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BR-112023017873-B1 - HETEROCYCLIC COMPOUNDS CAPABLE OF ACTIVATING THE STING

BR112023017873B1BR 112023017873 B1BR112023017873 B1BR 112023017873B1BR-112023017873-B1

Abstract

HETEROCYCLIC COMPOUNDS CAPABLE OF ACTIVATING STING. The present invention relates to heterocyclic compounds of formula (I) capable of activating STING (Interferon Gene Stimulator).

Inventors

  • Sebastian CAROTTA
  • Georg Dahmann
  • Cédrickx GODBOUT
  • SANDRA RUTH HANDSCHUH
  • Herbert Nar
  • Thorsten Oost
  • Ulrich Reiser
  • Matthias Treu

Assignees

  • BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Dates

Publication Date
20260310
Application Date
20220428
Priority Date
20210429

Claims (17)

  1. 1. Compound, characterized by the fact that it has the formula (I) where A is N or C, B is a group selected from the group consisting of: a 5- to 7-membered monocyclic heterocycline containing 1 or 2 N atoms, a 6-membered bicyclic heterocycline containing 1 N atom, a 7- to 11-membered bicyclic heterocycline containing 2 N atoms, a 7-membered bicyclic heterocycline containing 1 N atom and 1 O atom, a 6-membered monocyclic heterocycline containing 1 N atom and 1 heteroatom selected from the group consisting of O and S, a 9-membered bicyclic heterocycline containing 3 heteroatoms, 2 of which are N and the other is O, a 9-membered bicyclic heterocycline containing 1 N atom and 1 S atom, a 10-membered bicyclic heterocycline containing 3 N atoms, 2 of which are substituted with C1-6-alkyl, phenyl, and a 9-membered bicyclic heteroaryl containing 3 N atoms; D is a group selected from the group consisting of a 9-membered bicyclic heteroaryl containing 2 N atoms, a 10-membered bicyclic heteroaryl containing 1 N atom, and benzodioxol; R1 is selected from the group consisting of -H, -C1-6-alkyl, -CF3, -C2-6-alkynyl, -O-C1-6-alkyl, and halogen; R2 is selected from the group consisting of -H, -C1-6-alkyl, -C1-6-alkylene-OH, -C(O)OH, -C(O)O-C1-6-alkyl, and -pyrazolyl-C1-6-alkyl; R3 is -H or -C1-6-alkyl; R4 is selected from the group consisting of -H, -C1-3-alkyl, -NH2, -NHC1-3-alkyl and N(C1-3-alkyl)2; R5 is absent or selected from the group consisting of -H, -C1-6-alkyl, -S(O2)-C1-6-alkyl, -NH-S(O2)-C1-6-alkyl, =O, -C(O)-C1-6-alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)O-C1-6-alkyl, -NR5.1R5.2, -C1-6-alkylene-C(O)OH, -S(O2)-NH2, -pyrolidin-2-one-1-yl, -tetrazolyl, and a 5-membered heteroaryl with 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with R5.3; R5.1 is selected from the group consisting of -H, -C1-6-alkyl, - C(O)-C1-6-alkyl and -C1-6-alkylene-O-C1-6-alkyl; R5.2 is selected from the group consisting of -H, -C1-6-alkyl, - C(O)-C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl and -C1-6-alkylene-R5.3; R5.3 is selected from the group consisting of -H, -C1-6-alkyl and a 6-membered heteroaryl with 1 or 2 heteroatoms selected from a group consisting of N and O; R6 is absent or is selected from the group consisting of -H, - C1-6-alkyl, =O and -C(O)OH; or a salt thereof.
  2. 2. Compound according to claim 1, characterized in that R1 is selected from the group consisting of -C1-6-alkyl, -CF3, -O-C1-6-alkyl and halogen; R4 is -H or -C1-3-alkyl; or a salt thereof.
  3. 3. A compound according to claim 1 or 2, characterized in that D is selected from the group consisting of R1 is selected from the group consisting of -C1-6-alkyl, -CF3, -O-C1-6-alkyl, -Br and -Cl; R2 is -H; R3 is -H; or a salt thereof.
  4. 4. A compound describing any one of claims 1 to 3, characterized in that D is selected from the group consisting of or a salt of the same.
  5. 5. A compound according to any one of claims 1 to 4, characterized in that D is selected from the group consisting of or a salt of the same.
  6. 6. A compound according to any one of claims 1 to 5, characterized in that R5 is selected from the group consisting of -H, -C1-6-alkyl, -S(O2)-C1-6-alkyl, -O, -C(O)H, -C(O)NH2, -C(O)OH, -C(O)O-C1-6-alkyl, -NR5.1R5.2 and a 5-membered heteroaryl with 1 or 2 heteroatoms selected from a group consisting of N and O, substituted with R5.3; R5.1 is selected from the group consisting of -H, -C1-6-alkyl, -C(O)-C1-6-alkyl and -C1-6-alkylene-O-C1-6-alkyl; R5.2 is selected from the group consisting of -H, -C1-6-alkyl, -C(O)-C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl and -C1-6-alkyl-R5.3;R5.3 is -H or -C1-6-alkyl;or a salt thereof.
  7. 7. A compound describing any one of claims 1 to 6, characterized in that B is selected from the group consisting of or a salt of the same.
  8. 8. A compound according to any one of claims 1 to 7, or a salt thereof, characterized in that B is selected from the group consisting of or a salt of the same.
  9. 9. A compound according to any one of claims 1 to 8, characterized in that B is selected from the group consisting of or a salt of the same.
  10. 10. A compound describing any one of claims 1 to 9, characterized in that it is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  11. 11. A compound according to any one of claims 1 to 10, characterized in that it is in its salt-free form.
  12. 12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized in that it is for use as a medicament.
  13. 13. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment of a selected disease from the group consisting of inflammation, allergic and autoimmune diseases, infectious diseases and cancer, or for use as a vaccine adjuvant.
  14. 14. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment of cancer, wherein the compound is administered after radiotherapy.
  15. 15. Pharmaceutical composition, characterized in that it comprises at least one compound, as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.
  16. 16. Combination of medicines, characterized in that it comprises, in addition to one or more compounds as defined in any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as well as other active substances, a substance selected from the group consisting of cytostatic substances, cytotoxic substances, cell proliferation inhibitors, antiangiogenic substances, steroids, viruses, immunogenic cell death inducers, cancer targeting agents, immunomodulatory agents, antibodies and nanobodies.
  17. 17. Use of a compound, as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of a medicament, composition, combination, or product for treating and/or preventing a disease selected from the group consisting of inflammation, allergic and autoimmune diseases, infectious diseases, and cancer.

Description

FIELD OF THE INVENTION [0001] The present invention relates to small molecules capable of activating STING (Interferon Gene Stimulator), and its salts. Specifically, the present invention relates to heterocyclic compounds capable of activating STING. Furthermore, the invention relates to pharmaceutical compositions and combinations comprising these compounds, as well as their use in methods for treating diseases associated with or modulated by STING. In particular, the pharmaceutical compositions of the invention are suitable for the therapy of inflammation, allergic and autoimmune diseases, infectious diseases, cancer, and as vaccine adjuvants. BACKGROUND OF THE INVENTION [0002] STING is one of the pattern recognition receptors (PRRPs) that plays a central role in the innate immune system, distinguishing between pathogens and host cells by detecting extracellular and intracellular danger signals, including damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). These recognition processes constitute the first line of defense against viral and bacterial infections and malignant cells. However, pathogens, as well as cancer cells, have developed ways to escape recognition by the immune system. The goal of immunotherapies is therefore to initiate an antigen-specific immune response or reactivate a pre-existing response in certain types of immune system cells against pathogenic invaders or cancer cells. [0003] Among PRRPs, STING (also known as TMEM173, MPYS, MITA, ERIS) belongs to the nucleic acid sensor family and is the adapter for cytosolic DNA signaling. In healthy mammalian cells, DNA is compartmentalized in the nucleus. In pathogenic situations, such as invasions by DNA-containing pathogens, or in malignant cells, DNA is present in the cytoplasm. Here, STING is fundamental for detecting the cytosolic DNA described above and for inducing an immune response against the pathogenic event. [0004] In its basal state, STING exists as a dimer with its N-terminal domain anchored in the ER and the C-terminal domain residing in the cytosol. Cyclic dinucleotides (CDNs), generated by the cyclic protein GMP-AMP synthase (cGAS), are the natural ligands of STING (Ablasser et al, Nature 498, 380-384, 2013). The binding of CDNs to STING induces conformational changes that allow the binding and activation of TANK-binding kinase (TBK1) and interferon regulatory factor 3 (IRF3), followed by relocation from the ER to perinuclear endosomes (Liu et al, Science 347, Issue 6227, 2630-1-2630-14, 2015). Phosphorylation of the transcription factors IRF3 and NF-κB by TBK1 results in the expression of multiple cytokines, including type I interferon (IFN). [0005] The production of type I IFN by antigen-presenting cells and other cell types is considered a key event in T cell activation and, therefore, in the differentiation of antigen-specific effector CD4 and CD8 T cells. A lack of type I IFN has been shown to result in a reduced T cell-dependent immune response against viral infections or tumor cells (Zitvogel et al, Nature Reviews Immunology 15, 405-414, 2015). Conversely, the presence of a type I IFN signature during cancer therapy is associated with an increased number of tumor-infiltrating T cells and a potentially favorable clinical outcome (Sistigu et al, Nature Medicine 20, 1301-1309, 2014). [0006] The efficient secretion of type I IFN in the tumor microenvironment and the induction of a T cell-dependent immune response against cancer cells depends on the presence of STING, as shown in recent studies with mice (Woo et al, Immunity 41, 5, 830-842, 2014; Corrales et al, Cell Reports 11, 1018-1030, 2015; Deng et al, Immunity 41, 5, 843-852, 2014). Deletion of STING resulted in reduced levels of type I IFN in the tumor microenvironment and a reduced antitumor effect in several mouse tumor models, thus highlighting the importance of the presence of type I IFN. On the other hand, specific activation of STING resulted in an enhanced antigen-specific T cell immune response against cancer cells. [0007] Type I interferons can significantly enhance antitumor immune responses by inducing the activation of adaptive and innate immune cells. [0008] Given the importance of type I IFN in various malignancies, including viral infections and cancer therapy, strategies that allow for specific STING activation are of therapeutic interest. STING activation can be synergistic with several approved chemotherapeutic agents or other anticancer therapies such as radiotherapy (Wu et al., Med Res Rev 2020, May; 40(3): 1117-1141) or with therapies for infectious diseases. [0009] In the prior art, small molecule modulators of STING are described, for example, in WO2020075790. SUMMARY OF THE INVENTION [0010] The compounds according to the present invention are novel STING activators, as demonstrated in an in vitro reporter system using the THP1-Blue reporter cell line. [0011] In one aspect, the present invention relate