该专利优先权日为2018.4.29，本申请的化合物通过抑制Bcl-2治疗Bcl-2相关疾病，包括神经退行性疾病，如阿尔茨海默氏病，增生性疾病，如癌症，自身免疫性疾病和血栓形成前疾病等。
Bcl-2是最早发现的细胞抗凋亡蛋白Bcl-2家族的一员，Bcl-2家族蛋白通过与促凋亡蛋白BIM、BAD等形成二聚体以及自身二聚，在细胞凋亡的调控中发挥重要作用。Bcl-2家族蛋白在细胞凋亡和肿瘤治疗中所起的作用从被发现至今已近30年之久，以Bcl-2家族蛋白为靶点的药物研发被证实是极其困难的，但2016年4月成功上市的Bcl-2选择性抑制剂Venclexta/ABT-199为该靶点药物的开发提供了临床验证依据。
目前国内企业亚盛医药已经有个Bcl-2抑制剂APG-2575和Bcl-2/Bcl-xL抑制剂APG-1252处于临床I期，Bcl-2/Bcl-xL/Mcl-1抑制剂AT-101处于临床II/III期。
具体体外活性数据请联系小编索取专利。
Bcl-2是最早发现的细胞抗凋亡蛋白Bcl-2家族的一员，Bcl-2家族蛋白通过与促凋亡蛋白BIM、BAD等形成二聚体以及自身二聚，在细胞凋亡的调控中发挥重要作用。Bcl-2家族蛋白在细胞凋亡和肿瘤治疗中所起的作用从被发现至今已近30年之久，以Bcl-2家族蛋白为靶点的药物研发被证实是极其困难的，但2016年4月成功上市的Bcl-2选择性抑制剂Venclexta/ABT-199为该靶点药物的开发提供了临床验证依据。
目前国内企业亚盛医药已经有个Bcl-2抑制剂APG-2575和Bcl-2/Bcl-xL抑制剂APG-1252处于临床I期，Bcl-2/Bcl-xL/Mcl-1抑制剂AT-101处于临床II/III期。
具体体外活性数据请联系小编索取专利。
BACKGROUND OF THE INVENTION
[0003]
Programmed cell death or apoptosis occurs in multicellular organisms to dispose damaged or unwanted cells, which is critical for normal tissue homeostasis. (Br. J. Cancer 1972, 26, 239) . However defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer (Cell 2011, 144, 646) . Resistance to apoptotic cell death is a hallmark of cancer and contributes to chemoresistance (Nat Med. 2004, 10, 789-799) . Several key pathways controlling apoptosis are commonly altered in cancer. Some factors like Fas receptors and caspases promote apoptosis, while some members of the B-cell lymphoma 2 (Bcl-2) family of proteins inhibit apoptosis. Negative regulation of apoptosis inhibits cell death signaling pathways, helping tumors to evade cell death and developing drug resistance.
[0004]
There are two distinct apoptosis pathways including the extrinsic pathway and the intrinsic pathway. The extrinsic pathway is activated in response to the binding of death-inducing ligands to cell-surface death receptors (Nat Rev Drug Discov. 2017 16, 273-284) . The B cell lymphoma 2 (BCL-2) gene family, a group of proteins homologous to the Bcl-2 protein, encodes more than 20 proteins that regulate the intrinsic apoptosis pathway. Bcl-2 family proteins are characterized by containing at least one of four conserved Bcl-2 homology (BH) domains (BH1, BH2, BH3 and BH4) (Nat. Rev. Cancer 2008, 8, 121; Mol. Cell 2010, 37, 299; Nat. Rev. Mol. Cell Biol. 2014, 15, 49) . Bcl-2 family proteins, consisting of pro-apoptotic and anti-apoptotic molecules, can be classified into the following three subfamilies according to sequence homology within four BH domains: (1) a subfamily shares sequence homology within all four BH domains, such as Bcl-2, Bcl-XL and Bcl-w which are anti-apoptotic; (2) a subfamily shares sequence homology within BH1, BH2 and BH4, such as Bax and Bak which are pro-apoptotic; (3) a subfamily shares sequence homology only within BH3, such as Bik, Bid and HRK which are pro-apoptotic. One of the unique features of Bcl-2 family proteins is heterodimerization between anti-apoptotic and pro-apoptotic proteins, which is considered to inhibit the biological activity of their partners. This heterodimerization is mediated by the insertion of a BH3 region of a pro-apoptotic protein into a hydrophobic cleft composed of BH1, BH2 and BH3 from an anti-apoptotic protein. In addition to the BH1 and BH2, the BH4 domain is required for anti-apoptotic activity. In contrast, BH3 domain is essential and, itself, sufficient for pro-apoptotic activity.
[0005]
Similar to oncogene addiction, in which tumor cells rely on a single dominant gene for survival, tumor cells may also become dependent on Bcl-2 in order to survive. Bcl-2 overexpress is found frequently in acute myeloid leukemia (AML) , acute lymphocytic leukemia (ALL) , relapsed/refractory chronic lymphocytic leukemia (CLL) , follicular lymphoma (FL) , non-Hodgkin lymphoma (NHL) and solid tumors such as pancreatic, prostate, breast, and small cell and non-small cell lung cancers (Cancer 2001, 92, 1122-1129; Cancer Biol. 2003; 13: 115-23; Curr. Cancer Drug Targets 2008, 8, 207-222; Cancers 2011, 3, 1527-1549) . Dysregulated apoptotic pathways have also been implicated in the pathology of other significant diseases such as neurodegenerative conditions (up-regulated apoptosis) , e.g., Alzheimer's disease; and proliferative diseases (down-regulated apoptosis) , e.g., cancers, autoimmune diseases and pro-thrombotic conditions. Target to either Bcl-2 or Bcl-xL, a number of small-molecule BH3 mimetics have been reported in (Recent Patents on Anti-Cancer Drug Discovery, 2008, 3, 20-30; Bioorg. Med. Chem. Lett. 2016, 26, 2105-2114; Nature Reviews Drug Discovery 2017, 16, 273-284; WO2002024636; WO2005049593; WO2006127364; WO2006023778; WO2007040650; WO2008030836; WO2009152082; WO2009036051; WO2010065824; WO2010065865; WO2010083441; WO2010083442; WO2010067067; WO2011029842; WO2011068561; WO2011119345; WO2011149492; WO2011150016; WO2012058392; WO2012017251; WO2012162365; WO2012103059; WO2013053045; WO2013185202; WO2013096060; WO2013096059; WO2013096055; WO2013096051; WO2013096049; US2011312969; WO2014158528; WO2014113413; WO2018027097; WO2018041248; WO2018009444; CN106749233; CN106565706) . Some of the Bcl-2 small molecule inhibitors have been investigated at various stages of drug development: the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax, WO2009155386) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by platelet death and attendant thrombocytopenia caused by Bcl-xL inhibition (Lancet Oncol. 2010, 11, 1149; J. Clin. Oncol. 2011, 29, 909; J. Clin. Oncol. 2012, 30, 488) . The new generation of the BCL-2 selective inhibitor venetoclax (ABT-199/GDC-0199) was proceeded, which demonstrated robust activity in these cancers but also spared platelets (Journal of Hematology &Oncology 2015, 8, 129; Clinical Advances in Hematology &Oncology 2017, 15, 210) . S55746 (also known as BCL201) , APG-101, APG-1252 are being studied at clinical trial stage. Currently, Venetoclax (formerly ABT-199) is the only Bcl-2 selective inhibitor approved by FDA for the treatment of patients who have relapsed or refractory chronic lymphocytic leukemia (CLL) with the 17p deletion. Recently, however, a novel Gly101Val mutation in BCL2 was identified after the patients were treated with the Bcl-2 inhibitor venetoclax (ABT-199) for 19 to 42 months (Cancer Discov. 2019, 9, 342-353) . This mutation dramatically reduced the binding affinity of Bcl-2 for Venetoclax (ABT-199) by about 180-fold in cell based assay.
[0006]
Therefore, there is a need of new small molecules that selectively inhibit Bcl-2 proteins for the treatment of dysregulated apoptotic diseases such as cancers, autoimmune diseases and pro-thrombotic conditions. Unexpectedly, the inventors of the present application found some compounds disclosed herein show not only much higher potency and selectivity but also much lower CYP2C9 inhibition, indicating potential better efficacy and lower potential risk of drug-drug interaction (DDI) . Also, the inventors of the present application found that the compounds disclosed herein exhibit inhibitory activity against both Bcl-2 wild type and Bcl-2 G101V mutation type, suggesting a type of new potential Bcl-2 inhibitors without resistance concern.
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