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KR-102961396-B1 - Novel PIM kinase inhibitors and uses thereof

KR102961396B1KR 102961396 B1KR102961396 B1KR 102961396B1KR-102961396-B1

Abstract

The present invention relates to a novel PIM kinase inhibitor and its uses, and more specifically, to a novel compound having inhibitory activity against PIM protein kinase and a pharmaceutical composition for treating or preventing diseases of abnormal PIM kinase expression or activity containing the same as an active ingredient.

Inventors

  • 이진호
  • 홍빅터석봉
  • 추현성
  • 전민규

Assignees

  • 계명대학교 산학협력단

Dates

Publication Date
20260508
Application Date
20221128

Claims (11)

  1. A compound represented by the following chemical formula I, or a compound selected from pharmaceutically acceptable salts thereof: [Chemical Formula I] In the above chemical formula I, R 1 is or -Ar-R 2 and, Ar is or And, R2 is a (C1–C6)alkylamino, (C5–C6)cycloamino, or di(C1–C2)alkylamino(C1–C4)alkylamino, and X is CH or N.
  2. A compound according to claim 1, characterized in that the compound is a compound represented by the following chemical formula I-1: [Chemical Formula I-1] In the above chemical formula I-1, R1 is OH, and The above Ar is or And, n is an integer from 1 to 3, and X is CH or N.
  3. A compound according to claim 1, characterized in that the compound is a compound represented by the following chemical formula I-2: [Chemical Formula I-2] In the above chemical formula I-2, The above Ar is or And, n is an integer from 2 to 3, and X is CH or N.
  4. In claim 1, the compound is 2-(2-amino-6-((3-(dimethylamino)propyl)amino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (Compound 14), 2-(2-amino-6-((2-(dimethylamino)ethyl)amino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (Compound 7), 2-(2-amino-6-(cyclohexylamino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (Compound 8), 4-(2-aminopyrimidine-4-yl)-2-(6-((2-(dimethylamino)ethyl)amino)pyrimidine-4-yl)phenol (Compound 9), ( E A compound characterized by being one selected from the group consisting of )-1-(5-(2-aminopyrimidine-4-yl)-2-hydroxyphenyl)-3-(dimethylamino)-2-propen-1-one (compound 11) and 2-(2-amino-6-(pentylamino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (compound 13).
  5. A pharmaceutical composition for treating or preventing diseases with abnormal PIM kinase expression or activity comprising a compound according to any one of claims 1 to 4, wherein the disease with abnormal PIM kinase expression or activity is a disease selected from allergy, asthma, irritable bowel syndrome, pancreatitis, diverticulosis, Graves' disease, psoriatic arthritis, ankylosing spondylitis, myasthenia gravis, vasculitis, autoimmune thyroiditis, dermatitis, scleroderma, systemic sclerosis, vitiligo, graft-versus-host disease, Sjögren's syndrome, or cancer.
  6. delete
  7. In Article 5, A pharmaceutical composition in which the above-mentioned disease of abnormal PIM kinase expression or activity is a cancer in which the expression or activity of any one of the PIM kinases selected from the group consisting of PIM 1, PIM 2, and PIM 3 is upregulated.
  8. In Article 7, A pharmaceutical composition in which the above cancer is endometrial cancer, uterine cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, or lymphoma.
  9. delete
  10. A reagent composition for inhibiting PIM kinase overexpression or activity, comprising a compound according to any one of claims 1 to 4.
  11. In Article 10, The above composition is a reagent composition characterized by inhibiting at least one PIM kinase selected from the group consisting of PIM 1, PIM 2, and PIM 3.

Description

Novel PIM kinase inhibitors and uses thereof The present invention relates to a novel PIM kinase inhibitor and its uses, and more specifically, to a novel compound having inhibitory activity against PIM protein kinase and a pharmaceutical composition for treating or preventing diseases of abnormal PIM kinase expression or activity containing the same as an active ingredient. PIM kinases are known as oncogene-encoded serine/threonine kinases that are major downstream effectors of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway, which mediates cell growth, proliferation, metastasis, and drug resistance, and appear in three PIM isoenzyme forms: PIM-1, PIM-2, and PIM-3. PIM kinases are overexpressed in solid tumors such as triple-negative breast cancer, prostate cancer, multiple myeloma, and hematological cancers such as leukemia, and are known to phosphorylate downstream proteins or transcription factors that contribute to tumor growth and survival. Inhibitors of these kinases are expected to treat cancers associated with high expression of PIM kinases, and several PIM kinase inhibitors are currently undergoing clinical trials (Anizon, F., et al., Curr. Med. Chem., 17: 4114-33, 2010; Lee, J., et al., Chem. Pharm. Bull., 62: 906-914, 2014; Morwick, T. Expert Opin. Ther. Pat., 20:193-212, 2010). Therefore, PIM kinases have been considered a promising drug target for cancer treatment. Furthermore, because PIM kinases are involved in various immune and inflammatory responses and these indications require drug agents with minimal side effects, PIM kinase inhibitors are used for colitis (Shen et al., Dig. Dis. Sci., 2012, 57, 1822-31), peanut allergy (Wang et al., J. All. Clin. Immunol., 2012, 130, 932-44), multiple sclerosis, and lupus (Davis et al., "Small Molecule Dual Antagonist of Pim 1 and 3 Kinases Ameliorate Experimental Autoimmune Encephalomyelitis", 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 13-16 October 2010, Gothenburg, Sweden, Poster P436; Robinson et al., J. Immunol., 2012, 188). It is expected to be useful in treating patients with rheumatoid arthritis (Yang et al., Immunol. 2010, 131, 174-182) and other immunological and inflammatory disorders. Therefore, it is expected that the development of new PIM kinase inhibitors will enable the useful treatment of diseases related to the expression or activity of PIM kinase, such as cancer and other diseases. FIG. 1 is a schematic diagram showing the synthesis sequence of compound 14 according to one embodiment of the present invention. FIG. 2 is a schematic diagram showing the synthesis sequence of compound 7 according to one embodiment of the present invention. Figure 3 illustrates a molecular docking study performed to investigate the orientation of a compound according to one embodiment of the present invention in the ATP binding pocket of PIM kinase. The present invention will be described in more detail below. As a result of diligent efforts to develop novel PIM kinase inhibitors, the inventors have completed the present invention by synthesizing novel compounds that have superior PIM kinase inhibitory activity compared to 2,4-bis(2-aminopyrimidine-4-yl)phenol (BMI-1026), a 2-(2-aminopyrimidine-4-yl)phenol derivative known to have inhibitory activity against conventional PIM kinase. Accordingly, the present invention provides a compound selected from a compound represented by the following chemical formula I, or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, R1 is or -Ar-R 2 , and Ar is , or And, R2 is phenyl, (C1~C6)alkylamino, (C5~C6)cycloamino or di(C1~C2)alkylamino(C1~C4)alkylamino, and X can be CH or N. Preferably, the compound of the present invention may be a compound represented by the following chemical formula I-1: [Chemical Formula I-1] In the above chemical formula I-1, R1 is OH, and the Ar is or and n is an integer from 2 to 3, and X can be CH or N. More preferably, the compound of the present invention may be a compound represented by the following chemical formula I-2: [Chemical Formula I-2] In the above chemical formula I-2, the Ar is or and n is an integer from 2 to 3, and X can be CH or N. As one example of a compound according to the present invention, 2-(2-amino-6-((3-(dimethylamino)propyl)amino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (compound 14), 2-(2-amino-6-((2-(dimethylamino)ethyl)amino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (compound 7), 2-(2-amino-6-(cyclohexylamino)pyrimidine-4-yl)-4-(2-aminopyrimidine-4-yl)phenol (compound 8), 4-(2-aminopyrimidine-4-yl)-2-(6-((2-(dimethylamino)ethyl)amino)pyrimidine-4-yl)phenol (compound 9), It may be one selected from the group consisting of 4-(2-aminopyrimidine-4-yl)-2-(6-((2-(dimethylamino)ethyl)amino)pyrazine-2-yl)phenol (compound 10), ( E )-1-(5-(2-aminopyrimidine-4-yl)-2-hydroxyphenyl)-3-(dimethylamino)-2-propen-1-one (co