temperature for 1 hour, quenched with a saturated ammonium chloride solution, extracted twice with ethyl acetate after warming to room temperature, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography separation [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (2: 1).]To obtain (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-ol (1.50g, 32% yield). MS M/z (ESI) 637.6[ M + H-H₂O]⁺,oxonium。

The second step is that: synthesis of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

Reacting (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-ol (1.50g,2.29mmol), triethylsilane (1.06g,9.16mmol) were dissolved in a dichloromethane/acetonitrile mixed solution (30mL,1:1), boron trifluoride diethyl ether (1.62g,11.45mmol) was added dropwise at-20 ℃, the reaction was allowed to proceed for 1 hour, and then saturated carbon was addedQuenching reaction with sodium hydrogen carbonate, heating to room temperature, extracting twice with dichloromethane, mixing organic phases, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (2:1)]To give 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentylpyrrolo [2, 1-f)][1,2,4]Triazin-4-amine (1g, 68% yield). MS M/z (ESI) 639.6[ M + H ]]⁺。

6. Preparation of (2S,3R,4S,5R) -2- (4- (cyclopentylamino) -2-methylpyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

The first step is as follows: synthesis of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentyl-2-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

In a microwave reaction tube under the protection of nitrogen gas in a 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl pyrrolo [2,1-f ] group][1,2,4]Adding potassium carbonate (0.20g,1.4mmol) and tetratriphenylphosphine palladium (0.22g,0.19mmol) in sequence into dioxane (4 mL)/water (1mL) solution of triazine-4-amine (0.30g,0.48mmol) and trimethylcyclotriboroxane (0.12g,0.94mmol), microwave-insulating at 130 deg.C for 6 hours, adding ethyl acetate, washing with water and saturated common salt water in sequence, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (4:1) ]]To give 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentyl-2-methylpyrrolo [2, 1-f)][1,2,4]Triazin-4-amine (0.12g, 40% yield). MS M/z (ESI) 619.8[ M + H ]]⁺。

The second step is that: synthesis of (2S,3R,4S,5R) -2- (4- (cyclopentylamino) -2-methylpyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

Reacting 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentyl-2-methylpyrrolo [2,1-f ]][1,2,4]Triazine-4-amine (0.11g,0.18mmol) was dissolved in tetrahydrofuran solution (5mL), palladium hydroxide (66mg,15 wt%) was added, hydrogen gas was substituted three times, and then the mixture was allowed to react at 30 ℃ for 48 hours, filtered, concentrated and separated by column chromatography [ eluent: dichloromethane to dichloromethane/methanol (9:1) ]]To obtain (2S,3R,4S,5R) -2- (4- (cyclopentylamino) -2-methylpyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (50mg, yield 79%). MS M/z (ESI) 349.2[ M + H ]]⁺。

¹H NMR(400MHz,MeOH-d₄)δ6.81(d,J＝4.5Hz,1H),6.61(d,J＝4.4Hz,1H),5.14(d,J＝7.6Hz,1H),4.65–4.55(m,2H),4.21(dd,J＝5.3,3.0Hz,1H),4.06(q,J＝3.1Hz,1H),3.80(dd,J＝12.0,3.1Hz,1H),3.69(dd,J＝12.1,3.3Hz,1H),2.34(s,3H),2.13–1.58(m,8H)。

Preparation of intermediates 7-9 prepared according to intermediate 6 method:

10. preparation of (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) -5-fluoropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

The first step is as follows: synthesis of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-5-fluoropyrrolo [2,1-f ] [1,2,4] triazin-4-amine

Dissolving 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (0.20g,0.31mmol) in acetonitrile (1.5mL), adding Selectfluor (0.28g,0.78mmol) at room temperature, carrying out an incubation reaction for 2 hours, concentrating, and then carrying out column chromatography separation [ eluent: petroleum ether-petroleum ether/ethyl acetate (2:1) ] to obtain 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-5-fluoropyrrolo [2,1-f ] [1,2,4] triazin-4-amine (53mg, 32% yield).

¹H NMR(400MHz,CDCl₃)δ7.43–7.25(m,15H),6.37(s,1H),5.58–5.55(m,1H),4.80(s,2H),4.63–4.45(m,4H),4.39–4.29(m,2H),4.17–4.03(m,2H),3.83(dd,J＝10.9,3.2Hz,1H),3.64(dd,J＝10.7,3.7Hz,1H),2.20–2.10(m,2H),1.82–1.60(m,6H).MS m/z(ESI):657.7[M+H]⁺。

The second step is that: synthesis of (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) -5-fluoropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

Reacting 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -2-chloro-N-cyclopentyl-5-fluoropyrrolo [2, 1-f)][1,2,4]Dissolving triazine-4-amine (67mg,0.10mmol) and chlorobenzene (22mg,0.20mmol) in tetrahydrofuran solution (2mL), adding palladium hydroxide (34mg,15 wt%), replacing with hydrogen for three times, keeping the temperature at 35 ℃, stirring for reaction for 16 hours, filtering, concentrating, and performing column chromatography separation [ eluent: dichloromethane-dichloromethane/methanol (9:1)]To obtain (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) -5-fluoropyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (18mg, 44% yield). MS M/z (ESI) 387.4[ M + H ]]⁺。

¹H NMR(400MHz,MeOH-d₄)δ6.50(s,1H),5.17(d,J＝6.3Hz,1H),4.62–4.53(m,1H),4.42–4.26(m,1H),4.19–4.10(m,1H),4.05–3.95(m,1H),3.82–3.64(m,2H),2.15–2.04(m,2H),1.83–1.61(m,6H)。

11. Preparation of (2S,3R,4S,5R) -2- (4- (cyclopentylamino) imidazo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

The first step is as follows: synthesis of tert-butyl-7-bromoimidazo [2,1-f ] [1,2,4] triazin-4-yl-carbamate

7-bromoimidazo [2,1-f ] was added sequentially in a 100mL three-necked flask][1,2,4]Triazine-4-amine (1.76g, 68.1%, 6.4mmol), acetonitrile (15mL), di-tert-butyl dicarbonate (1.81g,8.4mmol), 4-dimethylaminopyridine (79mg,0.64mmol) and N, N-diisopropylethylamine (2.06g,16.0mmol), stirring and reacting at 30 ℃ for 13.5 hours, diluting with ethyl acetate after the reaction is completed, washing with water, a saturated ammonium chloride solution, water, a saturated sodium bicarbonate solution and a saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (2:1) ]]To obtain tert-butyl-7-bromoimidazo [2,1-f][1,2,4]Triazin-4-yl-carbamates (0.90g, 58% yield). MS M/z (ESI) 314.2 and 316.2[ M + H]⁺。

¹H NMR(400MHz,CDCl₃)δ8.60(s,1H),8.51(s,1H),7.68(s,1H),1.56(s,9H)。

The second step is that: synthesis of tert-butyl-7-bromoimidazo [2,1-f ] [1,2,4] triazin-4-cyclopentylcarbamate

At 0 ℃ in tert-butyl-7-bromoimidazo [2,1-f][1,2,4]Adding cyclopentanol (0.62g,7.2mmol) and triphenylphosphine (1.88g,7.2mmol) into a tetrahydrofuran (15mL) solution of triazin-4-yl-carbamate (0.90g,2.9mmol), reacting for 5 minutes while maintaining the temperature, dropwise adding diisopropyl azodicarboxylate (1.45g,7.2mmol), reacting for 10 minutes while warming to room temperature, then further heating to 45 ℃ and stirring for 2 hours, monitoring the reaction by LCMS, concentrating after completion of the reaction, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (9:1) ] [ eluent: petroleum ether-petroleum ether/ethyl acetate (eluent: 1 ]]To obtain tert-butyl-7-bromoimidazo [2,1-f][1,2,4]Triazine-4-cyclopentyl carbamate (0.74g, 67% yield). MS M/z (ESI) 382.4 and 384.4[ M + H]⁺。

¹H NMR(400MHz,CDCl₃)δ8.59(s,1H),7.78(s,1H),4.90(p,J＝8.7Hz,1H),2.00(dt,J＝8.3,5.7Hz,4H),1.81(dh,J＝11.4,4.9Hz,2H),1.63–1.51(m,2H),1.41(s,9H)。

The third step: synthesis of tert-butyl-7- (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-ylimidazo [2,1-f ] [1,2,4] triazin-4-ylcyclopentylcarbamate

Tert-butyl-7-bromoimidazo [2,1-f ] at-70 deg.C][1,2,4]Adding n-butyl lithium (1.0mL,2.5M,2.5mmol) dropwise into a 2-methyltetrahydrofuran (2.5mL) solution of triazine-4-cyclopentyl carbamate (0.74g,1.9mmol), reacting while maintaining the temperature for 20 minutes after the addition is finished, adding 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone (0.89g,2.1mmol) 2-methyltetrahydrofuran (1.5mL) dropwise again, reacting while maintaining the temperature and stirring for 2 hours, monitoring the reaction by LCMS, adding saturated ammonium chloride to quench the reaction, extracting with ethyl acetate, washing with saturated ammonium chloride solution, water and saturated salt water in sequence, drying with anhydrous sodium sulfate, concentrating, and separating [ eluent: petroleum ether-petroleum ether/ethyl acetate (1:1)]To obtain tert-butyl-7- (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-ylimidazo [2, 1-f)][1,2,4]Triazine-4-cyclopentylaminomethylAcid ester (0.36g, 12% yield). MS M/z (ESI) 722.8[ M + H ]]⁺。

The fourth step: synthesis of 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentylimidazo [2,1-f ] [1,2,4] triazin-4-amine

-20 ℃ in tert-butyl-7- (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-ylimidazo [2, 1-f-][1,2,4]Adding triethylsilane (0.26g,2.3mmol) into a solution of triazine-4-cyclopentyl carbamate (0.36g, 45.4%, 0.23mmol) in dichloromethane (5mL), then dropwise adding boron trifluoride diethyl etherate (0.16g,1.1mmol), reacting for 2 hours under stirring at constant temperature, heating to room temperature for reaction for 2.5 hours, monitoring the reaction by LCMS, adding a saturated sodium bicarbonate solution to quench the reaction, then extracting with dichloromethane, washing with the saturated sodium bicarbonate solution, water and a saturated common salt solution in sequence, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (2:1) ]]To give 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentylimidazo [2, 1-f)][1,2,4]Triazin-4-amine (0.19g, 61% yield). MS M/z (ESI) 606.8[ M + H ]]⁺。

The fifth step: synthesis of (2S,3R,4S,5R) -2- (4- (cyclopentylamino) imidazo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol

Reacting 7- ((2S,3S,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-yl) -N-cyclopentylimidazo [2, 1-f)][1,2,4]Dissolving triazine-4-amine (0.19g,0.31mmol) in tetrahydrofuran solution (5mL), adding palladium hydroxide (0.19g,15 wt%), replacing with hydrogen for three times, keeping the temperature at 30 deg.C, stirring for reaction for 22 hours, filtering, concentrating, and separating by column chromatography [ eluent: dichloromethane-dichloromethaneAlkane/methanol (9:1)]To obtain (2S,3R,4S,5R) -2- (4- (cyclopentylamino) imidazo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (78mg, 73% yield). MS M/z (ESI) 336.4[ M + H ]]⁺。

¹H NMR(400MHz,MeOH-d₄)δ8.09(s,1H),7.60(s,1H),5.19(d,J＝6.8Hz,1H),4.54(td,J＝7.6,6.9,5.5Hz,2H),4.20(dd,J＝5.3,3.9Hz,1H),4.04(q,J＝3.7Hz,1H),3.80(dd,J＝12.1,3.3Hz,1H),3.77–3.64(m,2H),2.18–2.05(m,2H),1.88–1.66(m,6H)。

12. Preparation of (2R,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile

The first step is as follows: synthesis of 2-chloro-N-cyclopentylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

2, 4-dichloro pyrrolo [2, 1-f)][1,2,4]Triazine (5.0g,26.6mmol) was dissolved in 1, 4-dioxane (50mL), N-diisopropylethylamine (9.73g,79.7mmol) was added at room temperature, cyclopentylamine (4.53g,53.2mmol) was further added, the reaction was stirred at room temperature for 1 hour, and then concentrated, ethyl acetate was added, each was washed with water, a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated common salt solution in this order, dried over anhydrous sodium sulfate, and concentrated to give 2-chloro-N-cyclopentylpyrrolo [2,1-f ] -pyrrolo [2,1-f ] a][1,2,4]Triazin-4-amine (5.60g, 89% yield). MS M/z (ESI) 237.2[ M + H]⁺。

The second step is that: synthesis of tert-butyl (2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

2-chloro-N-cyclopentyl pyrrolo [2, 1-f)][1,2,4]Triazine-4-amine (5.0g,26.6mmol) was dissolved in tetrahydrofuran (50mL), N, N-diisopropylethylamine (6.49g,53.2mmol), N, N-dimethylpyridin-4-amine (317mg,2.6mmol) were added at room temperature, di-tert-butyl dicarbonate (8.69g,39.9mmol) was further added, the reaction was stirred at room temperature for 16 hours, and column chromatography was performed after concentration [ eluent: Petroleum ether-Petroleum ether/Ethyl acetate (5:1) ]]To obtain tert-butyl (2-chloropyrrolo [2, 1-f)][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (7.20g, 90% yield). MS M/z (ESI) 337.2[ M + H ]]⁺。

The second step is that: synthesis of tert-butyl (7-bromo-2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

Reacting tert-butyl (2-chloropyrrolo [2, 1-f)][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (7.20g,21.4mmol) is dissolved in dichloromethane (50mL), N-bromosuccinimide (3.81g,21.4mmol) is added at-10 ℃, stirring is carried out for 10 minutes at the same temperature, then the mixture is heated to room temperature for reaction for 15.5 hours, N-dimethylformamide (0.5mL) is added for stirring for 10 minutes, the mixture is washed three times with saturated sodium bicarbonate solution, washed once with saturated saline solution, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether-dichloromethane (5:1) ]]To obtain tert-butyl (7-bromo-2-chloropyrrolo [2, 1-f)][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (8.0g, 89% yield). MS M/z (ESI) 415.2 and 417.2[ M + H ]]⁺。

The third step: synthesis of tert-butyl (7- ((3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) -2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

Reacting tert-butyl (7-bromo-2-)Chloro pyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (10g,24.1mmol) is dissolved in 2-methyltetrahydrofuran (60mL), n-butyllithium (11.55mL,2.5M,28.8mmol) is added dropwise at-78 ℃ with nitrogen, stirring with stirring for 1 hour with stirring, at this temperature, a solution of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (11.09g,26.5mmol) in 2-methyltetrahydrofuran (20mL) was added dropwise, and the reaction was stirred for 1 hour with heat preservation, quenching with saturated ammonium chloride solution, raising to room temperature, extracting twice with ethyl acetate, combining organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (4: 1).]To give tert-butyl (7- ((3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) -2-chloropyrrolo [2, 1-f)][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (12g, 65% yield). MS M/z (ESI) 737.2[ M + H-H₂O]⁺,oxonium。

The fourth step: synthesis of (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-carbonitrile

Tert-butyl (7- ((3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) -2-chloropyrrolo [2, 1-f)][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (9.0g,12mmol), trimethylsilyl cyanide (3.78g,48mmol), indium trifluoromethanesulfonate (13.47g,24mmol) were dissolved in acetonitrile solution (300mL), stirred at 70 ℃ for 16 hours, quenched with saturated sodium bicarbonate, warmed to room temperature, extracted twice with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether to petroleum ether/ethyl acetate (2.5:1) ]]To obtain (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-carbonitrile (7.2g, 90% yield). MS M/z (ESI) 664.2[ M + H ]]⁺。

The fifth step: synthesis of (2R,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile

Reacting (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-2-carbonitrile (9.6g,14.4mmol) was dissolved in dichloromethane (400mL), boron trichloride (72mL,1M,72mmol) was added at 0 deg.C, the reaction was stirred at that temperature for 4 hours, methanol was added to quench the reaction, the reaction was allowed to warm to room temperature, and after concentration, reverse phase column chromatography separation [ eluent: water-water/acetonitrile (7:3) ]]To obtain (2R,3R,4S,5R) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile (1g, 17% yield). MS M/z (ESI) 394.2[ M + H]⁺。

¹H NMR(400MHz,MeOH-d₄)δ6.96(d,J＝4.8Hz,1H),6.91(d,J＝4.4Hz,1H),4.88–4.85(m,1H),4.59–4.54(m,1H),4.27–4.22(m,1H),3.89–3.85(m,1H),3.76–3.72(m,1H),2.11–2.06(m,2H),1.80–1.77(m,2H),1.71–1.61(m,4H)。

13. Preparation of (1R,2S,3S,5R) -3- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) cyclopentane-1, 2-diol

The first step is as follows: synthesis of tert-butyl (7- ((3aR,6R,6aR) -6- (tert-butoxymethyl) -4-hydroxy-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxazol-4-yl) -2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

Tert-butyl (7-bromo-2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate (730mg,1.75mmol) was dissolved in 2-methyltetrahydrofuran (20mL), n-butyllithium (1mL,2.5M,2.5mmol) was added dropwise at-78 ℃ with nitrogen, the reaction was stirred with stirring at that temperature for 1 hour, a solution of (3aR,6R,6aR) -6- (tert-butoxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxazol-4-one (600mg,2.46mmol) in 2-methyltetrahydrofuran (5mL) was added dropwise at that temperature, the reaction was continued with stirring at that temperature for 1 hour, quenched with a saturated ammonium chloride solution, warmed to room temperature and extracted twice with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether-petroleum ether/ethyl acetate (2.5:1) ] to give tert-butyl (7- ((3aR,6R,6aR) -6- (tert-butoxymethyl) -4-hydroxy-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxazol-4-yl) -2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate (550mg, 54% yield).

The second step is that: synthesis of tert-butyl (7- ((3aR,4R,6aS) -4- (tert-butoxymethyl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxazol-6-yl) -2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

Tert-butyl (7- ((3aR,6R,6aR) -6- (tert-butoxymethyl) -4-hydroxy-2, 2-dimethyltetrahydro-4H-cyclopenta [ d)][1,3]Dioxazol-4-yl) -2-chloropyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (580mg,1.00mmol) is dissolved in tetrahydrofuran (10mL), Boji's reagent (1000mg,4mmol) is added at room temperature, the reaction is stirred at 80 ℃ for 16 hours, and after concentration column chromatography separation [ petroleum ether-petroleum ether/ethyl acetate (10:1)]To give tert-butyl (7- ((3aR,4R,6aS) -4- (tert-butoxymethyl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d)][1,3]Dioxazol-6-yl) -2-chloropyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (440mg, 78% yield). MS M/z (ESI) 561.6[ M + H ]]⁺。

The third step: synthesis of tert-butyl (7- ((3aS,4S,6R,6aR) -6- (tert-butoxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxazol-4-yl) -2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) (cyclopentyl) carbamate

Tert-butyl (7- ((3aR,4R,6aS) -4- (tert-butoxymethyl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d)][1,3]Dioxazol-6-yl) -2-chloropyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (440mg,0.78mmol) was dissolved in tetrahydrofuran (20mL), palladium hydroxide/carbon (400mg) was added at room temperature, the reaction was stirred at room temperature under hydrogen for 4 hours, and after filtration, column chromatography was performed [ petroleum ether to petroleum ether/ethyl acetate (10:1)]To give tert-butyl (7- ((3aS,4S,6R,6aR) -6- (tert-butoxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d)][1,3]Dioxazol-4-yl) -2-chloropyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (280mg, 63% yield). MS M/z (ESI) 563.6[ M + H ]]⁺。

The fourth step: synthesis of (1R,2S,3S,5R) -3- (2-chloro-4- (cyclopentylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) cyclopentane-1, 2-diol

Tert-butyl (7- ((3aS,4S,6R,6aR) -6- (tert-butoxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d)][1,3]Dioxazol-4-yl) -2-chloropyrrolo [2,1-f][1,2,4]Triazin-4-yl) (cyclopentyl) carbamate (260mg,0.46mmol) is dissolved in acetonitrile (0.5mL), concentrated hydrochloric acid (0.5mL) is added at room temperature, the mixture is stirred at room temperature for reaction for 16 hours, and column chromatography separation is carried out after concentration [ eluent: water to acetonitrile (10 to 100) ]]To obtain (1R,2S,3S,5R) -3- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) cyclopentane-1, 2-diol (140mg, 83% yield). MS M/z (ESI) 367.2[ M + H]⁺。

14. Preparation of (2R,3R,4S,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol

The first step is as follows: synthesis of (4S,5R) -4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one

(4S,5R) -4-hydroxy-5- (hydroxymethyl) dihydrofuran-2 (3H) -one (25.0g,0.189mol) was dissolved in DMF (230mL), imidazole (77.3g,1.14mol) was added, triisopropylsilylchloride (146g,0.757mol) was slowly added dropwise at 0 deg.C, and after completion of the addition, stirring was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (1L), extracted with ethyl acetate three times, and the organic phases were combined, washed successively with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography [ eluent: petroleum ether/ethyl acetate (19:1) ] to give (4S,5R) -4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (80.0g, yield 95%).

The second step is that: synthesis of (3S,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one

(4S,5R) -4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (10.0g,22.5mmol) was dissolved in anhydrous tetrahydrofuran (100mL), N-fluorobisbenzenesulfonamide (10.6g, 33.7mmol) was added, bistrimethylsilylamidolithium (1.0M tetrahydrofuran solution, 29.2mL,29.2mmol) was slowly added dropwise at-78 deg.C, the reaction was stirred at-78 deg.C for 2 hours after completion of the dropwise addition, and after completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution. Ethyl acetate was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: Petroleum ether/ethyl acetate (40/1) ] to give (3S,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (7.0g, 67% yield).

The third step: synthesis of (3S,4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol

After 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (1.50g,4.55mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (15mL), it was cooled to-78 deg.C, N-butyllithium (2.5M tetrahydrofuran solution, 2.7mL,6.37mmol) was slowly added dropwise, and after completion of the addition, the reaction was stirred at-78 deg.C for 1 hour, a solution of (3S,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (2.32g,5.01mmol) in 2-methyltetrahydrofuran (10mL) was added slowly and the reaction was stirred for 1 hour after the addition was complete. After the reaction was completed, the reaction was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether/ethyl acetate (8/1) ] to give (3S,4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol (2.0g, 61% yield).

The fourth step Synthesis of 2-chloro-N-cyclopentyl-7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

(3S,4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol (2.0g,2.8mmol) was dissolved in dichloromethane (30mL), adding boron trifluoride ether solution (2.0g,14.0mmol) at-20 ℃, stirring for five minutes, slowly adding triethylsilane (3.3g,28.0mmol), after finishing dropwise adding, continuing stirring and reacting for 2 hours at-20 ℃, after finishing the reaction, adding saturated sodium bicarbonate aqueous solution for quenching, and extracting with dichloromethane for three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether/ethyl acetate (10/1) ] to give 2-chloro-N-cyclopentyl-7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (1.6g, 82% yield).

The fifth step: synthesis of (2R,3R,4S,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol

2-chloro-N-cyclopentyl-7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2, 1-f)][1,2,4]Triazin-4-amine (600mg,0.86mmol) was dissolved in tetrahydrofuran (15mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.6mL,2.6mmol) was added at room temperature, stirred at room temperature overnight, concentrated and separated by reverse phase column chromatography [ eluent: acetonitrile/water (40/60)]To obtain (2R,3R,4S,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol (300 mg)Yield 91%). MS M/z (ESI) 385.4[ M + H ]]⁺。

Preparation of intermediates 15-29 prepared in accordance with the synthetic procedure for intermediate 14:

30. preparation of (2R,3R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol

The first step is as follows: synthesis of ((4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol

Dissolving 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolido [2,1-f ] [1,2,4] triazin-4-amine (2.90g,8.8mmol) in 2-methyltetrahydrofuran (20mL), dropwise adding N-butyllithium (4.95mL,2.5M,12.4mmol) under nitrogen at-78 deg.C, stirring and reacting under stirring at maintaining temperature for 1 hour, dropwise adding a solution of (4R,5R) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (4.23g,8.8mmol) in 2-methyltetrahydrofuran (5mL) at that temperature, further stirring and reacting under maintaining temperature for 1 hour, quenching with a saturated ammonium chloride solution, the temperature was raised to room temperature, ethyl acetate was extracted twice, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and after concentration, column chromatography separation [ eluent: petroleum ether to petroleum ether/ethyl acetate (2.5:1) ] was carried out to give ((4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol (3.15g, 50% yield).

The second step is that: synthesis of 2-chloro-N-cyclopentyl-7- ((2S,4R,5R) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine

((4R,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-ol (3.15g,4.4mmol), triethylsilane (7.03mL,44.0mmol) were dissolved in a dichloromethane/acetonitrile mixed solution (30mL,1:1), boron ethyl ether (2.78mL, 22.0mmol) was added dropwise at-20 ℃, the reaction was stirred for 1 hour with constant temperature, saturated sodium bicarbonate was added to quench the reaction, the reaction was warmed to room temperature, dichloromethane was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography was performed after concentration [ eluent: petroleum ether-petroleum ether/ethyl acetate (2.5:1) ] To give 2-chloro-N-cyclopentyl-7- ((2S,4R,5R) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (1.88g, 60% yield).

The third step: synthesis of (2R,3R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol

2-chloro-N-cyclopentyl-7- ((2S,4R,5R) -3, 3-difluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f][1,2,4]Triazin-4-amine (0.71g,1.0mmol) was dissolved in tetrahydrofuran solution (10mL), TBAF (2mL,1M/L) was added, the reaction was stirred at room temperature for 12 hours, and after concentration, column chromatography was performed [ eluent: dichloromethane to dichloromethane/methanol (9:1) ]]To obtain (2R,3R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol (0.30g, 75% yield). MS M/z (ESI) 403.4[ M + H ]]⁺。

Preparation of intermediates 31-34 reference was made to the synthesis of intermediate 30 to give:

35. preparation of 4- (cyclopentyl (methyl) amino) -7- ((2S,3S,4R,5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazine-2-carbonitrile

The first step is as follows: synthesis of 4- (cyclopentyl (methyl) amino) -7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazine-2-carbonitrile

2-chloro-N-cyclopentyl-7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (880mg,1.26mmol) was dissolved in anhydrous N, N-dimethylformamide (10mL), and tetrakis (triphenylphosphine) palladium (580mg,0.51mmol) and zinc cyanide (444mg,3.78mmol) were added. The reaction was stirred at 130 ℃ for 9 hours under microwave conditions, filtered, the filtrate was extracted three times with ethyl acetate after adding water (100mL), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed [ eluent: Petroleum ether/Ethyl acetate (10/1) ] to give 4- (cyclopentyl (methyl) amino) -7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazine-2-carbonitrile (690mg, 79% yield).

The second step is that: synthesis of 4- (cyclopentyl (methyl) amino) -7- ((2S,3S,4R,5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazine-2-carbonitrile

Reacting 4- (cyclopentyl (methyl) amino) -7- ((2S,3R,4R,5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f][1,2,4]Triazine-2-carbonitrile (690mg,1.0mmol) was dissolved in tetrahydrofuran (15mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 3.0mL,3.0mmol) was added at room temperature, stirred at room temperature overnight, concentrated and separated by reverse phase column chromatography [ eluent: acetonitrile/water (75/25)]To give 4- (cyclopentyl (methyl) amino) -7- ((2S,3S,4R,5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2, 1-f)][1,2,4]Triazine-2-carbonitrile (350mg, 93% yield). MS M/z (ESI) 376.4[ M + H ]]⁺。

Preparation of intermediates 36-37 reference was made to the synthesis of intermediate 35 to give:

38. preparation of ((2R,3R,4S,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate

First step Synthesis of ((2R,3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate

(4S,5R) -4-hydroxy-5- (hydroxymethyl) dihydrofuran-2 (3H) -one (10g,75.7mmol) was dissolved in dry dichloromethane (100mL), pyridine (18g,227mmol) was added, and after cooling to-20 deg.C a solution of benzoyl chloride (11.7g,83.3mmol) in dichloromethane (50mL) was added dropwise. The reaction was stirred at-20 ℃ for 2 hours, then quenched with saturated aqueous sodium bicarbonate (150mL), the organic phase separated, washed successively with saturated aqueous sodium bicarbonate, water, dilute hydrochloric acid, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether/ethyl acetate (2/1)]((2R,3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate (13.3g, 74% yield) was obtained. MS M/z (ESI) 237.0[ M + H ]]⁺。

Second step Synthesis of ((2R,3S) -5-carbonyl-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate

((2R,3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate (13.3g,56.3mmol) was dissolved in N, N-dimethylformamide (100mL), imidazole (11.5g,169mmol) was added, triisopropylsilyl chloride (16.3g,84.5mmol) was slowly added dropwise at 0 ℃, gradually warmed to room temperature and stirred overnight, and the mixture was washed with a saturated aqueous sodium bicarbonate solution (500 m)L) quench the reaction, extract three times with ethyl acetate, combine the organic phases and wash with water and saturated brine in succession. Drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: petroleum ether/ethyl acetate (15/1)]((2R,3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate (20.0g, yield 90.5%) was obtained. 393.2[ M + H ] in MS M/z (ESI)]⁺。

Third step Synthesis of ((2R,3R,4S) -4-fluoro-5-carbonyl-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate

((2R,3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate (12.0g,30.6mmol) was dissolved in anhydrous tetrahydrofuran (150mL), and N-fluoro-N- (benzenesulfonyl) benzenesulfonamide (14.5g,45.9mmol) was added. Lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 39.4mL,39.4mmol) was added dropwise at-78 ℃, the reaction was stirred at-78 ℃ for 2 hours after completion of the dropwise addition, quenched with saturated aqueous ammonium chloride (500mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography [ eluent: ethyl acetate/petroleum ether (1/20) ] was performed after concentration to give ((2R,3R,4S) -4-fluoro-5-carbonyl-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (9.5g, yield 75.7%).

The fourth step: synthesis of ((2R,3R,4S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-5-hydroxy-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate

7-bromo-2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazine (1.77g,6.64mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (25mL), n-butyllithium (2.5M tetrahydrofuran solution, 3.45mL,8.63mmol) was slowly added dropwise at-78 deg.C, and after completion of the addition, a solution of ((2R,3R,4S) -4-fluoro-5-carbonyl-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (3.0g,7.31mmol) in 2-methyltetrahydrofuran (7mL) was slowly added dropwise with stirring at-78 deg.C for 1 hour. After the completion of the dropwise addition, the reaction was continued with stirring for 2 hours. Quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: ethyl acetate/petroleum ether (1/10) ] to give ((2R,3R,4S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-5-hydroxy-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (1.8g, 45% yield).

The fifth step: synthesis of ((2R,3R,4R,5S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate

((2R,3R,4S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-5-hydroxy-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (1.8g,3.0mmol) was dissolved in dichloromethane (30mL), a boron trifluoride diethyl ether solution (2.1g,15.0mmol) was added at-20 ℃ and stirred for 5 minutes, then triethylsilane (1.4g,12.0mmol) was slowly added and the reaction was stirred for 2 hours after completion of the dropwise addition. Quenched with saturated aqueous sodium bicarbonate solution, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: ethyl acetate/petroleum ether (1/15) ] to give ((2R,3R,4R,5S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (1.3g, 74% yield).

And a sixth step: synthesis of ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate

((2R,3R,4R,5S) -5- (2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (300mg,0.51mmol) was dissolved in 1, 4-dioxane (20mL), and (R) -1- (2-fluorophenyl) ethan-1-amine (108mg,0.77mmol) and N, N-diisopropylethylamine (200mg,1.54mmol) were added. The reaction was stirred at room temperature for 1 hour, and after concentration, column chromatography separation [ eluent: ethyl acetate/petroleum ether (1/10) ] gave ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (330mg, 93% yield).

The seventh step: synthesis of ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methanol

((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (330mg,0.48mmol) was dissolved in methanol/tetrahydrofuran/water (10mL/10mL/5mL), potassium carbonate (665mg,4.82mmol) was added, the reaction was stirred at room temperature for 2 hours, and column chromatography was performed after concentration [ eluent: ethyl acetate/dichloromethane (1/3) ] to obtain ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ((R) -1, 4R, 5S)) ) Ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methanol (280mg, 100% yield).

Eighth step: synthesis of ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate

((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methanol (280mg,0.48mmol) was dissolved in anhydrous dichloromethane (15mL), 4-dimethylaminopyridine (147mg,1.20mmol) and N, N-diisopropylethylamine (249mg,1.93mmol) were added, a solution of p-toluenesulfonyl chloride (138mg,0.72mmol) in dichloromethane (1mL) was slowly added dropwise at 0 ℃ and, after the addition was complete, the temperature was slowly raised to room temperature and the reaction was stirred for 2 hours. After completion of the reaction, it was quenched with saturated sodium bicarbonate, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: ethyl acetate/petroleum ether (1/10) ] to give ((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate (330mg, 93% yield).

The ninth step: synthesis of ((2R,3R,4S,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate

((2R,3R,4R,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -4-fluoro-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate (330mg,0.45mmol) was dissolved in tetrahydrofuran (15mL) and tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.9mL,0.9mmol) was added at room temperature. The reaction was stirred at room temperature for 2 hours, concentrated and separated by column chromatography [ eluent: ethyl acetate/dichloromethane (1/10)]To obtain ((2R,3R,4S,5S) -5- (2-chloro-4- (((R) -1- (2-fluorophenyl) ethyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl methyl 4-methylbenzenesulfonate (250mg,yield 96%). MS M/z (ESI) 579.0[ M + H ]]⁺。

Intermediates 39-59 were prepared according to the synthetic procedure for intermediate 38:

preparation of the second, specific example Compounds

Example 1 preparation of ((((((2R, 3S,4R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphanyl) methyl) phosphonic acid

Reacting (2S,3R,4S,5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (100mg,0.26mmol) was dissolved in trimethyl phosphate (2.5mL), a solution of methylene bis (phosphonium) chloride (0.33g,1.3mmol) in trimethyl phosphate (0.5mL) was added dropwise at 0 deg.C, the reaction was stirred for 3 hours with complete incubation, and thenAdding 0.5N triethylamine bicarbonate solution to quench reaction, freeze-drying, and separating by reversed phase column chromatography₁₈Column, eluent water-water/acetonitrile (9:1) + 0.1% ammonia]To obtain (((((2R,3S,4R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphanyl) methyl) phosphonic acid (5.1mg, 3.6% yield). MS M/z (ESI) 541.4[ M + H]⁺。

¹H NMR(400MHz,D₂O)δ6.97(d,J＝4.9Hz,1H),6.81(d,J＝4.8Hz,1H),5.25(d,J＝6.6Hz,1H),5.18–5.01(m,1H),4.54(dd,J＝6.6,5.4Hz,1H),4.35(t,J＝4.9Hz,1H),4.20(q,J＝4.2Hz,1H),4.01(t,J＝5.0Hz,2H),3.20(s,3H),2.11(t,J＝19.9Hz,2H),1.96–1.84(m,2H),1.78–1.61(m,6H)。

Examples 2-29 were prepared according to the synthetic method of example 1:

the nuclear magnetic data obtained by preparing the compounds 2 to 29 of the above examples are listed as follows:

example 31 preparation of ((((((2R, 3S,4R,5S) -5- (2-chloro-4- (cyclohexyl (methyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphanyl) methyl) phosphonic acid

((2R,3R,4S,5S) -5- (2-chloro-4- (cyclohexyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl methyl 4-methylbenzenesulfonate (250mg,0.45mmol), methylenebis (phosphonic acid) tri-N-butylamine (1.97g,2.26mmol) dissolved in N, N-dimethylformamide (5mL) was stirred at room temperature for 16 hours, and then separated by reverse phase column chromatography [ C₁₈Column, eluent water-water/acetonitrile (9:1) + 0.1% formic acid]To obtain (((((2R,3S,4R,5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphanyl) methyl) phosphonic acid (12mg, 5% yield). MS M/z (ESI) 557.4[ M + H ]]⁺。

¹H NMR(400MHz,D₂O)δ7.39–7.38(m,1H),6.82–6.81(m,1H),5.61–5.53(m,1H),5.30–5.17(m,1H),4.67–4.63(m,1H),4.51–4.37(m,1H),4.11–4.10(m,1H),4.04–4.01(m,2H),3.30–3.13(m,3H),2.12–2.08(m,2H),1.80–1.73(m,2H),1.72-1.65(m,2H),1.65–1.50(m,4H),1.42–1.31(m,2H)。

Examples 32-51 were prepared according to the synthetic method of example 31:

the nuclear magnetic data of the compounds prepared in the above examples 32 to 51 are listed as follows:

biological test evaluation

In vitro enzyme Activity evaluation of CD73

The present invention uses the malachite green test of CD73 in the soluble state synthesized in vitro to determine the properties of compounds for their CD73 inhibitory activity. The experimental procedure was as follows:

1. the enzymatic reactions of this experiment were carried out in 384 well plates at a concentration of 36ng/ml CD73 (R)&D systems #5795-EN-010) and various concentrations of the compound and 50. mu.M AMP in a 40. mu.l reaction (25mM Tris pH 7.5,5mM MgCl₂0.005% Tween-20) was incubated at 25 ℃ for 30 minutes;

2. the reaction was then stopped by adding 10 μ L of malachite green solution (Sigma) per well;

3. the concentration of the non-organic phosphate produced was determined according to the instructions of the reagent manufacturer.

4. CD73 enzyme activity was calculated from the concentration of the product, and IC was determined by analyzing the percent inhibition of the compounds of the invention at various concentrations using non-linear regression₅₀The value is obtained.

The experimental results of the compounds of the examples of the present invention are shown in table 1.

Second, evaluation of Cell surface CD73 enzyme Activity (Cell Titer Glo (CTG) experiment)

The invention adopts human breast cancer cell MDA-MB-231 endogenously expressing CD73 to evaluate the inhibition effect of the compound on the enzymatic activity of CD73 expressed on the cell surface. The cells used were derived from the cell bank of the Chinese academy of sciences. The experimental procedure was as follows:

1. 20000/well MDA-MB231 cells were seeded into 96-well plates before testing;

2. in RPMI1640, 10% fetal bovine serum (Gibco,10099-141) at 37 ℃ with 5% CO₂Culturing overnight in an incubator (cells were washed 3 times with serum-free RPMI medium at the time of testing);

3.50 μ l of serum-free medium containing compounds diluted at different concentrations was added to the cells and incubated for 15 minutes;

4. mu.l of 1.2mM AMP was added, incubated at 37 ℃ for 2 hours, 25. mu.l of the supernatant was taken from the cells and mixed with 25. mu.l of 100. mu.M ATP, and then the concentration of AMP in the sample was determined by the method of CTG (Promega, # G7573).

5. The inhibitory effect of the compounds of the examples and positive compounds of the present invention on the enzymatic activity of CD73 on the cell surface was then evaluated by quantitative determination of the rate of decrease in the substrate AMP levels in the cell culture supernatants after the reaction.

6. Finally the concentration of compound that results in inhibition of absolute median enzyme activity (IC) was determined using four-parameter curve fitting in Graphpad Prism₅₀)。

The experimental results of the compounds of the examples of the present invention are shown in table 1.

Table 1: biological test results

From in vitro enzymology or cell activity data of specific example compounds, the series of compounds of the invention have strong inhibition effect on the activity of CD73 enzyme.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (22)

1. A compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof:

   

   wherein the content of the first and second substances,

   X₁、X₂each independently is selected from N or CH;

   X₃、X₄each independently is selected from N or C;

   X₅、X₆each independently selected from O, S, C (R)₁₀) N or N (R)₁₁)；

   Y₁Selected from-O-, -S-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆)-；

   Y₂、Y₃Each independently selected from-O-, -S-or-C (R)₁₇R₁₈)-；

   Z is selected from-O-, -S-or-NH-;

   R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₃、R₄each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、 -C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₅、R₆each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Or, R₅And R₆Together with the carbon atom to which they are directly attached form a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₇、R₈、R₉each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃or-C_0-8-C(O)NR₂₄R₂₅Or, R₇And R₈Or R₉Together with the group to which they are directly attached form a 6-to 10-membered heterocyclic group, R₈And R₉And the directly attached groups thereof together form a 4-10 membered heterocyclic group, said groups optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₁₀、R₁₂、R₁₃、R₁₄、R₁₅、R₁₇、R₁₈Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-to 10-membered heterocyclic group,C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₁₁、R₁₆Each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_3-10Cycloalkyl radical C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₁₉、R₂₀Each independently selected from hydrogen, deuterium and C_1-10Alkyl radical, C_3-10Cycloalkyl radical C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkenyl group, 3-to 10-membered heterocyclic group, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Or, R₁₉、R₂₀Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂、-C_0-8-C(O)OR₂₂、-C_0-8-C(O)R₂₃、-C_0-8-O-C(O)R₂₃、-C_0-8-NR₂₄R₂₅、-C_0-8-C(O)NR₂₄R₂₅or-C_0-8-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₂₁Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

   each R₂₂Selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

   each R₂₃Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₂₄R₂₅Substituted with the substituent(s);

   each R₂₄、R₂₅Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C_1-8Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heteroEpoxy group, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   or, R₂₄、R₂₅Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   each r is independently 0,1 or 2.
2. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₅、R₆Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Or, R₅And R₆Together with the carbon atom to which they are directly attached form a 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Is substituted by a substituent of (A), R₂₂、R₂₄、R₂₅As claimed in claim 1;

   preferably, R₅、R₆Each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, aminoOr dimethylamino, or, R₅And R₆And the carbon atoms to which they are directly attached form a 3-4 membered cycloalkyl group, a 4-5 membered heterocyclyl group.
3. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₃、R₄Each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl or C_2-4Alkynyl, said group being optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Is substituted by a substituent of (A), R₂₂、R₂₄、R₂₅As claimed in claim 1; preferably, R₃、R₄Each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl.
4. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein Y is₂、Y₃Each independently selected from-C (R)₁₇R₁₈)-；

   Each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, halogen, cyano, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -C_0-4-O-R₂₂or-C_0-4-O-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, -O-R₂₂or-O-C (O) R₂₃Is substituted by a substituent of (A), R₂₂、R₂₃As claimed in claim 1; superior foodOptionally, each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy.
5. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₁Selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅The above radicals being optionally further substituted by oneOne or more selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅r is as defined in claim 1.
6. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to any one of claims 1-5, wherein X is₃、X₄Each independently selected from N or C, and X₃、X₄Comprises at least one N;

   Y₁selected from-O-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆)-；

   Y₂、Y₃Each independently selected from-C (R)₁₇R₁₈)-；

   R₁Selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6CycloalkanesA group, a 3-6 membered heterocyclic group, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

   R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

   R₃、R₄each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl;

   R₅、R₆each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;

   each R₁₂、R₁₃、R₁₄、R₁₅Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₁₆Each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

   each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxyacyl or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

   R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅r is as defined in claim 1.
7. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 6, selected from compounds of formula (iia) or formula (iib):

   

   wherein, X₁、X₂Each independently is selected from N or CH; x₅、X₆Each independently selected from C (R)₁₀) Or N; y is₁Selected from-O-, -C (R)₁₂R₁₃)-、-(C＝CR₁₄R₁₅) -or-N (R)₁₆) -; z is selected from-O-or-NH-;

   R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

   R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

   R₃、R₄each independently selected from hydrogen, deuterium, cyano, methyl, vinyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

   R₅、R₆each independently selected from hydrogen, deuterium, methyl, cyclopropyl, trifluoromethyl or trideuterium methyl;

   each R₁₂、R₁₃、R₁₄、R₁₅Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-to 8-membered heteroarylradical-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent(s);

   each R₁₆Each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or-C_0-4-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

   each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxyacyl or acetoxy, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

   R₇、R₈、R₉、R₁₀、R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅r is as defined in claim 1.
8. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 7, wherein X is₅Is selected from C (R)₁₀) Or N; x₆Is selected from CH;

   R₁₀each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent(s);

   R₂₂、R₂₃、R₂₄、R₂₅as claimed in claim 1.
9. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to claim 7 or 8, which is selected from a compound of formula (iiia):

   

   wherein, X₁、X₂Each independently is selected from N or CH; x₅Is selected from C (R)₁₀) Or N; y is₁Is selected from-O-or-C (R)₁₂R₁₃)-；

   R₁Is selected from C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_5-8Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or-NR₁₉R₂₀Optionally, said group is further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;

   R₂selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, and mixtures thereof,Pyridyl, hydroxy, methoxy, amino, methylamino or dimethylamino, which are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridyl, hydroxy or methoxy;

   R₃selected from hydrogen, deuterium, cyano, methyl, ethenyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

   R₁₀selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy, methoxy, amino, methylamino or dimethylamino, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;

   R₁₂、R₁₃each independently selected from hydrogen, deuterium, fluoro, chloro, methyl, vinyl, cyclopropyl, hydroxy, trifluoromethyl or cyclopropylmethyl;

   R₁₇、R₁₈each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, trifluoromethyl, trideuteromethyl, trifluoromethoxy, trideuteromethoxy, cyclopropylmethyl, methoxymethyl, ethoxyacyl or acetoxy;

   R₁₉、R₂₀each independently selected from hydrogen, deuterium and C_1-4Alkyl radical, C_3-10Cycloalkyl radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl radical, C_4-10Cycloalkenyl group, 3-to 10-membered heterocyclic group, C_5-10Aryl, 5-10 membered heteroaryl, hydroxy, acetyl or-C (O) NH₂Or, R₁₉、R₂₀Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl, vinyl, trifluoromethyl, cyclopropyl, cyclopentyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy.
10. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, which is selected from the group consisting of:

    

    

    

    

    

    
11. the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to any of claims 1 to 5, selected from compounds of formula (iic):

    

    wherein, X₅、X₆One is selected from C (R)₁₀) And the other is selected from O or S;

    R₁selected from hydrogen, deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR₁₉R₂₀or-C_0-8-S(O)_rR₂₁Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁or-C_0-4-O-R₂₂Substituted with the substituent(s);

    R₂selected from hydrogen, deuterium, halogen, cyano, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₂₁、-C_0-8-O-R₂₂or-C_0-8-NR₂₄R₂₅Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂or-C_0-4-NR₂₄R₂₅Substituted with the substituent of (1);

    R₃、R₄each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, vinyl or ethynyl, optionally further substituted by one or more substituents selected from deuterium, halogen or cyclopropyl;

    R₅、R₆each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;

    each R₁₀Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₂₁、-C_0-4-O-R₂₂、-C_0-4-C(O)OR₂₂、-C_0-4-C(O)R₂₃、-C_0-4-O-C(O)R₂₃、-C_0-4-NR₂₄R₂₅、-C_0-4-C(O)NR₂₄R₂₅or-C_0-4-N(R₂₄)-C(O)R₂₃Substituted with the substituent(s);

    each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy, any of the above groupsOptionally further substituted with one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;

    R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅r is as defined in claim 1.
12. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 11, wherein X is₅、X₆One is selected from C (R)₁₀) And the other is selected from O;

    R₃、R₄each independently selected from hydrogen or deuterium;

    R₅、R₆each independently selected from hydrogen, deuterium, methyl or cyclopropyl;

    each R₁₀Each independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4An alkyl group;

    each R₁₇、R₁₈Each independently selected from hydrogen, deuterium, fluoro, methyl or hydroxy, said groups being optionally further substituted by one or more substituents selected from deuterium or fluoro.
13. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 11 to 12, which is selected from the group consisting of:

    
14. a process for the preparation of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13, which comprises the steps of:

    

    wherein Pg is hydrogen, a hydroxyl protecting group, a mercapto protecting group or an amino protecting group, preferably hydrogen, tert-butyloxycarbonyl or p-toluenesulfonyl; x₁、X₂、X₃、X₄、X₅、X₆、Y₁、Y₂、Y₃、Z、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉As claimed in claim 1.
15. A pharmaceutical composition which comprises a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, and a pharmaceutically acceptable carrier.
16. Use of a compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment of cancer or tumors, immune-related diseases and disorders, metabolic disorders mediated at least in part by CD 73.
17. The use of claim 16, wherein the cancer or tumor is 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 cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma;

    preferably, the composition is used for treating melanoma, colon cancer, pancreatic cancer, breast cancer, prostatic cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi sarcoma.
18. The use of claim 16, wherein the immune related diseases and disorders are selected from the group consisting of rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.
19. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 15 for use as a medicament in the treatment of cancer or tumors, autoimmune diseases and disorders, metabolic diseases mediated at least in part by CD 73.
20. A compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 15 for use as a medicament in the treatment of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma, adrenal cancer, thyroid cancer, renal cell carcinoma, bone cancer, brain cancer, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kap, Rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis.
21. A method of treating cancer or tumors, immune related diseases and disorders, metabolic diseases mediated at least in part by CD73, comprising administering to a patient a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 15.
22. The method of claim 21, wherein the cancer or tumor is 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 cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminoma; the immune-related and metabolic disorders are selected from the group consisting of rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis, and multiple sclerosis.