阅读说明：本技术 用于治疗癌症的环状二核苷酸衍生物 (Cyclic annular dinucleotides derivative for treating cancer ) 是由 金大式 方家范 远藤笃史 崔亨旭 郝鸣鸿 鲍幸峰 黄冠群 于 2018-02-17 设计创作，主要内容包括：本文提供可用于治疗癌症的化合物。(Provided herein is the compounds that can be used for treating cancer.)

1. a kind of compound, with following formula:

Background technique

STING (interferon gene stimulating factor) is in cytosol to the signaling molecule of dsDNA innate response.It has reported STING missing in a variety of human cancers.In addition, in melanoma (Xia T et al., " Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis" Cancer Res.2016) and colon cancer (Xia T et al., " Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis"Cell Rep.2016；Also the mistake of STING signal transduction in human cancer is reported in 14:282-97) It adjusts.It is interesting that in these researchs, the expression deletion of genome analysis STING as the result is shown be not due to gene delection or Mutation, but (Xia, Cancer Res.2016 is changed by epigenetic；Xia,Cell Rep.2016).It is ground from mouse model The evidence for studying carefully acquisition also supports the cancer protection activity of STING.STING knock-out mice shows that tumour controls defect (Woo SR Et al., " STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors"Immunity 2014；41:830-42).

In addition, effect of the STING in protection ontogeny has been confirmed in several mouse spontaneous models, including Glioma (Ohkuri T et al., " Protective role of STING against gliomagenesis:Rational use of STING agonist in anti-glioma immunotherapy"Oncoimmunology.2015；4: ) and colon cancer (Zhu Q et al., " Cutting edge:STING mediates protection against e999523 colorectal tumorigenesis by governing the magnitude of intestinal inflammation"J.Immunol.2014；193:4779-82).This antitumor action may be since it fights NF-kB With the ability (Okihuri 2015) of STAT3 excessive activation.The activation of STING approach is also shown in preclinical mouse tumor model Effective activity (Woo 2014 is shown；Chandra D et al., " STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer"Cancer Immunol Res.2014；2:901- 10；Corrales L et al., " Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity"Cell Rep.2015；11: 1018-30；Curran E et al., " STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia"Cell Rep.2016；15:2357-66；Tang CH et al., " Agonist- Mediated Activation of STING Induces Apoptosis in Malignant B Cells"Cancer Res.2016；76:2137-52).This anti-tumor activity may be the destruction due to tumor vascular system, and then induction adapts to Property immune response (Corrales L et al., " The host STING pathway at the interface of cancer and immunity"J.Clin.Invest.2016；126:2404-11) cause.Therefore, tumour is directly stimulated by agonist STING in microenvironment can represent the new method for the treatment of kinds cancer type.

Summary of the invention

Detailed description of the invention

Fig. 1 shows the synthesis of compound 1a and compound 2a.

Fig. 2A and Fig. 2 B shows compound 1 and the substitution synthesis of compound 1a.Substitution synthesis is also shown in Fig. 2 C.

Fig. 3 shows compound 1¹H NMR spectra figure.

Fig. 4 A, Fig. 4 B and Fig. 4 C respectively illustrate the asymmetric crystal of compound 1, the first molecule from asymmetric crystal With the dimolecular X-ray crystallography result (ORTEP figure) from asymmetric crystal.

Fig. 4 D shows the X-ray crystallography result (ORTEP figure) of 2 crystal of compound.

Fig. 5 A and Fig. 5 B show the route of synthesis of compound 18,19 and 20.

Fig. 6 shows the expression vector figure of WT STING (pLenti-WT people STING-Puro).

Fig. 7 and Fig. 8 is with embodiment 108, and it is living to show healing of the compound 1a in the dual tumor model of CT26 Property.

Fig. 9 shows the gross tumor volume figure and survival curve of treated tumour with embodiment 109.

Figure 10 shows the gross tumor volume figure and survival curve of treated tumour with embodiment 110.

Figure 11 shows the photo of the x-ray crystal structure of the people WT STING compound with compound 1.

Figure 12 shows the people REF STING C-terminal structural domain compound with compound 1.

Figure 13 shows the synthesis example of compound 38 and compound 39.

Embodiment can provide the compound of Formulas I:

(wherein P₁It is the phosphorus of discribed lower left as above, P₂It is the phosphorus in discribed upper right side as above), the compound With substituent group and spatial chemistry or its pharmaceutically acceptable salt shown in as follows 71.Indicate singly-bound or double Key.

When phosphorus atoms tool is there are four when different substituent groups, which is Stereocenter.SpSp/RpRp/SpRp/RpSp Phosphorus spatial chemistry shown in finger.

Table 1