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KR-20260062876-A - Heteroaryl derivative compounds, and uses thereof

KR20260062876AKR 20260062876 AKR20260062876 AKR 20260062876AKR-20260062876-A

Abstract

The present invention relates to heteroaryl derivative compounds and their uses. Since the heteroaryl derivatives of the present invention exhibit excellent inhibitory activity against AKT and/or AKT1 E17K, they can be usefully used for the treatment or prevention of diseases associated with the overactivation, amplification, or overexpression of AKT and/or AKT1 E17K, and in particular, they can be usefully used as therapeutic agents for cancer.

Inventors

  • 황선아
  • 조서현
  • 고이경
  • 김대권

Assignees

  • 보로노이 주식회사

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241029

Claims (15)

  1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, W is CH or N; Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring may be substituted with -C1-3 alkyl, -C1-3 haloalkyl, or -halo; Y 1 to Y 5 are each independently CR Y or N; RY is -H, -C1-3 alkyl, -C1-3 haloalkyl, -NH2 , -NH- C1-3 alkyl, -N( C1-3 alkyl)( C1-3 alkyl), -OH, -OC1-3 alkyl, or -halo; Z 1 to Z 5 are each independently CR Z or N; R Z is -H, -C 1-3 alkyl, -CN, -C(=O)H, -OH, -OC 1-3 alkyl, or -halo; Ring A is -phenyl, -(9-10-membered aryl), -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), wherein one or more H of ring A may be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring may be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; m is 0, 1, or 2, and; L is -NH-, -NH-C(=O)-(CH 2 )n-, or -C(=O)-NH-(CH 2 )n- and; n is 0, 1, or 2.
  2. In Article 1, W is CH or N; Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring may be substituted with -C 1-3 alkyl or -halo; Y 1 to Y 5 are each independently CR Y or N; RY is -H, -NH2 , or -halo; Z 1 to Z 5 are each independently CR Z or N; R Z is -H, -CN, -C(=O)H, or -OH; Ring A is -phenyl, -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), wherein one or more H of ring A may be substituted with -C 1-3 alkyl; Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring may be substituted with -halo; L is -NH-, -NH-C(=O)-(CH 2 )n-, or -C(=O)-NH-(CH 2 )n- and; m is 0 or 1 and; n is 0 or 1; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  3. In Article 1, go In the case of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more H of the ring can be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  4. In Article 1, Is , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more H of the ring can be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  5. In Article 1, Is , , , . , , , , , or, and, here One or more H of the ring can be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -NH-C 1-3 alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OH, -OC 1-3 alkyl, or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  6. In Article 1, Is , , , , , , , , , or and, here One or more H of the ring can be substituted with -C 1-3 alkyl, -CN, -C(=O)H, -OH, -OC 1-3 alkyl, or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  7. In Article 1, Ring A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And; #Is Connected to, where one or more H of ring A can be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; ## is connected to (CH 2 )m; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  8. In Article 1, Ring B is , , , , , , , , , , , , , , , , , or nothing (null), where one or more H of ring B can be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, or -halo; * is connected to L; ** is connected to (CH 2 )m; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  9. In Article 1, L is -NH-, -NH-C(=O)-, -NH-C(=O)-(CH 2 )-, -C(=O)-NH-, or -C(=O)-NH-(CH 2 )-; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  10. A compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .
  11. A pharmaceutical composition comprising a compound according to claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  12. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient a compound according to claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  13. In Article 12, A pharmaceutical composition that inhibits AKT and/or AKT1 E17K.
  14. In Article 12, A pharmaceutical composition in which the above cancer is a disease associated with AKT and/or AKT1 E17K overactivation, amplification, or overexpression.
  15. In Article 14, The above cancers include uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, serous ovarian cancer, breast cancer, Luminal A breast cancer, Luminal B breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colorectal cancer (CRC), rectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), cholangioduct cancer, liver cancer, liver hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, lymphoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), prostate cancer, and bladder cancer. A pharmaceutical composition comprising one or more selected from the group consisting of testicular cancer, kidney cancer, bone cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, thyroid cancer, skin cancer, melanoma, mesothelioma, and thymoma.

Description

Heteroaryl derivative compounds and uses thereof The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivative compounds having AKT inhibitory activity and their pharmaceutical uses. The AKT enzyme is a type of serine/threonine protein kinase, also known as protein kinase B (PKB). AKT exists in three subtypes with very similar structures: AKT1, AKT2, and AKT3. AKT is part of the PI3K/AKT/mTOR signaling pathway and regulates fundamental cellular activities such as growth, division, metabolism, transcription, and apoptosis. Dysregulation of AKT signaling is known to be a cause of cancer and metabolic disorders. AKT hyperactivation has been identified in breast, ovarian, pancreatic, and prostate cancers, and this is known to promote cancer cell survival and proliferation. For this reason, research is underway to develop AKT inhibitors as potential therapeutic agents that disrupt abnormal AKT signaling. AKT inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric AKT inhibitors (CAAI). ATP-competitive inhibitors compete with ATP to bind to AKT, allosteric inhibitors interact with the Pleckstrin homology (PH) domain to maintain the AKT protein in an inactive form, and covalent-allosteric AKT inhibitors form covalent bonds to exhibit stronger inhibitory activity and can also act selectively. The most common mutation in AKT is AKT1 E17K (E17K: mutation of glutamic acid at position 17 to lysine), and it has been reported in 6–8% of breast cancers, 2–6% of colorectal cancers, and 6% of meningiomas. This patent proposes a compound that is a covalent-allosteric AKT inhibitor that exhibits potent and selective inhibitory activity by forming a covalent bond with lysine of AKT, specifically AKT1 E17K. The present invention will be explained in detail below through examples and experimental examples. However, the following manufacturing examples, examples, and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto. <Analysis and Purification Conditions> The compounds synthesized in the manufacturing examples and embodiments of the present invention were purified or structurally analyzed under the following conditions. 1. LC-MS, Prep-HPLC, MPLC Analytical LC-MS (Liquid Chromatography-Mass Spectrometry) A Waters-manufactured UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters-manufactured mass QDa Detector was used. A Waters-manufactured ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 Х 50 mm) column was used, and the column temperature was set to 30 ℃. Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid. Gradient condition (10-100% B for 3 min, flow rate = 0.6 mL/min) Preparative Preparative-Liquid chromatography UV spectrometry (Prep-HPLC) The ACCQPrep HP150 instrument manufactured by Teledyne was used. A Waters XTERRA® Prep RP18 OBD ™ (10 µm, 30 Х 300 mm) column was used, and the column temperature was set to room temperature. Gradient condition (10-100% B for 120 min, flow rate = 42 mL/min) Medium pressure liquid chromatography (MPLC) for purification Medium pressure liquid chromatography was performed using Teledyne ISCO's CombiFlash RF + UV. 2. NMR Interpretation NMR analysis was performed using a Bruker NMR AVANCE NEO 400 MHz, and data were expressed in ppm (parts per million(δ)). The commercially available reagents used were used without additional purification. In the present invention, room temperature or ambient temperature refers to a temperature of approximately 5°C to 40°C, for example, 10°C to 30°C, or for another example, 20°C to 27°C, but is not strictly limited to the above range. A rotary evaporator was used for concentration under reduced pressure or solvent distillation removal. Preparation Example: Preparation of the intermediate compound of the present invention Preparation Example 1. Preparation of 2-chloro-3-nitro-quinoline [Reaction Equation 1] 3-Nitroquinoline-2-ol (450.00 mg, 2.37 mmol) phosphoryl chloride ( POCl₃ , It was added to 4.50 mL and stirred at 95 °C for 12 hours. After confirming the target compound using LC-MS, the reaction mixture was added to 10 mL of water at 0 °C. Water ammonia was added to adjust the pH of the solution to 8, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated to remove the remaining water using sodium sulfate, thereby obtaining the target compound as a yellow solid (400 mg, 80% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.75 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.04 - 7.90 (m, 2H), 7.82 - 7.69 (m, 1H); MS (ESI): m/z = 208.9 [M+H] + Example: Preparation of the compound of the present invention Example 1. Preparation of 4-((1-(4-(2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]quinoline-3-yl)benzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitri