KR-20260065587-A - Improved Derivatives of Cereblon-Binding Small Molecules and Use Thereof

Abstract

The present invention relates to an improved small molecule compound having excellent cereblon (CRBN) binding activity and enhanced anticancer activity, and to the use thereof. Based on its cereblon binding ability, the compound of the present invention can effectively function as a novel anticancer agent for the treatment of various solid tumors and hematological cancers.

Inventors

• 김동석

Assignees

• 주식회사 아이비스바이오

Dates

Publication Date

20260508

Application Date

20251103

Priority Date

20241101

Claims (8)

1. A compound represented by the following chemical formula (I), its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt: Chemical formula (I) In chemical formula (I), R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.
2. In claim 1, the above formula (I) is a compound, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof represented by the following formula (II): Chemical formula (II) R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and R 2 to R 6 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.
3. In paragraph 2, The compound of formula (II) above is any one of the compounds selected from the group consisting of formulas (i) to (xiv) below, its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts: [Table 1]
4. A pharmaceutical composition for the prevention or treatment of benign tumors or cancer comprising, as an active ingredient, a compound of any one of claims 1 to 3, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in paragraph 4, the cancer is a blood cancer or a solid tumor.
6. A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in claim 5, the blood cancer is selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.
7. In paragraph 5, A pharmaceutical composition for the prevention or treatment of benign tumors or cancers, characterized in that the above-mentioned solid tumor is selected from the group consisting of melanoma, myoma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer.
8. A reagent composition comprising a compound of any one of claims 1 to 3, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, or a solvate thereof.

Description

Improved Derivatives of Cereblon-Binding Small Molecules and Use Thereof The present invention relates to a novel small molecule compound having excellent cereblon binding activity and its use in the treatment of tumors or cancer. The ubiquitin-proteasome pathway (UPP) is an important pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to various cellular processes, and defects or imbalances in it lead to the development of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases consist of over 500 different proteins and are classified into several classes defined by structural elements of E3 functional activity. Cereblon (CRBN) interacts with damaged DNA binding protein 1 (DDB1) and forms the DDB1-CUL4a-Roc1 ubiquitin ligase complex with Cullin 4, and functions as a substrate receptor through which proteins recognized by CRBN are ubiquitinated and can be degraded by the proteasome. Cereblon (CRBN) is known as a molecular target for immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide (Lopez-Girona et al; Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide Leukemia 2012; 26:2326-2335). Specifically, thalidomide, a drug approved for the treatment of multiple myeloma in the late 1990s, binds to Cereblon and modulates the substrate specificity of the CRL4CRBN ubiquitin ligase complex, and this mechanism forms the basis of thalidomide's pleiotropic effect on immune cells and cancer cells. However, as side effects of thalidomide were reported, various studies were conducted to develop analogs with higher efficacy and fewer side effects for its use as an anticancer treatment. Consequently, cereblon modulators such as lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106 were developed, and their clinical applicability in hematological malignancies, such as multiple myeloma, myelodysplastic syndrome, lymphoma, and leukemia, has been demonstrated (Le Roy A et al: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities Front Immunol 2018; 9: 977). The antitumor activity of cereblon modulators is mediated by the following: 1) Inhibition of cancer cell proliferation and induction of apoptosis, 2) Discontinuation of nutritional support from the tumor stroma, 3) Proliferation of T cells, production of cytokines, and activation of NK (natural killer) cells following stimulation of immune cells. Accordingly, the inventors have developed a novel small molecule compound capable of effectively killing tumor cells by possessing substrate specificity for cereblon (Korean Patent Publication No. 10-2024-0146608). In the present invention, structural changes capable of enhancing anticancer activity while maintaining cereblon binding characteristics were explored, and a new cereblon-bound small molecule compound exhibiting superior anticancer effects compared to existing compounds was developed. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled expert in the art to which this invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art. The inventors have selected compounds having excellent binding affinity to Cereblon (e.g., the following chemical formula (II-4)) and confirmed their tumor cell death effects (Korean Patent Publication No. 10-2024-0146608). Chemical formula (II-4) Any benzene ring present in chemical formula (II-4) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted, and any one or more hydrogens are each independently alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, urea, sulfonyl, hydroxy, aldehyde, carboxy, alkyl halide, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo(＝O); Amino, alkylamino, cycloalkylamino, arylamino, heterocyclilamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclilalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; hydroxyl; alkoxy; alkoxyalkyl; amino; It may be characterized by being substituted with alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imid