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CN-115260207-B - Tri-fused ring compound and pharmaceutical composition and application thereof

CN115260207BCN 115260207 BCN115260207 BCN 115260207BCN-115260207-B

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a tricyclic compound, a pharmaceutical composition and application thereof. In particular, the invention relates to a tricyclic compound shown as a formula I, a pharmaceutical composition containing the same and application of the tricyclic compound as an SOS1 inhibitor in the field of medicines. The tricyclic compound of the invention has excellent bioactivity and patentability, and has great medicine development prospect.

Inventors

  • FANG HUAXIANG
  • HUANG YANGQING
  • GU JIANING
  • HANG WENMING
  • YUAN JIANDONG

Assignees

  • 赣江新区博瑞创新医药有限公司

Dates

Publication Date
20260508
Application Date
20210430

Claims (10)

  1. 1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, Wherein, the A is phenyl, said phenyl being substituted with 1R 6 ; R 6 is C 1 -C 6 alkyl, said alkyl being substituted with at least 1R 8 ; Each R 8 is independently selected from chlorine and fluorine; X and Y are CH; q 1 is selected from the group consisting of-O-and-NR 9 -; If present, R 9 is selected from-C (=o) -R 7 and C 1 -C 6 alkyl, said alkyl being substituted with 1C 6 -C 10 aryl; r 7 , if present, is selected from C 1 -C 6 alkyl and 3 to 14 membered heterocycloalkyl, said heterocycloalkyl being substituted with 1 methyl; q 2 is-O-; L 1 and L 2 are- (CH 2 ) m ) -in which m is 1; R 1 and R 2 are each independently selected from hydrogen and methyl; r 3 is methyl; R 4 is selected from halogen and-NH 2 ; r 5 is selected from hydrogen and-C (=O) -OC 1 -C 6 alkyl.
  2. 2. A compound according to claim 1, wherein the compound is a compound of formula I-1, Wherein, the Q is 1; X, Y, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined in claim 1.
  3. 3. A compound according to claim 1 or 2, wherein the compound is a compound of formula I-1-2, Wherein, the Q is 1; R 7 is C 1 -C 6 alkyl; X, Y, R 1 、R 2 、R 3 、R 4 and R 6 are as defined in claim 1.
  4. 4. A compound according to claim 1, wherein the compound is a compound represented by the formula I-3-1, Wherein, the Q is 1; X, Y, R 1 、R 2 、R 3 、R 4 、R 6 and R 9 are as defined in claim 1.
  5. 5. A compound according to claim 4, wherein, R 9 is selected from any one of the following groups: 。
  6. 6. Compound according to claim 1, characterized in that it is selected from the following compounds: 。
  7. 7. a pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.
  8. 8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder caused by SOS1 overexpression.
  9. 9. The use according to claim 8, wherein, The disease or disorder caused by SOS1 overexpression is cancer.
  10. 10. The use according to claim 9, wherein, The cancer is selected from pancreatic cancer, colorectal cancer and lung cancer.

Description

Tri-fused ring compound and pharmaceutical composition and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a tricyclic compound, a pharmaceutical composition containing the compound and application of the compound in the field of medicines. Background Starting from the discovery of cancer-related by the end of 1982 of RAS family gtpases (which contain members KRAS, NRAS, and HRAS), the incidence in human cancers is as high as 20% -30%. The RAS proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Activated by guanine nucleotide exchange factor (GEF), the RAS in its GTP-bound state interacts with a number of effectors. Returning to the inactive state is driven by Gtpase Activating Proteins (GAPs), which down-regulate the active RAS by accelerating weak intrinsic gtpase activity by up to 5 orders of magnitude. Whether mutant RAS proteins require GEF activity to be fully activated remains to be fully investigated and may vary from one particular mutation to another. The most studied protein of RAS SEVENLESS son (SOS), two human isoforms SOS1 and SOS2 are known. Attempts to recognize RAS-SOS interactions of hydrocarbon binding peptides by inhibiting peptide mimicking the nanomolar affinity orthotopic SOS helix, but with only low cellular activity. Fragment-based screening, rational design, and high throughput screening methods have led to the identification of small molecule addressing KRAS-SOS1 interactions resulting in moderate micromolar affinities. SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein having two N-terminal Histone Domains (HD) in tandem, followed by a Dbl homology Domain (DH), a Pleckstrin (PLECKSTRIN) homology domain (PH), a helical junction (HL), a RAS Exchange Motif (REM), a CDC25 homology domain and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins, a catalytic site that binds GDP-bound RAS family proteins to promote guanine nucleotide exchange, and an allosteric site that binds GTP-bound RAS family proteins, which results in a further increase in catalytic GEF function of SOS 1. Published data indicate that SOS1 is critically involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al, nat. Commun.,2012, 3:1168). Depletion of SOS1 levels reduced proliferation and survival of tumor cells harboring KRAS mutations, whereas no effect was observed in KRAS wild-type cell lines. The effect of SOS1 loss cannot be complemented by SOS1 introduced with catalytic site mutations, demonstrating the important role of SOS1GEF activity in KRAS mutant cancer cells. SOS1 is critically involved in activation of RAS family protein signaling in cancer by mechanisms other than RAS family protein mutation. SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases (e.g., ,EGFR、ErbB2、ErbB3、ErbB4、PDGFR-A/B、FGFR1/2/3、IGF1R、INSR、ALK、ROS、TrkA、TrkB、TrkC、RET、c-MET、VEGFR1/2/3、AXL)(Pierre et al, biochem. Pharmacol.,2011,82 (9): 1049-56). SOS1 is also recruited to other phosphorylated cell surface receptors such as T Cell Receptor (TCR), B Cell Receptor (BCR) and monocyte colony stimulating factor receptor (Salojin et al, J.biol. Chem.2000,275 (8): 5966-75). This localization of SOS1 to the plasma membrane proximal to the RAS family proteins enables SOS1 to promote RAS family protein activation. SOS1 activation of RAS family proteins can also be mediated through SOS1/Grb2 interactions with BCR-ABL oncoproteins common in chronic myeloid leukemia. SOS1 is also a GEF for activating GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al, J.cell biol.,2002,156 (1): 125-36). As with RAS family proteins, RAC1 is involved in the pathogenesis of a variety of human cancers and other diseases (Bid et al mol. Cancer ter.2013, 12 (10): 1925-34). Herein, we describe novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and at the same time prevent interaction with RAS family proteins and their activation. This results in a significant inhibition of the interaction of SOS1 with RAS family proteins, in particular KRAS (with low number of units nanomolar IC50 activity), and thus significantly reduces ERK phosphorylation in KRAS mutant cancer cell lines. The selective SOS1 inhibitor compounds described herein are expected to provide pharmacological benefits to patients suffering from cancers associated with dependence on RAS family protein signaling. Such cancers contemplated to be targeted by SOS1 inhibitor compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components of the RAS family protein pathway (proteins, genes) such as KRAS, NRAS, HRAS, receptor tyrosine kinases (e.g., ,EGFR、ErbB2、ErbB3、ErbB4、PDGFR-A/B、FGFR1/2/3、IGF1R、INSR、ALK、ROS、TrkA、TrkB、T