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CN-114907377-B - Fused tetracyclic compound, preparation method thereof and application thereof in medicines

CN114907377BCN 114907377 BCN114907377 BCN 114907377BCN-114907377-B

Abstract

The present disclosure relates to fused tetracyclic compounds, methods of preparing the same, and their use in medicine. In particular, the disclosure relates to a fused tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a therapeutic agent, and particularly application thereof in preparing medicines for inhibiting HPK 1. Wherein each group in the general formula (I) is defined in the specification.

Inventors

  • LI XIN
  • FENG BINQIANG
  • CAI GUODONG
  • HE FENG
  • TAO WEIKANG

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20220209
Priority Date
20210210

Claims (20)

  1. 1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: Wherein: ring a is phenyl or 5 or 6 membered heteroaryl; t 1 is CR T1 ; G 3 and G 4 are the same or different and are each independently CR 1 ; G 8 is CR G8 or a nitrogen atom; g 1 is a nitrogen atom; G 2 is NR 3 ; G 5 and G 6 are the same or different and are each independently selected from CR 4 R 5 and an oxygen atom; G 7 is selected from CR G7a R G7b ; g 9 is selected from CR G9a R G9b 、NR G9c , an oxygen atom, and a sulfur atom; r is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, and C 1-6 hydroxyalkyl; R 0 、R 3 and R G9c are the same or different and are each independently selected from a hydrogen atom or a C 1-6 alkyl group; R', R 1 、R T1 and R G8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and- (CH 2 ) m NR 7 R 8 ); R 4 、R 5 、R G7a 、R G7b 、R G9a and R G9b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, or R 7 and R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a 3-to 10-membered cycloalkyl group and a 3-to 10-membered heterocyclyl group; m is 0, 1,2, 3 or 4;q is 0, 1,2, 3 or 4, and N is 0,1, 2, 3,4, 5 or 6.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is a5 membered heteroaryl.
  3. 3. The compound according to claim 1, which is a compound represented by the general formula (II) or (III): Wherein: T 1 、G 3 、G 4 、G 5 、G 6 、G 9 , R, R', q and n are as defined in claim 1.
  4. 4. The compound according to claim 1, which is a compound represented by the general formula (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof: t 1 、G 3 、G 4 、G 5 、G 6 、G 9 , R, R', q and n are as defined in formula (I).
  5. 5. A compound according to any one of claims 1 to 4, wherein one of G 5 and G 6 is CR 4 R 5 and the other is an oxygen atom, and R 4 and R 5 are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
  6. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein one of G 5 and G 6 is CH 2 and the other is an oxygen atom.
  7. 7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G 5 is an oxygen atom and G 6 is CH 2 .
  8. 8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G 9 is NR G9c ,R G9c is a hydrogen atom or C 1-6 alkyl.
  9. 9. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G 9 is NCH 3 .
  10. 10. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.
  11. 11. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein T 1 is C-NH 2 .
  12. 12. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is the same or different and each is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group.
  13. 13. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom.
  14. 14. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R' are the same or different and are each independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group.
  15. 15. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom or halogen.
  16. 16. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.
  17. 17. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
  18. 18. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is a compound of:
  19. 19. A compound of the general formula (IA): Wherein R w is C 1-6 alkyl; G 1 to G 9 , R and n are as defined in claim 1.
  20. 20. A compound selected from the following compounds:

Description

Fused tetracyclic compound, preparation method thereof and application thereof in medicines Technical Field The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic compound, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to fused tetracyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds and application thereof in preparing medicines for inhibiting HPK 1. Background Anticancer therapy has been advanced from chemotherapy, targeted therapy, to the age of immunotherapy. Targets for tumor immunotherapy mainly include immune checkpoints, immune agonists, tregs, macrophages, tumor microenvironment metabolites such as IDO, the A2AR pathway, and the like. Hematopoietic progenitor kinase1 (Hematopoietic Progenitor Kinase, abbreviated as HPK1; also known as Mitogen-activated protein kinase1 or Mitogen-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE, abbreviated as MAP4K 1) is a negative regulator in T cells and functions as negative feedback regulator after TCR activation, and is associated with T cell depletion. The clearer signaling pathway was that LAT was phosphorylated after TCR binding to MHC-peptide, recruiting GADS-SLP76 complex, leading to downstream PLC phosphorylation and pathway activation. While at the same time ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thereby phosphorylating the S376 site of the latter. SLP 76S 376 phosphorylates recruitment 14-3-3, resulting in ubiquitination, resulting in disintegration of the whole TCR signalosome. The HPK1 is considered to be a better immunotherapy target point at present based on 3 reasons that (1) the expression profile of the HPK1 is limited to immune cells, the safety is good, (2) the HPK1 has various negative regulation and control effects in different stages of a cancer-immune cycle, the inhibition of the HPK1 can regulate the immunosuppression functions of NK cells, DC cells and T cells and can regulate the activation of B cells, wherein the activation of the T cells is the most studied, and (3) the kinase activity of the HPK1 is important in inhibiting anticancer immune response. Studies have shown that HPK1 expression is associated with T cells exhaustion signature, including CD3E, PD1, CTLA4, TIM-3, LAG-3, and TIGIT, and that high expression of HPK1 is associated with short survival. TCGA PANCANCER database analysis showed a positive correlation between HPK1 (and not other MAP4K family members) expression and PD 1. HPK1 expression was up-regulated in exhausted T cells, with HPK1, TIM3 and LAG3 expressed in PD1 high T cells being higher than PD1 low T cells. In contrast, HPK1 is down-regulated in cd4+ T cells in patients with Systemic Lupus Erythematosus (SLE), and SLEDAI scores are inversely correlated with HPK1 mRNA levels. HPK1 expression is also down-regulated in peripheral blood cells of psoriatic arthritis (PsA) patients. The HPK1 knockout mice were free of any abnormalities in the resting state. Once the TCR is activated, the immune response is activated in mice, whether HPK1 knockdown, HPK1 KINASE DEAD knockdown, or SLP76S376A knockdown, with similar results. HPK1 deficient mice are more susceptible to Experimental Autoimmune Encephalomyelitis (EAE). HPK1 kinase activity regulates TCR signaling and cytokine secretion in vitro, inhibition of HPK1 reduces PGE2 and adenosine mediated immunosuppression. HPK1 KINASE DEAD mice inhibited tumor growth in vivo, and after removal of CD8+ or CD4+ T cells, the anti-tumor effect of HPK 1-/-mice was almost lost, indicating that T cells mediate most of the immunosuppressive effects of HPK 1. The above mouse data for HPK1 knockdown and KINASE DEAD knockdown indicate that HPK1 is mainly still acting through kinase activity, but some documents report that its scaffold also has a certain function, so the drug development concept for inhibiting HPK1 is mainly kinase inhibitor, and some PROTAC molecules are also available. Related patents which have been disclosed at present are WO2016205942A1, WO2019238067A1, WO2021013083A1, WO2021000925A1 and the like. Disclosure of Invention The purpose of the present disclosure is to provide a compound represented by general formula (I): Wherein: Ring a is selected from aryl, heterocyclyl and heteroaryl; T 1 is CR T1 or a nitrogen atom; G 3 and G 4 are the same or different and are each independently CR 1 or a nitrogen atom; G 8 is CR G8 or a nitrogen atom; g 1 and G 2 are the same or different and are each independently selected from CR 2、NR3, a nitrogen atom, an oxygen atom and a sulfur atom; G 5 and G 6 are the same or different and are each independently selected from CR 4R5、NR6, an oxygen atom and a sulfur atom; G 7 is selected from CR G7aRG7b、NRG7c, an oxygen atom, and a sulfur atom; g 9 is selected from CR G9aRG9b、NRG9c, an oxygen atom, and a sulfur atom; R are the s