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CN-121974911-A - Compounds for degrading proteins, application and medicaments thereof

CN121974911ACN 121974911 ACN121974911 ACN 121974911ACN-121974911-A

Abstract

The invention discloses a compound for degrading protein, application and a medicine thereof, and relates to the technical field of protein degradation medicines. The compound disclosed by the invention comprises a structure shown in a formula (I), can degrade Bcl-2 and other proteins, has the activity of inhibiting the growth and survival of tumor cells, can be used for preparing antitumor drugs, and is used for treating diseases related to the Bcl-2 proteins.

Inventors

  • SUN NING
  • HAN XIAORAN
  • YANG TING
  • DING JIE

Assignees

  • 上海睿跃生物科技有限公司

Dates

Publication Date
20260505
Application Date
20220901

Claims (10)

  1. 1. A compound or salt thereof, characterized in that it has a structure represented by formula (I): Wherein A is ; X is-CH 2 -; Y is-CONH-; Z is- (CH 2 ) n-or (Z1) n-CH 2 -CH 2 -, wherein Z1 is-CH 2 -CH 2 -O-, and n is 1,2,3,4,5,6 or 7.
  2. 2. The compound or a salt thereof according to claim 1, wherein the compound has a structure represented by the following formula (II) or formula (III): Wherein A is When the compound has a structure shown in the following formula (II), n is 2,3,4,5 or 6, and when the compound has a structure shown in the following formula (III), n is1, 2,3,4 or 5.
  3. 3. The compound or a salt thereof according to claim 1, wherein the compound is 、 、 、 、 、 、 、 、 Or (b) 。
  4. 4. Use of a compound or salt thereof according to any one of claims 1 to 3, wherein the use comprises the following: (1) The preparation method is used for preparing medicines for preventing or treating diseases related to the activity or high expression level of Bcl-2 protein, ikaros protein or Aiolos protein; (2) The method is used for preparing a targeted inhibitor for degrading Bcl-2 protein, ikaros protein or Aiolos protein; (3) For non-therapeutically inhibiting the activity of a Bcl-2 protein, ikaros protein or Aiolos protein in vitro; (4) For preventing or treating diseases associated with the activity or high expression level of Bcl-2 protein, ikaros protein or Aiolos protein; (5) For non-therapeutic inhibition of tumor cell proliferation in vitro, and/or (6) Bcl-2 proteins, ikaros proteins and/or Aiolos proteins are degraded in vitro in a non-disease diagnostic and therapeutic manner.
  5. 5. The use according to claim 4, wherein in use (1) and in use (4), the disease is cancer; Preferably, the cancer is acute/chronic lymphocytic leukemia, small lymphocytic lymphoma, acute/chronic myelogenous leukemia, mantle cell lymphoma, multiple myeloma, non-hodgkin's lymphoma, lung cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, melanoma, prostate cancer, breast cancer, or ovarian cancer; Preferably, in use (5), the tumor is acute/chronic lymphocytic leukemia, small lymphocytic lymphoma, acute/chronic myelogenous leukemia, mantle cell lymphoma, multiple myeloma, non-hodgkin lymphoma, lung cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, melanoma, prostate cancer, breast cancer, or ovarian cancer.
  6. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
  7. 7. A method for non-therapeutic degradation of a protein of interest in vitro, characterized in that a sample is admixed with a compound or salt thereof according to any one of claims 1-3, said protein of interest contained in said sample being Bcl-2 protein, ikaros protein, and/or Aiolos protein.
  8. 8. A method of preparing a compound or salt thereof according to any one of claims 1 to 3, wherein the method is a method of degrading a protein of interest in vitro in a non-disease diagnostic and therapeutic manner; the method comprises the following steps: s400, preparing a compound of the formula (I) by using the formulas (1-10) and (1-11) as raw materials to obtain the compound; The formulas (1-10) are as follows: Wherein X1 is-CH 2 -COOH-; The formulas (1-11) are as follows: Wherein Y1 is-NH 2 ; preferably, the chemical reaction conditions in the step S400 comprise a solvent of DMSO, a base of NMM, a condensing agent of EDCI and HOAT, and a reaction temperature of room temperature.
  9. 9. The method of preparing according to claim 8, further comprising the step of preparing a compound of formula (1-11): Reacting a compound of formula (II-2) with a compound of formula (II-3) or a compound of formula (III-2) to obtain a compound of formula (1-11); the formula (II-2) is as follows: ; the formula (II-3) is as follows: Boc is t-butoxycarbonyl; The formula (III-2) is as follows: wherein M is tert-butyl.
  10. 10. The preparation method according to claim 9, wherein when Y1 in the formula (1-11) is-NH 2 , the compound of the formula (II-4) is prepared by reacting the formula (II-2) with the formula (II-3), and then removing the protecting group to prepare the compound of the formula (II-1); Wherein formula (II-4) is: The formula (II-1) is: Preferably, the reaction conditions for preparing the compound of formula (II-4) comprise DMF as solvent, DIEA as base, microwave reaction at 148-152 deg.C; Preferably, the reaction conditions for removing the protecting group from the formula (II-4) to obtain the formula (II-1) comprise the reagent of trifluoroacetic acid, the solvent of dichloromethane and the reaction temperature of room temperature.

Description

Compounds for degrading proteins, application and medicaments thereof RELATED APPLICATIONS The present application is a divisional application of China patent application with application number CN202211059402X, entitled "Compounds degrading proteins and their applications and drugs", filed on month 09 of 2022 and 01, which is incorporated herein by reference in its entirety. Technical Field The invention relates to the technical field of protein degradation medicines, in particular to a compound for degrading protein, application thereof and a medicine. Background Bcl-2 protein is one of the members of the B-cell lymphoma-2 (Bcl-2) family and is also an important anti-apoptotic factor in humans. The Bcl-2 family plays an important role in regulating the process of endogenous apoptosis and can be divided into two main classes, anti-apoptotic proteins and pro-apoptotic proteins, according to functional activity. Anti-apoptotic proteins all have four BH (BCL-2 homology) domains, including Bcl-2, bcl-xL, bcl-w, mcl-1, bcl-2-related protein A, and the like. Pro-apoptotic proteins can be further divided into two classes, multi-domain pro-apoptotic factors, including Bak, bax, bok, etc., and pro-apoptotic proteins containing only BH3 domains, including Bad, bid, bik, NOXA, PUMA, bim, etc., depending on their structure. The balance and interaction between anti-apoptotic and pro-apoptotic proteins together determine whether a cell enters the apoptotic program. Anti-apoptotic proteins such as Bcl-2 inhibit the formation of active states by forming heterodimers with pro-apoptotic proteins, protecting cells from the apoptotic program. When the cell receives an endogenous apoptosis signal, the pro-apoptosis protein containing only the BH3 structural domain can be combined with anti-apoptosis protein Bcl-2 protein, so that the inhibition of Bcl-2 on multi-structural-domain pro-apoptosis factors can be relieved, the multi-structural-domain pro-apoptosis factors can be directly activated, the apoptosis induction factors are promoted to form oligomers on the outer membrane of mitochondria, the permeation of the outer membrane of mitochondria (MOMP) is caused, cytochrome c and other pro-apoptosis factors are released, and the apoptosis cascade reaction in cytoplasm is activated, so that apoptosis is caused. Apoptosis plays an important role in the development and progression of tumors and in their development of drug resistance. The role of high expression of Bcl-2 protein in promoting survival of malignant tumors of the blood system has been widely demonstrated. the t (14; 18) chromosomal translocation is the most common mutation in follicular lymphoma (FCL) patients (science.1985, 228, 1440-1443) and is also present in about 30% of patients with diffuse large B-cell lymphomas (DLBCL), and this chromosomal translocation mutation leads to overexpression of Bcl-2 protein (blood. 2002, 99, 2285-2290). Amplification of the 18q21 chromosomal region where the Bcl-2 gene resides results in high expression of Bcl-2 protein, commonly found in Chronic Myeloid Leukemia (CML) and activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCL), which are significantly associated with lower survival and poor prognosis (j. Clin. Oncol. 2006.24, 961-968). Bcl-2 protein is highly expressed in more than 80% of Chronic Lymphocytic Leukemia (CLL) patients, mainly due to the deletion of chromosome 13q14 region, the expression level of microRNAs (miR-15A and miR 16-1) that inhibit Bcl-2 protein expression is reduced (BioCHemical journal. 2017, 474 3643-3657;Journal of Hematology & oncology. 2018, 11:65). Bcl-2 is also highly expressed in patients with Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) (blood 2007, 109, 2589-2596; blood 1996, 87, 1140-1146). In addition to hematological malignancies, bcl-2 is also highly expressed in many solid tumors, including 80% of Small Cell Lung Cancers (SCLC), 20% of MYCN-amplified neuroblastomas, 85% of estrogen receptor positive breast cancers (er+bc), melanoma, prostate cancer, gastric cancer, pancreatic cancer, and the like (BioCHemical Society transactions 2021, 49 2397-2410). In addition, the anti-apoptotic effects of Bcl-2 are also one of the factors responsible for the resistance of tumors to various chemotherapeutics, e.g., over-expression of Bcl-2 is significantly associated with resistance of gastric cancer to 5-FU, resistance of ovarian cancer to CISPLATIN, resistance of estrogen receptor positive breast cancer to paclitaxel, etc. (ADV CANCER Res. 2018; 137:37-75.). The anti-apoptosis effect of Bcl-2 makes it a popular drug target in the field of tumor treatment. Current developments for Bcl-2 protein inhibitors are based on BH3 structural analogs of the pro-apoptotic proteins bound thereto, competing for inhibition of Bcl-2 binding to inhibit the function of the pro-apoptotic proteins. Navitoclax (ABT-263) is the first inhibitor of oral activity targeting Bcl-2 and Bcl-x