CN111094317B - Phosphonic acid derivative with CD73 inhibitory activity, and preparation method and application thereof - Google Patents
Phosphonic acid derivative with CD73 inhibitory activity, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a phosphonic acid derivative with a structure shown in formula (I) and CD73 inhibition activity, and a preparation method and application thereof. The series of compounds can be widely applied to preparing medicines for treating at least part of CD 73-mediated cancers or tumors, autoimmune diseases and disorders and metabolic diseases, in particular to medicines 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 new-generation CD73 inhibitor medicines.
Description
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 extramembranous nucleoside diphosphate hydrolase-NTPDase 1) catalyzes the production of Adenosine Monophosphate (AMP) from ATP, producing only a small amount of Adenosine Diphosphate (ADP) and the primary function of CD73 catalyzes 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.
CD73 expression 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, CD73 expression 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, is active as an immunosuppressive agent. It is important that the tumor adenosine, by activating adenosine receptors (such as A2A), inhibits infiltrating effector T lymphocytes, thereby promoting tumor development. The accumulation of extracellular adenosine in tumor tissue is therefore an important mechanism for tumor immune escape.
Reduction of CD73 expression by interfering RNA or overexpression of CD73 in tumor cells can modulate tumor growth and migration. CD73 knockout mice are less likely to develop 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 antibodies that bind mouse CD73 inhibits the growth and migration of breast tumors in mouse models.
Therefore, targeting CD73 represents a potential therapeutic strategy that enhances the efficacy of anti-tumor immunotherapy and provides a new therapeutic strategy for limiting 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 demand for targeted drugs 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,
X 1 、X 2 each independently is selected from N or CH;
X 3 、X 4 each independently selected from N or C;
X 5 、X 6 each independently selected from O, S, C (R) 10 ) N or N (R) 11 )；
Y 1 Selected from-O-, -S-, -C (R) 12 R 13 )-、-(C＝CR 14 R 15 ) -or-N (R) 16 )-；
Y 2 、Y 3 Each independently selected from-O-, -S-or-C (R) 17 R 18 )-；
Z is selected from-O-, -S-or-NH-;
R 1 selected from hydrogen, deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or-C 0-8 -S(O) r R 21 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
R 2 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with a substituent of (a);
R 5 、R 6 each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Or, R 5 And R 6 Together 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 substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic ringBase, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
R 7 、R 8 、R 9 each independently selected from hydrogen, deuterium and C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 or-C 0-8 -C(O)NR 24 R 25 Or, R 7 And R 8 Or R 9 Together with the group to which they are directly attached form a 6-to 10-membered heterocyclic group, R 8 And R 9 And 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
each R 10 、R 12 、R 13 、R 14 、R 15 、R 17 、R 18 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
each R 11 、R 16 Each independently selected from hydrogen, deuterium and C 1-10 Alkyl radical, C 3-10 Cycloalkyl radical C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, haloSubstituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
each R 19 、R 20 Each independently selected from hydrogen, deuterium and C 1-10 Alkyl radical, C 3-10 Cycloalkyl radical C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkenyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Or, R 19 、R 20 Together 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
each one of which isR 21 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 24 R 25 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 24 R 25 Substituted with the substituent(s);
each R 22 Selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl or 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR 24 R 25 Substituted with the substituent(s);
each R 23 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR 24 R 25 Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy groupA group of 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 24 R 25 Substituted with a substituent of (a);
each R 24 、R 25 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino or C 1-10 Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-8 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 Substituted by a substituent of alkanoyl;
or, R 24 、R 25 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 Substituted 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 thereof 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl、-C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Or, R 5 And R 6 Together 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 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Is substituted by a substituent of (A), R 22 、R 24 、R 25 R is as described for compounds of formula (I); preferably, R 5 、R 6 Each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino or dimethylamino, or, R 5 And R 6 Together with the carbon atom to which they are directly attached, form a 3-4 membered cycloalkyl group, a 4-5 membered heterocyclyl group.
As a further preferred embodiment, R in said compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof 3 、R 4 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl or C 2-4 Alkynyl, said group being optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Is substituted by a substituent of (3), R 22 、R 24 、R 25 And r is as described for compounds of formula (I); preferably, R 3 、R 4 Each 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, Y in said compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof 2 、Y 3 Each of which isIndependently selected from-C (R) 17 R 18 ) -; each R 17 、R 18 Each independently selected from hydrogen, deuterium, halogen, cyano, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 -O-R 22 or-C 0-4 -O-C(O)R 23 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -O-R 22 or-O-C (O) R 23 Is substituted by a substituent of (3), R 22 、R 23 As described for compounds of formula (I); preferably, each R is 17 、R 18 Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy, optionally further substituted by one or more substituents selected from deuterium, fluoro, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy.
As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or-C 0-8 -S(O) r R 21 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
R 2 selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 or-C 0-8 -NR 24 R 25 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Substituted with a substituent of (a);
R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and r is as described for compounds of formula (I).
As a still further preferred embodiment, X in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof 3 、X 4 Each independently selected from N or C, and X 3 、X 4 Comprises at least one N; y is 1 Selected from-O-, -C (R) 12 R 13 )-、-(C＝CR 14 R 15 ) -or-N (R) 16 )-；Y 2 、Y 3 Each independently selected from-C (R) 17 R 18 )-；
R 1 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or-C 0-8 -S(O) r R 21 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 or-C 0-4 -O-R 22 Substituted with a substituent of (a);
R 2 selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 or-C 0-8 -NR 24 R 25 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Substituted with the substituent(s) of (1);
R 3 、R 4 each 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;
R 5 、R 6 each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;
each R 12 、R 13 、R 14 、R 15 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Substituted with a substituent of (a);
each R 16 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Substituted with the substituent(s);
each R 17 、R 18 Each 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;
R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and r is as described for compounds of formula (I).
As a still further preferred embodiment, said compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the structure of a compound of formula (IIa) or formula (IIb) as follows:
wherein, X 1 、X 2 Each independently is selected from N or CH; x 5 、X 6 Each independently selected from C (R) 10 ) Or N; y is 1 Selected from-O-, -C (R) 12 R 13 )-、-(C＝CR 14 R 15 ) -or-N (R) 16 ) -; z is selected from-O-or-NH-;
R 1 selected from hydrogen, deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical、C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or-C 0-8 -S(O) r R 21 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 or-C 0-4 -O-R 22 Substituted with the substituent(s);
R 2 selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 or-C 0-8 -NR 24 R 25 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Substituted with the substituent of (1);
R 3 、R 4 each 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;
R 5 、R 6 each independently selected from hydrogen, deuterium, methyl, cyclopropyl, trifluoromethyl or trideuterium methyl;
each R 12 、R 13 、R 14 、R 15 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Substituted with the substituent(s);
each R 16 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or-C 0-4 -C(O)R 23 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 or-C 0-4 -NR 24 R 25 Substituted with the substituent of (1);
each R 17 、R 18 Each 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;
R 7 、R 8 、R 9 、R 10 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and r is as described for compounds of formula (I).
As a still further preferred embodiment, said compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereofIn salt X 5 Is selected from C (R) 10 ) Or N; x 6 Is selected from CH;
R 10 each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 22 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Substituted with the substituent(s);
R 22 、R 23 、R 24 、R 25 as described for the 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 of formula (IIIa):
wherein, X 1 、X 2 Each independently is selected from N or CH; x 5 Is selected from C (R) 10 ) Or N; y is 1 Is selected from-O-or-C (R) 12 R 13 )-；
R 1 Is selected from C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy, C 5-8 Aryl radical, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or-NR 19 R 20 Optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropylMorpholinyl, oxetanyl, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;
R 2 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuryl, 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, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;
R 3 selected from hydrogen, deuterium, cyano, methyl, ethenyl or ethynyl, which are optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;
R 12 、R 13 each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, vinyl, cyclopropyl, hydroxy, trifluoromethyl or cyclopropylmethyl;
R 17 、R 18 each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxyl, methoxy, trifluoromethyl, trideuteromethyl, trifluoromethoxy, trideuteromethoxy, cyclopropylmethyl, methoxymethyl, ethoxyacyl or acetoxy;
R 10 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuryl, 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, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;
R 19 、R 20 each independently selected from hydrogen, deuterium and C 1-4 Alkyl radical, C 3-10 Cycloalkyl radical C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-10 Cycloalkyl radical, C 4-10 Cycloalkenyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, hydroxy, acetyl or-C (O) NH 2 Or, R 19 、R 20 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, C 1-4 Alkyl, vinyl, trifluoromethyl, cyclopropyl, cyclopentyl, morpholinyl, oxetanyl, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy, or methoxy.
As a most preferred embodiment, the compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include, but are not limited to, the following:
as a further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the following structure as the compound of formula (IIc):
wherein, X 5 、X 6 One is selected from C (R) 10 ) And the other is selected from O or S;
R 1 selected from hydrogen, deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or-C 0-8 -S(O) r R 21 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 or-C 0-4 -O-R 22 Substituted with the substituent(s);
R 2 selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 or-C 0-8 -NR 24 R 25 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 or-C 0-4 -NR 24 R 25 Substituted with a substituent of (a);
R 3 、R 4 each 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;
R 5 、R 6 each independently selected from hydrogen, deuterium, fluoro, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, amino, or dimethylamino;
each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 、-C 0-4 -O-R 22 、-C 0-4 -C(O)OR 22 、-C 0-4 -C(O)R 23 、-C 0-4 -O-C(O)R 23 、-C 0-4 -NR 24 R 25 、-C 0-4 -C(O)NR 24 R 25 or-C 0-4 -N(R 24 )-C(O)R 23 Substituted with a substituent of (a);
each R 17 、R 18 Each independently is selected fromHydrogen, 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;
R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and r is as described for compounds of formula (I).
As a still further preferred embodiment, X in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof 5 、X 6 One is selected from C (R) 10 ) And the other is selected from O;
R 3 、R 4 each independently selected from hydrogen or deuterium;
R 5 、R 6 each independently selected from hydrogen, deuterium, methyl or cyclopropyl;
each R 10 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 An alkyl group;
each R 17 、R 18 Each 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 compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include, but are not limited to, the following:
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; x 1 、X 2 、X 3 、X 4 、X 5 、X 6 、Y 1 、Y 2 、Y 3 、Z、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 As described for the 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, stomach 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), cancer of the mesothelial lining, 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, basal cell carcinoma of the epidermis, and 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.
Preferably, 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.
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, as hereinbefore described, or a pharmaceutical composition as hereinbefore described for use in the treatment of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial lining 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 tumors, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, seminoma of the testis, rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, fibromyalgia, alzheimer's disease, heart failure, stroke, valve stenosis, congestive heart disease, artherosclerosis, contact sclerosis, multiple sclerosis, psoriasis, and contact sclerosis.
In a seventh aspect, the present invention provides a method for 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, or a pharmaceutical composition thereof.
Preferably, the cancer or tumor is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, stomach 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 tumors, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the epidermis, 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 represented by the following formula (I), a preparation method thereof, and pharmaceutical applications thereof. The series of compounds have strong inhibition effect on the activity of CD73 enzyme, 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, prostate 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 1-10 Alkyl "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-ethylhexyl, 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s).
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C 3-10 Cycloalkyl "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 having a single ring with a common carbon atom (called the spiro atom) between them, 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 according to the number of spiro atoms shared between rings, including but not limited to:
"fused-ring 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, and in which 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. Bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls may be classified according to 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, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s).
"Heterocyclyl" refers to 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 portion 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 rings in which one atom (called the spiro atom) is shared between the monocyclic ringsHeterocyclic radical 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 heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, wherein 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 groups depending on the number of constituent rings, and fused heterocyclic groups include, but are not limited to:
"bridged heterocyclyl" refers to 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted 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 have an adjacent pair of carbon atoms) group having a conjugated pi-electron system, e.g., "C 5-10 Aryl "refers to all carbon aryl groups containing 5-10 carbons, and" 5-10 membered aryl "refers to all carbon aryl groups containing 5-10 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with a substituent (b).
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and heteroatoms of 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with a substituent (b).
"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 2-10 Alkenyl 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.
Alkenyl 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted 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 2-10 Alkynyl 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s).
"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above, e.g., "C 1-10 Alkoxy "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 unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with a substituent (b).
"Cycloalkoxy" means and-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C 3-10 Cycloalkoxy "refers to cycloalkyloxy groups containing 3-10 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
Cycloalkoxy 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with the substituent(s).
"Heterocyclyloxy" means and-O-heterocyclyl, wherein heterocyclyl is as defined above, e.g. "C 3-10 Heterocyclyloxy "refers to heterocyclyloxy having 3 to 10 carbons, including but not limited to azetidinyloxy, oxetanyloxy, cyclopentyloxy, 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 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 、-C 0-8 -O-R 22 、-C 0-8 -C(O)OR 22 、-C 0-8 -C(O)R 23 、-C 0-8 -O-C(O)R 23 、-C 0-8 -NR 24 R 25 、-C 0-8 -C(O)NR 24 R 25 or-C 0-8 -N(R 24 )-C(O)R 23 Substituted with a substituent (b).
“C 1-10 Alkanoyl "means C 1-10 The 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.," C 1 -C (O) - "means acetyl; "C 2 -C (O) - "refers to propionyl; ' C 3 -C (O) - "means butyryl or isobutyryl.
“-C 0-8 -S(O) r R 21 "finger-S (O) r R 21 With sulfur atoms bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -O-R 22 "means-O-R 22 In which the oxygen atom is bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -C(O)OR 22 "refers to-C (O) OR 22 In which the carbonyl group is attached to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -C(O)R 23 "means-C (O) R 23 Wherein the carbonyl group is bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -O-C(O)R 23 "means-O-C (O) R 23 In which the oxygen atom is bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -NR 24 R 25 "means-NR 24 R 25 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -C(O)NR 24 R 25 "means-C (O) NR 24 R 25 In which the carbonyl group is attached to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
“-C 0-8 -N(R 24 )-C(O)R 23 "means-N (R) 24 )-C(O)R 23 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, wherein C 0 Alkyl means a bond, C 1-8 The alkyl group is as defined above.
"halogen substituted C 1-10 Alkyl "refers to a 1-10 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl group, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"halogen substituted C 1-8 Alkoxy "alkyl groupsAnd (c) 1-8 carbon alkoxy groups optionally substituted with fluorine, chlorine, bromine, 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, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated bond (e.g., an olefin).
"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 units of parts per million (ppm). NMR was measured by Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard ofTetramethylsilane (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 C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 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 Futai 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).
1. Synthesis of intermediates
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 (20 mL), N-diisopropylethylamine (2.08g, 16.1mmol) was added at room temperature, N-methylcyclopentylamine (1.44g, 66wt%,9.6 mmol) was further added, the reaction was stirred at room temperature for 1 hour, followed by concentration, ethyl acetate was added, andwashing with water, saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, drying with sodium sulfate, and concentrating to obtain 2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ]][1，2，4]Triazin-4-amine (1.97 g, 96% yield). MS m/z (ESI): 251.2 2[ 2 ] M + H] + 。
1 H NMR(400MHz，CDCl 3 )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-methylpyrrolido [2,1-f ] [1,2,4] triazin-4-amine
Reacting 2-chloro-N-cyclopentyl-N-methylpyrrolido [2,1-f][1，2，4]Triazine-4-amine (2.66g, 10.6 mmol) was dissolved in methylene chloride (20 mL), N-bromosuccinimide (1.89g, 10.6 mmol) was added at-10 ℃, stirring was continued for 10 minutes and then warmed to room temperature to react for 15.5 hours, N-dimethylformamide (0.5 mL) was added and stirred for 10 minutes, followed by washing three times with saturated sodium bicarbonate, washing once with saturated brine, drying over anhydrous sodium sulfate, concentration and 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 (2.90 g, 82% yield). MS m/z (ESI): 329.2 and 331.2[ M ] +H] + 。
1 H NMR(400MHz，CDCl 3 )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-methylpyrrolido [2,1-f][1，2，4]Triazine-4-amine (2.90g, 8.8mmol) was dissolved in 2-methyltetrahydrofuran (20 mL), n-butyllithium (4.95ml, 2.5m, 12.4mmol) was added dropwise at-78 ℃ under nitrogen, the reaction was stirred at the same temperature for 1 hour, a solution of (3r, 4r, 5r) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (3.68g, 8.8mmol) in 2-methyltetrahydrofuran (5 mL) was added dropwise at the same temperature, the reaction was stirred at the same temperature for 1 hour, quenched with a saturated ammonium chloride solution, extracted twice with ethyl acetate after warming to room temperature, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated and separated by column chromatography [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (2.5: 1)]To give (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 (3.80 g, 64% yield). MS m/z (ESI): 651.6 2[ 2 ] M + H-H 2 0] + ，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-methylpyrrolido [2,1-f ] [1,2,4] triazin-4-amine
(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, 5.7 mmol), triethylsilane (9.07ml, 56.8mmol) were dissolved in a dichloromethane/acetonitrile mixed solution (30ml, 1: 1), boron trifluoride ether (3.50ml, 28.4 mmol) was added dropwise at-20 ℃, the reaction was stirred at room temperature for 1 hour, then quenched by addition of saturated sodium bicarbonate, warmed to room temperature, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and isolated [ 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-methylpyridinePyrrolo [2, 1-f)][1，2，4]Triazin-4-amine (2.35 g, 63% yield). MS m/z (ESI): 653.5[ M ] +H] + 。
1 H NMR(400MHz，CDCl 3 )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
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]Triazine-4-amine (0.70g, 1.1mmol), chlorobenzene (0.12g, 1.1mmol) were dissolved in a tetrahydrofuran solution (10 mL), palladium hydroxide (0.14g, 15wt%) was added, the reaction was stirred at room temperature and pressure for 13 hours after three times of hydrogen substitution, filtered, and separated by column chromatography after concentration [ eluent: dichloromethane to dichloromethane/methanol (9: 1)]To give (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 (0.33 g, 80% yield). MS m/z (ESI): 383.4[ m ] +H] + 。
1 H NMR(400MHz，CDCl 3 )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-cyclopentylpyrrolo [2,1-f ]][1，2，4]Triazine-4-amine (2.20g, 6.97mmol) was dissolved in 2-methyltetrahydrofuran (20 mL), n-butyllithium (6.41ml, 2.5m, 16.0mmol) was added dropwise at-78 ℃ under nitrogen, stirring was performed while maintaining the temperature for 1 hour, trimethylchlorosilane (752mg, 6.97mmol) was added dropwise at that temperature, reaction was performed 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 (5 mL) was added dropwise at that temperature, reaction was continued while maintaining the temperature for 1 hour, quenching was performed with a saturated ammonium chloride solution, ethyl acetate extraction was performed twice after warming to room temperature, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separation after concentration [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (2: 1)]To give (3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2- (2-chloro-4- (cyclopentylamino) pyrrolo [2, 1-f)][1，2，4]Triazine-7-yl) tetrahydrofuran-2-ol (1.50 g, 32% yield). MS m/z (ESI): 637.6[ M ] +H-H 2 O] + ，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
(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 ether (1.62g, 11.45mmol) was added dropwise at-20 ℃, after 1 hour of incubation, saturated sodium bicarbonate was added to quench the reaction, warmed to room temperature, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated 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 (1 g, 68% yield). MS m/z (ESI): 639.6[ 2 ] 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-cyclopentylpyrrolo [2,1-f ]][1，2，4]To a dioxane (4 mL)/water (1 mL) solution of triazin-4-amine (0.30g, 0.48mmol) and trimethylcyclotriboroxane (0.12g, 0.94mmol) were added potassium carbonate (0.20g, 1.4mmol) and tetratriphenylphosphine palladium (0.22g, 0.19mmol) in this order, and the reaction was carried out by microwave incubation at 130 ℃ for 6 hours, ethyl acetate was added, washing with water and saturated brine in this order, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated followed 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 (0.12 g, 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
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 a tetrahydrofuran solution (5 mL), palladium hydroxide (66mg, 15wt%) was added, hydrogen gas was substituted three times, and then the mixture was reacted at 30 ℃ for 48 hours, filtered, concentrated, and separated by column chromatography [ eluent: dichloromethane to dichloromethane/methanol (9: 1)]To give (2S, 3R,4S, 5R) -2- (4- (cyclopentylamino) -2-methylpyrrolido [2, 1-f)][1，2，4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (50 mg, yield 79%). MS m/z (ESI): 349.2[ 2 ] M + H] + 。
1 H 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
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) was dissolved in acetonitrile (1.5 mL), selectfluor (0.28g, 0.78mmol) was added at room temperature, the reaction was incubated for 2 hours, and after concentration, column chromatography was performed [ eluent: petroleum ether to Petroleum ether/ethyl acetate (2: 1) ] yielded 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 (53 mg, 32% yield).
1 H NMR(400MHz，CDCl 3 )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: 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
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]Triazine-4-amine (67mg, 0.10mmol) and chlorobenzene (22mg, 0.20mmol) were dissolved in a tetrahydrofuran solution (2 mL), palladium hydroxide (34mg, 15wt%) was added, hydrogen gas was substituted three times, and after incubation at 35 ℃, stirring and reaction were carried out for 16 hours, filtration, concentration, and column chromatography separation [ eluent: dichloromethane to dichloromethane/methanol (9: 1)]To give (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 (18 mg, 44% yield). MS m/z (ESI): 387.4[ mu ] M + H] + 。
1 H 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-carbamates
7-bromoimidazo [2,1-f ] in sequence in a 100mL three-necked flask][1，2，4]Triazine-4-amine (1.76g, 68.1%,6.4 mmol), acetonitrile (15 mL), di-tert-butyl dicarbonate (1.81g, 8.4 mmol), 4-dimethylaminopyridine (79mg, 0.64mmol) and N, N-diisopropylethylamine (2.06g, 16.0 mmol) were reacted with stirring at 30 ℃ for 13.5 hours, diluted with ethyl acetate after completion of the reaction, washed with water, a saturated ammonium chloride solution, water, a saturated sodium hydrogen carbonate solution, a saturated saline solution in this order, dried over anhydrous sodium sulfate, concentrated and separated 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 (0.90 g, 58% yield). MS m/z (ESI): 314.2 and 316.2[ m ] +H] + 。
1 H NMR(400MHz，CDCl 3 )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]After adding cyclopentanol (0.62g, 7.2 mmol) and triphenylphosphine (1.88g, 7.2 mmol) to a solution of triazin-4-yl-carbamate (0.90g, 2.9 mmol) in tetrahydrofuran (15 mL), after 5 minutes of incubation, diisopropyl azodicarboxylate (1.45g, 7.2 mmol) was added dropwise, the reaction was warmed to room temperature for 10 minutes after the addition was complete and then further warmed to 45 ℃ and stirred for 2 hours, the reaction was monitored by LCMS, concentrated after completion of the reaction, and then separated by column chromatography [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (9: 1)]To obtain tert-butyl-7-bromoimidazo [2,1-f ]][1，2，4]Triazine-4-cyclopentyl carbamate (0.74 g, 67% yield). MS m/z (ESI): 382.4 and 384.4[ m ] +H] + 。
1 H NMR(400MHz，CDCl 3 )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-cyclopentylcarbamate
Tert-butyl-7-bromoimidazo [2,1-f ] at-70 deg.C][1，2，4]After the addition of n-butyllithium (1.0 mL,2.5M,2.5 mmol) was added dropwise to a solution of triazine-4-cyclopentylcarbamate (0.74g, 1.9 mmol) in 2-methyltetrahydrofuran (2.5 mL), the reaction was allowed to proceed while maintaining the temperature for 20 minutes, 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone (0.89g, 2.1 mmol) in 2-methyltetrahydrofuran (1.5 mL) was added dropwise again, the reaction was allowed to proceed while maintaining the temperature and stirring for 2 hours, the reaction was monitored by LCMS, saturated ammonium chloride was added thereto to quench the reaction, the reaction was extracted with ethyl acetate, washed with a saturated ammonium chloride solution, water and saturated common salt solution in this order, dried over anhydrous sodium sulfate, concentrated and then separated [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (1: 1)]To give 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-cyclopentyl carbamate (0.36 g, 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 ℃ at 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-cyclopentylcarbamate (0.36g, 45.4%,0.23 mmol) in dichloromethane (5 mL) was added triethylsilane (0.26g, 2.3 mmol), followed by dropwise addition of boron trifluoride diethyl etherate (0).1691, 1.1mmol), stirring while maintaining the temperature for 2 hours, warming to room temperature for 2.5 hours, monitoring the reaction by LCMS, quenching the reaction by adding saturated sodium bicarbonate solution, extracting with dichloromethane, washing with saturated sodium bicarbonate solution, water, and saturated brine in this order, drying over 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 (0.19 g, 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]Triazine-4-amine (0.19g, 0.31mmol) was dissolved in tetrahydrofuran solution (5 mL), palladium hydroxide (0.19g, 15wt%) was added, hydrogen gas was substituted three times, and then the mixture was stirred at 30 ℃ for reaction for 22 hours, filtered, concentrated, and separated by column chromatography [ eluent: dichloromethane to dichloromethane/methanol (9: 1)]To give (2S, 3R,4S, 5R) -2- (4- (cyclopentylamino) imidazo [2, 1-f)][1，2，4]Triazin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (78 mg, 73% yield). MS m/z (ESI): 336.4[ 2 ] M + H] + 。
1 H 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
Reacting 2, 4-dichloropyrrolo [2,1-f ]][1，2，4]Triazine (5.0g, 26.6 mmol) was dissolved in 1, 4-dioxane (50 mL), N-diisopropylethylamine (9.73g, 79.7 mmol) was added at room temperature, cyclopentylamine (4.53g, 53.2 mmol) was further added, the reaction mixture was stirred at room temperature for 1 hour, and then concentrated, ethyl acetate was added, each was washed successively with water, a saturated ammonium chloride solution, a saturated sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate and concentrated to give 2-chloro-N-cyclopentylpyrrolo [2,1-f ] -pyrrole][1，2，4]Triazin-4-amine (5.60 g, 89% yield). MS m/z (ESI): 237.2[ M ] +H] + 。
The second step: 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, 26.6 mmol) was dissolved in tetrahydrofuran (50 mL), N, N-diisopropylethylamine (6.49g, 53.2mmol), N, N-dimethylpyridin-4-amine (317mg, 2.6 mmol) were added at room temperature, di-tert-butyl dicarbonate (8.69g, 39.9 mmol) 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 give tert-butyl (2-chloropyrrolo [2,1-f ]][1，2，4]Triazin-4-yl) (cyclopentyl) carbamate (7.20 g, 90% yield). MS m/z (ESI): 337.2[ 2 ] M + H] + 。
The second step: 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) was dissolved in methylene chloride (50 mL), N-bromosuccinimide (3.81g, 21.4mmol) was added at-10 ℃, stirred at room temperature for 10 minutes, warmed to room temperature for reaction for 15.5 hours, N-dimethylformamide (0.5 mL) was added, stirred for 10 minutes, washed three times with saturated sodium bicarbonate in this order, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography [ eluent: petroleum Ether-Petroleum Ether/Dichloromethane (5: 1)]To give tert-butyl (7-bromo-2-chloropyrrolo [2, 1-f)][1，2，4]Triazin-4-yl) (cyclopentyl) carbamate (8.0 g, 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-chloropyrrolo [2,1-f ]][1，2，4]Triazin-4-yl) (cyclopentyl) carbamate (10g, 24.1mmol) was dissolved in 2-methyltetrahydrofuran (60 mL), n-butyllithium (11.55ml, 2.5m, 28.8mmol) was added dropwise at-78 ℃ under nitrogen, stirring was performed at the same temperature for 1 hour, a solution of (3r, 4r, 5r) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (11.09g, 26.5mmol) in 2-methyltetrahydrofuran (20 mL) was added dropwise at that temperature, the reaction was stirred at the same temperature for 1 hour, quenched with a saturated ammonium chloride solution, extracted twice with ethyl acetate after warming to room temperature, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography was performed after concentration [ 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 (12 g, 65% yield). MS m/z (ESI): 737.2[ M ] +H-H 2 O] + ，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 chloride (3.78g, 48mmol), indium trifluoromethanesulfonate (13.47g, 24mmol) were dissolved in acetonitrile solution (300 mL), stirred at 70 ℃ for reaction for 16 hours, quenched with saturated sodium bicarbonate, warmed to room temperature, extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (2.5: 1)]To give (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 (7.2 g, 90% yield). MS m/z (ESI): 664.2[ 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
(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 (9.6 g,14.4 mmol) was dissolved in dichloromethane solution (400 mL) at 0 deg.CBoron trichloride (72ml, 1m, 72mmol) was added thereto, the reaction was stirred at that temperature for 4 hours, and methanol was added thereto to quench the reaction, and the reaction was warmed to room temperature, concentrated and separated by reverse phase column chromatography [ eluent: water-water/acetonitrile (7: 3)]To give (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 (1 g, 17% yield). MS m/z (ESI): 394.2[ M ] +H] + 。
1 H 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 (20 mL), n-butyllithium (1ml, 2.5m, 2.5mmol) was added dropwise at-78 ℃ under nitrogen, the reaction was stirred at an incubation 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 (5 mL) was added dropwise at that temperature, the reaction was continued for 1 hour under agitation at an incubation temperature, quenched with a saturated ammonium chloride solution, and after warming to room temperature, ethyl acetate was extracted twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after concentration, column chromatography separation [ eluent: petroleum Ether-Petroleum ether/Ethyl acetate (2.5: 1) ] gave tert-butyl (7- ((3aR, 6R,6 aR) -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 (550 mg, 54% yield).
The second step: synthesis of tert-butyl (7- ((3aR, 4R, 6aS) -4- (tert-butoxymethyl) -2, 2-dimethyl-3a, 6a-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) was dissolved in tetrahydrofuran (10 mL), boji reagent (1000mg, 4 mmol) was added at room temperature, the reaction was stirred at 80 ℃ for 16 hours, and after concentration, column chromatography was performed to separate [ petroleum ether-petroleum ether/ethyl acetate (10: 1)]To give tert-butyl (7- ((3aR, 4R, 6aS) -4- (tert-butoxymethyl) -2, 2-dimethyl-3a, 6a-dihydro-4H-cyclopenta [ d ] s][1，3]Dioxazol-6-yl) -2-chloropyrrolo [2,1-f][1，2，4]Triazin-4-yl) (cyclopentyl) carbamate (440 mg, 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-3a, 6a-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 (20 mL), palladium hydroxide/carbon (400 mg) was added at room temperature, the reaction was stirred at room temperature under hydrogen for 4 hours, and after filtration, column chromatography was performed to separate [ 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 (280 mg, 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) was dissolved in acetonitrile (0.5 mL), concentrated hydrochloric acid (0.5 mL) was added at room temperature, the reaction was stirred at room temperature for 16 hours, concentrated and separated by column chromatography [ eluent: water acetonitrile (10-100)]To give (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 (140 mg, 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 (230 mL), imidazole (77.3g, 1.14mol) was added, triisopropylsilylchloride (146g, 0.757mol) was slowly added dropwise at 0 ℃ and, after completion of the addition, stirred 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, combined with the organic phase, washed with water and a saturated saline solution, respectively, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography [ eluent: petroleum ether/ethyl acetate (19: 1) ] gave (4S, 5R) -4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (80.0 g, 95% yield).
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 (10.0 g,22.5 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), N-fluorobisbenzenesulfonamide (10.6 g,33.7 mmol) was added, bistrimethylsilylaminolithium (1.0M tetrahydrofuran solution, 29.2mL, 29.2mmol) was slowly added dropwise at-78 ℃, the reaction was stirred at-78 ℃ 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 extraction was carried out 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) ] gave (3S, 4R, 5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (7.0 g, 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
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 (15 mL), cooled to-78 deg.C, N-butyllithium (2.5M tetrahydrofuran solution, 2.7mL, 6.37mmol) was slowly added dropwise, and after completion of dropwise addition, a 2-methyltetrahydrofuran solution (10 mL) of (3S, 4R, 5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) dihydrofuran-2 (3H) -one (2.32g, 5.01mmol) was slowly added after 1 hour of stirring reaction at-78 deg.C, and after completion of dropwise addition, the reaction was continued for 1 hour of stirring. After the reaction was completed, it 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) ] gave (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 (2.0 g, 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 (30 mL), a boron trifluoride diethyl ether solution (2.0g, 14.0mmol) was added at-20 ℃ C, and after stirring for five minutes, triethylsilane (3.3g, 28.0mmol) was slowly added, and after completion of dropwise addition, the reaction was further stirred at-20 ℃ C for 2 hours, and after completion of the reaction, a saturated aqueous sodium bicarbonate solution was added to quench, and dichloromethane 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 (10/1) ] gave 2-chloro-N-cyclopentyl-7- ((2S, 3R,4R, 5R) -3-fluoro-4- ((triisopropylsilyl) oxo) -5- (((triisopropylsilyl) oxo) methyl) tetrahydrofuran-2-yl) -N-methylpyrrolido [2,1-f ] [1,2,4] triazin-4-amine (1.6 g, 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 (15 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.6mL,2.6 mmol) was added at room temperature, stirred at room temperature overnight, concentrated and separated by reverse phase column chromatography [ eluent: acetonitrile/water (40/60)]To give (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, 91% yield). 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
7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-amine (2.90g, 8.8mmol) was dissolved in 2-methyltetrahydrofuran (20 mL), N-butyllithium (4.95mL, 2.5M, 12.4mmol) was added dropwise at-78 ℃ with nitrogen, the reaction was stirred with stirring at constant temperature for 1 hour, 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 (5 mL) was added dropwise at this temperature, the reaction was stirred with further stirring with constant temperature for 1 hour, quenched with a saturated ammonium chloride solution, warmed to room temperature, extracted twice with ethyl acetate, the combined organic phases were washed with saturated common salt, dried over anhydrous sodium sulfate, and separated after concentration [ eluent: petroleum ether-Petroleum ether/Ethyl acetate (2.5: 1) ] yielded ((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 (3.15 g, 50% yield).
The second step: 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 heat preservation, saturated sodium bicarbonate was added to quench the reaction, warmed to room temperature, dichloromethane was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentration, column chromatography was performed [ eluent: petroleum ether-Petroleum ether/Ethyl acetate (2.5: 1) ] yielded 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 (1.88 g, 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, 1.0 mmol) was dissolved in tetrahydrofuran solution (10 mL), TBAF (2ml, 1m/L) was added, and then 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 (0.30 g, 75% yield). MS m/z (ESI): 403.4[ 2 ] 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 (10 mL), and tetrakis (triphenylphosphine) palladium (580mg, 0.51mmol) and zinc cyanide (444mg, 3.78mmol) were added. The reaction was stirred at 130 ℃ under microwave conditions for 9 hours, filtered, the filtrate was extracted three times with ethyl acetate after water (100 mL) was added, the organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether/ethyl acetate (10/1) ] gave 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 (690 mg, yield 79%).
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 ] pyrrole][1，2，4]Triazine-2-carbonitrile (690mg, 1.0mmol) was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 3.0mL, 3.0mmol) was added at room temperature, and stirred at room temperature overnight, followed by concentration and separation 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 (350 mg, 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 (100 mL), pyridine (18g, 227mmol) was added, and after cooling to-20 ℃, a solution of benzoyl chloride (11.7g, 83.3mmol) in dichloromethane (50 mL) was added dropwise. The reaction was stirred at-20 ℃ for 2 hours, then quenched with saturated aqueous sodium bicarbonate (150 mL), the organic phase separated, washed sequentially 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 was obtained (13.3 g, yield 74%). 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 (100 mL), imidazole (11.5g, 1699 mmol) was added, triisopropylsilyl chloride (16.3g, 84.5mmol) was slowly added dropwise at 0 ℃, gradually warmed to room temperature and stirred overnight, the reaction was quenched with a saturated aqueous sodium bicarbonate solution (500 mL), extracted three times with ethyl acetate, the organic phases were combined, and washed successively with water and saturated brine. Dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: petroleum ether/Ethyl acetate (15/1)]((2R, 3S) -3-hydroxy-5-carbonyltetrahydrofuran-2-yl) methylbenzoate (20.0 g, yield 90.5%) was obtained. MS m/z (ESI): 393.2[ M ] +H] + 。
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, 30.6 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), and N-fluoro-N- (benzenesulfonyl) benzenesulfonamide (14.5g, 45.9mmol) was added. Lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 39.4mL,39.4 mmol) 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 (500 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [ eluent: ethyl acetate/petroleum ether (1/20) ] gave ((2R, 3R, 4S) -4-fluoro-5-carbonyl-3- ((triisopropylsilyl) oxo) tetrahydrofuran-2-yl) methylbenzoate (9.5 g, 75.7% yield).
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 (25 mL), 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 (7 mL) 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. Adding saturated ammonium chloride solution for quenching, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography separation [ eluent: ethyl acetate/petroleum ether (1/10) ] gave ((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 (1.8 g, 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 (30 mL), 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. Quenching by adding saturated aqueous sodium bicarbonate, extracting with dichloromethane three times, combining organic phases, drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography [ eluent: ethyl acetate/petroleum ether (1/15) ] gave ((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 (1.3 g, 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 (20 mL), 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, concentrated and column chromatographed [ 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 (330 mg, 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 (10 mL/5 mL), potassium carbonate (665mg, 4.82mmol) was added, the reaction was stirred at room temperature for 2 hours, and after concentration, column chromatography was performed [ eluent: ethyl acetate/dichloromethane (1/3) ] yielded ((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 (280 mg, 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 (15 mL), 4-dimethylaminopyridine (147mg, 1.2 mmol) and N, N-diisopropylethylamine (249mg, 1.93mmol) were added, a solution of p-toluenesulfonyl chloride (138mg, 0.72mmol) in dichloromethane (1 mL) was slowly added dropwise at 0 ℃, and after completion of the addition, the temperature was slowly raised to room temperature, and the reaction was stirred for 2 hours. After completion of the reaction, the reaction mixture 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) ] 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) methyl 4-methylbenzenesulfonate (330 mg, 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 (15 mL) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.9mL,0.9 mmol) 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 give ((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 (250 mg, 96% yield). MS m/z (ESI): 579.0[ M ] +H] + 。
Intermediates 39-59 were prepared according to the synthetic procedure for intermediate 38:
2. preparation of the Compounds of specific examples
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) phosph-nyl) methyl) phosphonic acid
Reacting (2S, 3R,4S, 5R) -2- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f)][1，2，4]Dissolving triazine-7-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (100mg, 0.26mmol) in trimethyl phosphate (2.5 mL), dropwise adding a solution of methylene dichloride phosphorus (0.33g, 1.3 mmol) in trimethyl phosphate (0.5 mL) at 0 ℃, stirring for reaction for 3 hours after the completion of the incubation, adding 0.5N triethylamine bicarbonate solution to quench the reaction, and performing reverse phase column chromatography separation after freeze-drying [ C 18 Column, eluent: water-water/acetonitrile (9: 1) +0.1% ammonia]To give (((((2R, 3S,4R, 5S) -5- (2-chloro-4- (cyclopentyl (methyl) amino) pyrrolo [2, 1-f))][1，2，4]Triazin-7-yl) -3, a pharmaceutically acceptable salt thereof,4-Dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphanyl) methyl) phosphonic acid (5.1 mg, 3.6% yield). MS m/z (ESI): 541.4[ M ] +H] + 。
1 H NMR(400MHz，D 2 O)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 from 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) phosph-nyl) 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 (5 mL) was stirred at room temperature for 16 hours and then separated by reverse phase column chromatography [ C 18 Column, eluent: water-water/acetonitrile (9: 1) +0.1% formic acid]To give (((((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 (12 mg, 5% yield). MS m/z (ESI): 557.4[ M ] +H] + 。
1 H NMR(400MHz，D 2 O)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 by the synthetic method of reference example 31:
the nuclear magnetic data of the compounds prepared in examples 32 to 51 are as follows:
biological test evaluation
1. Evaluation of CD73 in vitro enzyme Activity
The present invention employs the malachite green assay of CD73 in the soluble state synthesized in vitro to determine the properties of compounds for CD73 inhibitory activity. The experimental procedure was as follows:
1. the enzymatic reactions of this experiment were carried out in 384 well plates and incubated for 30 minutes at 25 ℃ with CD73 (R & D systems # 5795-EN-010) at a concentration of 36ng/ml and various concentrations of compounds and 50. Mu.M AMP in a 40. Mu.l reaction system (25mM Tris pH 7.5,5mM MgCl2,0.005% Tween-20);
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 analysis of the percent inhibition of the compounds of the invention at different concentrations using non-linear regression 50 The value is obtained.
The experimental results of the compounds of the examples of the present invention are shown in table 1.
2. Evaluation of Cell surface CD73 enzyme Activity (Cell Titer Glo (CTG) assay)
The invention adopts human breast cancer cells 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 ℃ 5% 2 Culturing 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 removed 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 cell surface CD73 enzyme activity was then evaluated by quantitative determination of the rate of decrease of the substrate AMP level in the cell culture supernatant 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 Prism 50 )。
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 (9)
1. A compound of formula (IIIa), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, X 1 、X 2 Each independently is selected from N or CH; x 5 Is selected from C (R) 10 ) Or N; y is 1 Is selected from-O-or-C (R) 12 R 13 )-；
R 1 Is selected from C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 5-8 Aryl radical, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or-NR 19 R 20 Optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazineSubstituted with a substituent selected from the group consisting of phenyl, pyridyl, hydroxy and methoxy;
R 2 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuryl, 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, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;
R 3 selected from hydrogen, deuterium, cyano, methyl, ethenyl or ethynyl, said groups being optionally further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;
R 10 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuryl, 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, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy or methoxy;
R 12 、R 13 each independently selected from hydrogen, deuterium, fluoro, chloro, methyl, vinyl, cyclopropyl, hydroxy, trifluoromethyl or cyclopropylmethyl;
R 17 、R 18 each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxyl, methoxy, trifluoromethyl, trideuteromethyl, trifluoromethoxy, trideuteromethoxy, cyclopropylmethyl, methoxymethyl, ethoxyacyl or acetoxy;
R 19 、R 20 each independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 3-10 Cycloalkyl radical C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-10 Cycloalkyl radical, C 4-10 Cycloalkenyl group, 3-to 10-membered heterocyclic group, C 5-10 Aryl, 5-to 10-membered heteroaryl, hydroxy, acetyl or-C (O) NH 2 Or, or R 19 、R 20 Together 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 1-4 Alkyl, vinyl, trifluoromethyl, cyclopropyl, cyclopentyl, morpholinyl, oxetanyl, tetrahydrofuryl, piperazinyl, piperidinyl, phenyl, pyridinyl, hydroxy, or methoxy.
2. A compound of formula (iiia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds:
3. a process for the preparation of a compound of formula (iiia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, comprising the steps of:
wherein Pg is hydrogen, tert-butyloxycarbonyl or p-toluenesulfonyl; x 1 、X 2 、X 5 、Y 1 、R 1 、R 2 、R 3 、R 17 、R 18 As claimed in claim 1.
4. A pharmaceutical composition comprising a compound of formula (iiia) according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound of formula (iiia) according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of cancer or tumors, immune-related diseases and disorders, or metabolic diseases, mediated at least in part by CD 73.
6. The use of claim 5, 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, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, connective tissue cancer, lung cancer, adrenal gland cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma.
7. The use of claim 5, wherein the cancer or tumor is selected from the group consisting of: testicular seminoma, epidermal basal cell carcinoma, muscle cancer, melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, kaposi's sarcoma.
8. The use according to claim 6, wherein the skin cancer is melanoma or basal cell carcinoma; the white blood cell cancer is lymphoma or leukemia; the lung cancer is small cell lung cancer or non-small cell lung cancer; the sarcoma is Kaposi's sarcoma.
9. The use according to claim 5, wherein the immune related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infections, crohn's disease, allergic contact dermatitis and eczema, systemic sclerosis or multiple sclerosis.
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| JP7114076B2 (en) | 2015-12-22 | 2022-08-08 | シャイ・セラピューティクス・エルエルシー | Compounds for the treatment of cancer and inflammatory diseases |
| MX2019014875A (en) | 2017-06-21 | 2021-01-29 | SHY Therapeutics LLC | Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease. |
| WO2020210970A1 (en) * | 2019-04-16 | 2020-10-22 | Bioardis Llc | Imidazotriazine derivatives as cd73 inhibitors |
| TWI821559B (en) * | 2019-04-28 | 2023-11-11 | 大陸商上海和譽生物醫藥科技有限公司 | A CD73 inhibitor, its preparation method and application |
| WO2021040356A1 (en) * | 2019-08-23 | 2021-03-04 | Kainos Medicine, Inc. | C-nucleosides, c-nucleotides and their analogs, equivalents and prodrugs thereof for ectonucleotidase inhibition |
| TWI794742B (en) | 2020-02-18 | 2023-03-01 | 美商基利科學股份有限公司 | Antiviral compounds |
| CN115667190A (en) * | 2020-06-17 | 2023-01-31 | 贝达药业股份有限公司 | Bicyclic compounds and application thereof |
| US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
| WO2023102472A1 (en) * | 2021-12-01 | 2023-06-08 | The Scripps Research Institute | Antiviral prodrugs and formulations thereof |
| WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
| CN115960106B (en) * | 2022-11-03 | 2024-03-26 | 中国药科大学 | Mitochondrial RNA polymerase inhibitor and derivatives, pharmaceutical composition and medical application thereof |
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| US9029346B1 (en) * | 2013-12-13 | 2015-05-12 | The Johns Hopkins University | Irreversible inhibitors of DNA polymerase beta |
| WO2017120508A1 (en) * | 2016-01-08 | 2017-07-13 | Arcus Biosciences, Inc. | Modulators of 5'-nucleotidase, ecto and the use thereof |
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| US11129841B2 (en) * | 2017-05-10 | 2021-09-28 | Oric Pharmaceuticals, Inc. | CD73 inhibitors |
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