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EP-4737453-A1 - NOVEL SELENOPHENE DERIVATIVES

EP4737453A1EP 4737453 A1EP4737453 A1EP 4737453A1EP-4737453-A1

Abstract

Provided are a compound defined by chemical formula 1 or a tautomer thereof and pharmaceutically acceptable salts thereof. The compound of the present invention can inhibit SOS1 activity.

Inventors

  • LEE, KWANG-OK
  • LEE, HO-JEONG
  • KIM, SUNKYU
  • KIM, JIHYE
  • PARK, Sejeong
  • LEE, SANGHOON
  • YOO, Kiwoong
  • YOO, Hyerim

Assignees

  • Aigen Sciences Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (5)

  1. A compound of formula 1 or a tautomer thereof and pharmaceutically acceptable salts thereof: in the Chemical Formula 1, R 1 and R 2 are functional groups independently selected from the group consisting of H, C 1∼4 alkyl, and C 1∼4 alkyl substituted with deuterium, or R 1 and R 2 form a 4 to 6 membered heterocyclic alkyl ring together with nitrogen atom to which R 1 and R 2 are bonded, except that both of R 1 and R 2 are H, is wherein Q 1 and Q 2 are functional groups independently selected from C 1∼4 alkyl and 4 to 8 membered monocyclic heterocyclyl, Q 3 is 4 to 8 membered monocyclic heterocyclyl, and symbol " " indicates the position that Ⓐ is connected to remaining part of the compound.
  2. The compound according to claim 1, wherein the 4 to 6 membered heterocyclic alkyl ring is azetidinyl or pyrrolidinyl.
  3. The compound according to claim 1, characterized in that both Q 1 and Q 2 are methyl, or one of Q 1 and Q 2 is methyl and the other is tetrahydrofuranyl.
  4. A compound selected from the group consisting of the following compounds, a stereoisomer, a tautomer, a solvate thereof or a pharmaceutically acceptable salt thereof: ( R )-6,7-dimethoxyl-2-methyl- N -(1-(4-(2-((methylamino)methyl)phenyl)selenophen-2-yl)ethyl)quinazolin-4-amine; 7-methoxy-2-methyl- N -(( R )-1-(4-(2-((methylamino)methyl)phenyl)selenophen-2-yl)ethyl)-6-((( S )-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine; ( R )-(2-chloro-4-((1-(4-(2-((methylamino)methyl)phenyl)selenophen-2-yl)ethyl)amino)-5,7-dihydro-6 H -pyrolo[3,4- d ]pyrimidine-6-yl)(4-methoxytetrahydro-2 H -pyran-4-yl)methanone; ( R )-4-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)selenophen-2-yl)ethyl)-7-morpholinopyrido[3,4-d]pyridazine-1-amine; ( R )- N -(1-(4-(2-((dimethylamino)methyl)phenyl)selenophen-2-yl)ethyl)-6,7-dimethoxyl-2-methylquinazolin-4-amine; ( R )-6,7-dimethoxyl-2-methyl- N -(1-(4-(2-(pyrrolidine-1-ylmethyl)phenyl)selenophen-2-yl)ethyl)quinazolin-4-amine; ( R )-6,7-dimethoxyl-2-methyl- N -(1-(4-(2-(((methyl- d 3 )amino)methyl)phenyl)selenophen-2-yl)ethyl)quinazolin-4-amine; N -(( R )-1-(4-(2-((dimethylamino)methyl)phenyl)selenophen-2-yl)ethyl)-7-methoxy-2-methyl-6-((( S )-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine, and 7-methoxy-2-methyl- N -(( R )-1-(4-(2-(pyrrolidine-1-ylmethyl)phenyl)selenophen-2-yl)ethyl)-6-((( S )-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine.
  5. A pharmaceutical composition for treatment of cancer, comprising a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically acceptable excipient.

Description

[TECHNICAL FIELD] The present invention relates to small organic compounds having inhibitory activity against biological enzymes. The present invention also relates to a pharmaceutical composition containing such small organic compounds. [BACKGROUND ART] SOS1 (Son of Sevenless 1) is known as a key factor in the activation of small GTPases such as RAS (Rat Sarcoma viral oncogene homolog) and Rac1 (Ras-related C3 botulinum toxin substrate 1). These small GTPases are critical components of cell signaling pathways that regulate various cellular processes, including cell growth, differentiation, and migration. SOS1 acts as a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP (guanosine diphosphate)-bound Ras to GTP (guanosine triphosphate)-bound Ras, thereby activating Ras. Activated Ras bound to GTP subsequently interacts with downstream effector proteins to initiate signaling pathways. The activation of Ras by SOS1 is a critical step in various cellular processes, such as cell proliferation, survival, and differentiation. Activated Ras then initiates downstream signaling pathways, such as the MAPK (Mitogen-Activated Protein Kinase) cascade, and thus regulating gene expression and cellular responses to external signals. Abnormal regulation of the Ras pathway is closely associated with mutations in tumors, making it a significant focus in cancer research. RAS are subtyped to three isoforms of KRAS, NRAS, and HRAS. It is known that KRAS is the most frequently mutated among them, and that SOS1 plays a critical role in the activation of oncogenic signaling by mutant KRAS (Jeng et al., Nat. Commun., 2012, 3:1168). Specifically, depletion of intracellular SOS1 concentration led to decreased proliferation rate and viability in tumor cells having KRAS mutations, whereas no such effect was observed in cell lines with wild-type KRAS. Moreover, the detrimental effects resulting from deletion of SOS1 could not be rescued by introducing SOS1 having a modified catalytic region, demonstrating that the GEF activity of SOS1 is essential for the survival of KRAS-mutant cancer cells. Besides RAS, SOS1 is also involved in the activation of Rac1. Rac1 is another small GTPase that belongs to the Rho protein family and plays a crucial role in regulating the cytoskeleton, cell migration, and other cellular processes. SOS1 acts by exchanging GDP-bound on Rac1 for GTP, thereby switching it to its active state. Activated Rac1 involves in processes such as cell adhesion, migration, and invasion, and is known to play a significant role in both normal cellular functions and pathological conditions such as cancer metastasis. In view of these points, SOS1 inhibitors may be developed as therapeutic drugs for diseases caused by KRAS mutations or Rac1 activation. [PRIOR ART DOCUMENT] NON-PATENT DOCUMENT: Jeng et al., Nat. Commun., 2012, 3:1 168 [DISCLOSURE] [TECHNICAL PROBLEM] An object of the present invention is to provide a novel selenophene derivative compound that is an SOS1 inhibitor with excellent activity in inhibiting protein-protein interaction of KRAS-SOS1. Another object of the present invention is to provide a pharmaceutical composition comprising the compound in a therapeutically effective amount. [TECHNICAL SOLUTION] In one aspect of the present invention, a selenophene compound defined by chemical formula 1 having an inhibitory activity on SOS1 or a tautomer thereof and pharmaceutically acceptable salts thereof are provided. In the Chemical Formula 1, R1 and R2 are functional groups independently selected from the group consisting of H, C1~4 alkyl, and C1~4 alkyl substituted with deuterium, or R1 and R2 form a 4 to 6 membered heterocyclic alkyl ring together with nitrogen atom to which R1 and R2 are bonded, except that both of R1 and R2 are H, is wherein Q1 and Q2 are functional groups independently selected from C1~4 alkyl and 4 to 8 membered monocyclic heterocyclyl, Q3 is 4 to 8 membered monocyclic heterocyclyl, and symbol " " indicates that Ⓐ is connected to the remaining part of the compound at the position. In another aspect of the present invention, there is provided a pharmaceutical composition for treatment of cancer comprising a therapeutically effective amount of the compound described above, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect of the present invention, a method for treating cancer is provided. The method comprises administering to a patient a therapeutically effective amount of a compound of the present invention, such as a compound defined by Chemical Formula 1, or a pharmaceutical composition comprising such a compound of the present invention. [ADVANTAGOUS EFFECT] The compound of the present invention can inhibit an activity of SOS1. Furthermore, the compound of the present invention exhibits a synergistic cell death effect in conjunction with blockade of RAS signaling or EGFR signaling. In a pref