Beta-polypeptides having cytotoxic activity against cancer cells

Abstract

This invention relates to novel β-peptide compounds or pharmaceutically acceptable salts thereof, comprising the portion of formula (I): -[A-Z-A] n -(I), particularly relating to compounds of formula (II) or their pharmaceutically acceptable salts: X-[Z] p -[A-Z-A] n -Y(II), and pharmaceutical compositions comprising the said compound and at least one pharmaceutically acceptable carrier. The compounds and pharmaceutical compositions of the present invention can be used as pharmaceutical agents, particularly for the treatment or prevention of cancer.

Description

[0001] This application claims priority to European patent application EP23188230.9, filed on 27 July 2023, the entire contents of which are incorporated herein by reference.

[0002] This invention relates to novel beta-peptide (β-peptide) compounds or pharmaceutically acceptable salts thereof, comprising a portion of formula (I), particularly compounds of formula (II) or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising said compounds and at least one pharmaceutically acceptable carrier. The compounds and pharmaceutical compositions of this invention can be used as pharmaceutical agents, particularly for the treatment or prevention of cancer.

[0003] β-peptides are a class of poorly studied peptides based on non-natural β-amino acids (β-AAs), considered promising for drug development due to their proteolytic stability and generally well-defined secondary structures. However, to date, no such compounds have been approved for clinical use. Examples of bioactive β-peptides with antibacterial or fungicidal activity are rare.

[0004] β-peptides are artificial oligoamides composed of β-amino acid units. Compared to protein-derived α-amino acids, β-amino acids contain an additional carbon atom (H₂N-βC) between the amino and carboxyl groups. -α C -COOH, β-amino acids, are rarely found in nature. β-peptides were developed simultaneously by two researchers in the late 1990s: Prof. Seebach (ETH Zurich) used acyclic β-amino acids (D. Seebach and JL Matthews, Chem Commun, 1997, 2015-2022), while Prof. Gellman (Wisconsin University) used cyclic β-amino acids (SH Gellman, Accounts Chem Res, 1998, 31, 173-180). These novel oligoamides exhibit the ability to adopt periodic secondary structures without overlapping with the secondary structures of α-peptides.

[0005] The cyclic β-amino acid trans-2-aminocyclopentanecarboxylic acid ([trans-ACPC)) is known. n=6.8 (DH Appella, LA Christianson, DAKlein, DR Powell, XL Huang, JJ Barchi and SH Gellman, Nature, 1997, 387, 381-384) and trans-2-aminocyclobutanecarboxylic acid ([trans-ACBC))n=6.8 Homooligomers (C. Fernandes, S. Faure, E. Pereira, V. Thery, V. Declerck, R. Guillot and DJ Aitken, Org Lett, 2010, 12, 3606-3609) can form so-called 12 (=2.5) homooligomers in both solution and crystals. 12 -- Helical (RP Cheng, SH Gellman and WF DeGrado, Chem Rev, 2001, 101, 3219-3232) (Scheme 1). Cyclic β-amino acid trans-2-aminocyclohexanecarboxylic acid ([trans-ACHC) n=6 (DH Appella, LA Christianson, IL Karle, DR Powell and SH Gellman, J Am Chem Soc, 1996, 118, 13071-13072; DH Appella, LA Christianson, IL Karle, DR Powell and SH Gellman, J Am Chem Soc, 1999, 121, 6206-6212) and non-cyclic β 3 -amino acid([β) 3 -AA] n=6 )(D.Seebach, PE Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel, R.Amstutz and H. Widmer, Helv Chim Acta, 1996, 79, 2043-2066; D. Seebach, M.Overhand, FNM Kuhnle, B. Martinoni, L. Oberer, U. Hommel and H. Widmer, HelvChim Acta, 1996, 79, 913-941) and the corresponding heterooligomers (heteroligomers) (L. Fulop, IM Mandity, G. Juhasz, V. Szegedi, A. Hetenyi, E. Weber, Z. Bozso, D. Simon, R. Benko, Z. Kiraly and TA Martinek, Plos One, 2012, 7) tends to form 14(=3 14— A helix, but shorter oligomers (n=3) form extended structures (Scheme 1). Different combinations of β-amino acids may result in different structures: for example, cis-ACPC and β-... 3 - Amino acid alterations have been shown to form mixed 14 / 16-helices (IM Mandity, E. Weber, TA Martinek, G. Olajos, GK Toth, E. Vass, F. Fulop, Angew Chem Int Ed 2009, 48, 2171-2175).

[0006] Scheme 1. Based on examples of β-homogeneous oligomers from Gellman (Appella et al., 1996 and 1997), Aitken (Fernandes et al., 2010), and Seebach (Seebach et al., 1997), and examples of β-heterogeneous oligomers from Martinek (Fulop et al., 2012), all exhibit a defined non-natural helical structure (2.5). 12 -or 3 14 --spiral).

[0007]

[0008] Over the past three decades, very few bioactive β-peptides have been reported. Most are antibacterial and antifungal β-peptides with amphiphilic helical structures (C. Cabrele, TA Martinek, O. Reiser, and L. Berlicki, J MedChem, 2014, 57, 9718-9739). β-peptides are a very promising class of molecules for drug discovery due to their greater stability to proteases and peptidases, and their structural differences from α-peptides.

[0009] The purpose of this invention is to provide a novel, highly active β-peptide with anticancer activity.

[0010] The inventors have developed β-heteromeric oligomers derived from cyclic and acyclic building blocks, exhibiting different secondary structure tendencies. On one hand, using acyclic β-... 3 -amino acid (β) 3Cyclic β-amino acids (-AAs) serve as building blocks for β-peptides, allowing naturally occurring amino acid side chains to be inserted into the sequence. On the other hand, cyclic β-amino acids can effectively control the geometry of the β-peptide backbone. To combine the advantages of both acyclic and cyclic β-amino acids, β-peptides containing both have been developed. When determining the geometry of the β-peptide backbone, cyclic building blocks are expected to be preferred over acyclic building blocks; however, acyclic building blocks are expected to have a destructive effect, thereby reducing the rigidity of the final structure.

[0011] This invention provides a β-peptide with bioactive properties that surpasses existing technologies and shows promise for cancer treatment. The β-peptide is composed of cyclic subunits, such as the β-amino acid trans-2-aminocyclopentanecarboxylic acid (trans-ACPC), combined with acyclic subunits, such as β... 3 -amino acid (β) 3 -AA), arranged in a [acyclic-cyclic-acyclic] configuration. In other words, the polypeptide of the present invention comprises repeating unit chains, which are composed of acyclic residues linked to cyclic residues via amide bonds, and cyclic residues, in turn, linked to another acyclic residue via amide bonds. The polypeptide of the present invention differs in secondary structure from the known homologous oligomer [trans-ACPC]. n and [β] 3 -AA] n In particular, the peptides provided herein appear to possess greater flexibility, thus enabling them to better adapt to given cellular components (membranes and / or biomolecules). The β-peptides provided herein exhibit high cleavage activity against cancer cells, thus showing promise for cancer therapy. Meanwhile, the peptides of the present invention exhibit no or low activity against non-cancer cells, such as MRC-5 human lung fibroblasts and BEAS-2B human bronchial epithelial cells, as illustrated in the appended examples.

[0012] The invention is summarized in the following embodiments.

[0013] In a first embodiment, the present invention relates to compounds comprising a portion of formula (I):

[0014] -[AZA] n -

[0015] (I)

[0016] in:

[0017] Each A is independently a group of the following formula:

[0018]

[0019] Each R 1 Independently for C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety in the alkylene group and the -(C 0-6 In each of the alkylene-heterocyclic groups, the heterocyclic moiety is optionally substituted by one or more groups, said groups being independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl and heterocycloalkyl, wherein -(C 0-6 alkylene)-carbocyclic or the -(C 0-6 C in alkylene-heterocyclic group 0-6 One of the -CH2- units in the alkylene group is optionally replaced by -O-, -S-, -NH- or -N(C 1-6 Alkyl)-substitution;

[0020] Each Z is independently a group of the following formula:

[0021]

[0022] Each m is independently 0 or 1; and

[0023] n is 2, 3, or 4;

[0024] Or its pharmaceutically acceptable salt.

[0025] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the first embodiment of the invention and a pharmaceutically acceptable carrier.

[0026] In a third embodiment, the present invention relates to a compound of the first embodiment of the invention or a pharmaceutical composition of the second embodiment of the invention used as a pharmaceutical agent.

[0027] In the fourth embodiment, the present invention relates to a compound of the first embodiment of the invention or a pharmaceutical composition of the second embodiment of the invention for treating or preventing cancer.

[0028] In the fifth embodiment, the present invention relates to a compound of the first embodiment of the invention or a pharmaceutical composition of the second embodiment of the invention in the preparation of an anticancer agent.

[0029] In a sixth embodiment, the present invention relates to a method of treating cancer, comprising the step of administering to an individual in need a compound of the first embodiment of the invention or a pharmaceutical composition of the second embodiment of the invention. It is understood that a therapeutically effective amount of the compound or composition is administered.

[0030] The invention is illustrated in the following figures.

[0031] Figure 1The CD-spectrums of β-peptides with cyclic-acyclic arrangement (1b and 1_ALA) or acyclic-cyclic-acyclic arrangement (1a) in methanol and water are shown, and the effects of replacing the cyclic subunits of monomers with noncyclic subunits of monomers (as in 1b and 1_ALA) or dimers (as in 1a) are compared.

[0032] Figure 2 This demonstrates that (A) treatment with 20 μM 1aR for 24 hours induced cell death in human cell lines, and (B) treatment with 20 μM 1aR for 1 hour induced cell death in A549 cells. Data represent at least three independent experiments, and values ​​are expressed as mean ± standard error.

[0033] Figure 3 Co-localization of peptide FAM-1aR with mitochondria in A549 cells. Fluorescence microscopy images were acquired after incubation at 37°C for 1 hour with 10 μM FAM-1aR. Cell nuclei were stained with Hoechst 33342, and mitochondria were stained with the mitochondrial probe MitoView™ 720. Scale bar: 20 µm.

[0034] Figure 4 Temperature-independent uptake of the fluorescently labeled peptide FAM-1aR in A549 cells is described. Fluorescence microscopy images are shown after incubation at 37 °C and 4 °C for 1 hour with 5 μM FAM-1aR. Cell nuclei were stained with Hoechst 33342. Scale bar: 20 µm.

[0035] Figure 5 This image shows the uptake of the fluorescently labeled peptide FAM-1aR in MRC-5 cells. Images were captured by fluorescence microscopy after incubation at 37°C for 1 hour with 5 μM FAM-1aR. Cell nuclei were stained with Hoechst 33342. Scale bar: 20 µm.

[0036] Figure 6 Bright-field images of cancer cell line A549 and healthy lung fibroblast line MRC-5 after treatment with 10 μM 1aR for 24 hours are shown. Black arrows indicate membrane blebbing in A549 cells (formation of protrusions and blister-like bodies characteristic of pyroptosis), which is not observed in healthy MRC-5 fibroblasts. Scale bar: A549 at 20 μM, MRC-5 at 50 μM.

[0037] Figure 7The study demonstrates LDH release from A549 and MRC-5 cells after treatment with 10 μM 1aR for a specified incubation time.

[0038] Figure 8 This shows the uptake of propidium iodide (PI) by A549 and MRC-5 cells after treatment with 10 μM 1aR for 30 min. Cell nuclei were stained with Hoechst 33342. Scale bar: 20 µm.

[0039] Figure 9 It was demonstrated that using scanning electron microscopy to treat cancer cells with 1aR disrupted their cell membranes, while healthy cells remained undamaged.

[0040] Figure 10 The figures show (A) caspase-1-induced flow cytometry and (B) IL-1β release after A549 and MRC-5 cells were treated with 10 μM 1aR for a specified incubation time. Data represent at least three independent experiments and are expressed as mean ± standard error.

[0041] Figure 11 This shows mitochondrial membrane depolarization in A549 cells after treatment with 10 μM 1aR. Cell nuclei were stained with Hoechst 33342, and mitochondrial membrane depolarization was visualized by the disappearance of the mitochondrial dye MitoView™ at 720 nm. Scale bar: 50 µm.

[0042] Figure 12 This shows ROS induction in A549 cells after treatment with 10 μM 1aR. Data represent at least three independent experiments, and values ​​are expressed as mean ± standard error.

[0043] Figure 13 The left panel shows (A) death induction in senescent A549 cells after treatment with 20 μM 1aR; and (B) SA-β-gal staining in untreated A549 cells identified senescent cells. No senescent cells were identified in A549 cells treated with 1aR (right panel). Data represent at least three independent experiments, and values ​​are expressed as mean ± standard error.

[0044] Figure 14 This shows the uptake of FAM-1aR into A549 cells and the morphological features induced by pyroptosis. White arrows indicate vesicle formation. Cell membranes were analyzed using MemBrite. TM Fix 660 / 680 staining was used, and cell nuclei were stained with Hoechst 33342. Scale bar: 20 µm

[0045] Figure 15This image shows the uptake of FAM-1aR into A549 cells and the resulting morphological changes. The left and right images were taken three minutes apart. The image illustrates the uptake of the peptide FAM-1aR. The membrane was stained with MemBrite™ Fix 660 / 680, and the cell nuclei were stained with Hoechst 33342. Scale bar: 20 µM.

[0046] Figure 16 The viability of selected human cancer cells after treatment with peptides 1b, 1-ALA, and 1a (100 µM) for 24 hours is shown. Data represent at least three independent experiments, and values ​​are expressed as mean ± standard error.

[0047] Therefore, as mentioned above, in one embodiment, the present invention relates to compounds comprising the portion of formula (I):

[0048] -[AZA] n -

[0049] (I)

[0050] Or its pharmaceutically acceptable salt.

[0051] In formula (I), each A is independently a group of the following formula:

[0052] .

[0053] Each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl and heterocycloalkyl, wherein -(C 0-6 alkylene)-carbocyclic or the -(C 0-6 C in alkylene-heterocyclic group 0-6 One of the -CH2- moieties in an alkylene group is optionally surrounded by -O-, -S-, -NH-, or -N(C) 1-6 Alkyl)-substitution. If one of the -CH2- units is substituted, as described above, preferably substituted with -O- or -S-, more preferably substituted with -O-.

[0054] Preferably, each R 1 Independently for C 1-6 Alkyl groups (e.g., methyl, isopropyl, isobutyl, sec-butyl, or n-butyl), C 2-6 alkenyl (e.g., allyl), C 2-6alkynyl (e.g., propargyl), -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl, and heterocyclic alkyl. 1 Relevant examples include, in particular, methyl, isopropyl, isobutyl, sec-butyl, n-butyl, allyl, propyne, phenethyl, benzyloxymethyl, and 4-(trifluoromethyl)benzyl.

[0055] More preferably, each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each of the heterocyclic groups of the (alkylene)-heterocyclic group is optionally substituted with one or more groups, said groups being independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO-(C 1-6alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 Alkyl), and -SO-(C 1-6 alkyl).

[0056] Even more preferably, each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C1-6 -haloalkyl), -CF3, -CN, and -NO2.

[0057] Even more preferably, each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-S(C 1-6 alkyl), -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 (halogenated alkyl) and -CF3.

[0058] Even more preferably, each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0059] Even more preferably, each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0060] Even more preferably, each R 1 Independently for C 1-6 alkyl.

[0061] Even more preferably, each R 1 Independently for C 2-5 alkyl.

[0062] Even better for each R 1 Independently for C 3-4 alkyl.

[0063] Most preferably, each R 1 It is either isopropyl or isobutyl.

[0064] In formula (I), each Z is independently a group of the following formula:

[0065] ,

[0066] Each m is independently 0 or 1, preferably each m is 1.

[0067] In equation (I), n is 2, 3, or 4.

[0068] Preferably, n is 2 or 3.

[0069] More preferably, n is 2.

[0070] It is understood that, regarding formula (I) as shown above, the divalent groups A and Z are connected to other groups in the following ways: A or Z is connected to the group to its left through its -NH- portion, and A or Z is connected to the group to its right through its -CO- portion.

[0071] Preferably, in formula (I), each A has the following configuration: .

[0072] Preferably, in formula (I), each Z has the following configuration: .

[0073] Compounds of formula (I) can be compounds of formula (II):

[0074] X-[Z] p -[AZA] n -Y

[0075] (II)

[0076] Or its pharmaceutically acceptable salt.

[0077] In equation (II), A, Z and n are as defined in equation (I) above.

[0078] In equation (II), p is 0 or 1. Preferably, p is 1.

[0079] In formula (II), X is selected from the hydrophobic portion, PEG consisting of 2-10 ethylene glycol repeats, and an amino acid sequence of 1-5 hydrophobic amino acid residues, wherein the amino acid sequence is linked to the remainder of the compound of formula (II) via its C-terminus, and optionally, wherein the amino acid sequence has an alkanoyl group (e.g., acetyl) at its N-terminus.

[0080] More preferably, X is an amino acid sequence of 1-5 hydrophobic amino acid residues, wherein X is connected to the remainder of the compound of formula (II) via its C-terminus, and optionally, wherein X has an alkanoyl group at its N-terminus, preferably selected from butyryl, propionyl, and acetyl. Preferably, X has an alkanoyl group (e.g., butyryl, propionyl, or acetyl; particularly acetyl) at its N-terminus.

[0081] The amino acid sequence of 1-5 hydrophobic amino acid residues is preferably an amino acid sequence of 1-3 hydrophobic amino acid residues, more preferably an amino acid sequence of 1-2 hydrophobic amino acid residues, and even more preferably a single amino acid residue.

[0082] Preferably, the hydrophobic amino acid residues in X are each independently selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Met, and Trp; more preferably from Val, Leu, Ile, Phe, Tyr, and Trp; even more preferably from Phe, Tyr, and Trp; and even more preferably from Phe and Tyr. Preferably, the amino acid residues referred to herein are L-amino acid residues.

[0083] Therefore, even more preferably, X is alkylyl-Tyr-, for example, butyryl-Tyr-, propionyl-Tyr-, or acetyl-Tyr-(Ac-Tyr-), particularly Ac-Tyr-. Even more preferably, X is alkylyl-(L-Tyr)-, for example, butyryl-(L-Tyr)-, propionyl-(L-Tyr)-, or Ac-(L-Tyr)-.

[0084] In formula (II), Y is the polar part. Preferably, Y is neutral or positively charged, and more preferably, Y exhibits a positive net charge.

[0085] Preferably, Y is an amino acid sequence of 1-5 polar amino acid residues (preferably basic amino acid residues or a combination of basic amino acid residues and polar neutral amino acid residues), wherein Y is linked to the remainder of the compound of formula (II) via its N-terminus, optionally wherein the C-terminal COOH group of Y is replaced by -CONH2 or -CH2OH. Preferably, the C-terminal COOH group of Y is replaced by -CONH2 or -CH2OH, more preferably by -CONH2.

[0086] The amino acid sequence of 1-5 polar amino acid residues is preferably an amino acid sequence of 1-3 polar amino acid residues, more preferably an amino acid sequence of 2-3 polar amino acid residues. As mentioned above, the polar amino acid residues are preferably basic amino acid residues (e.g., selected from Arg, Lys, and His) or a combination of basic amino acid residues and polar neutral amino acid residues (e.g., selected from Ser, Thr, Asn, and Gln).

[0087] Preferably, all polar amino acid residues in Y are basic amino acid residues. More preferably, each polar amino acid residue in Y is independently selected from Arg, Lys, and His, more preferably from Arg and Lys, and even more preferably each is Arg. Therefore, it is particularly preferred that Y is composed of basic amino acids, each independently selected from Arg, Lys, and His, more preferably from Arg and Lys, and even more preferably each is Arg.

[0088] Therefore, more preferably, Y is -Arg-Arg-NH2 or -Arg-Arg-Arg-NH2. Even more preferably, Y is –(D-Arg)-(D-Arg)-NH2 or –(D-Arg)-(D-Arg)-(D-Arg)-NH2.

[0089] In the first specific implementation scheme, each A is selected from... and .

[0090] In the second specific implementation, R 1 Independently for -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6 Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl, and heterocyclic alkyl.

[0091] In a second specific embodiment, the -(C) is preferred. 0-6 The carbocyclic moiety of the alkylene group and the -(C 0-6Each heterocyclic moiety of the (alkylene)-heterocyclic group may optionally be substituted by one or more groups, said groups being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-S(C 1-6 alkyl), -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 (halogenated alkyl), and -CF3, more preferably independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 The alkyl halogroup and -CF3, even more preferably independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, or even more preferably independently, is C. 1-6 Alkyl group. C4 is particularly preferred. 1-6 Alkyl groups are C1-3 alkyl groups, especially methyl and ethyl.

[0092] In the third specific implementation, R 1 Independently benzyl or pyrrole, wherein the benzyl phenyl and pyrrole are each optionally constituting one or more C 1-6 Alkyl group substitution. Particularly preferred, C 1-6 Alkyl groups are C1-3 alkyl groups, especially methyl and ethyl.

[0093] In the fourth specific implementation, each Z is: .

[0094] In a fifth specific embodiment, n is 3 or 4. Preferably, n is 3.

[0095] In the sixth specific implementation, p is 0.

[0096] In a seventh specific embodiment, portion X is a hydrophobic portion. Preferably, X is (C 1-20 Alkyl)-CO-.

[0097] In the eighth specific implementation, X is (C 1-20 Alkyl)-CO-. Particularly suitable, C1-20 Alkyl is C 10-20 Alkyl, more preferably selected from C 10 Alkyl, C 12 Alkyl, C 14 Alkyl, C 16 Alkyl and C 18 alkyl.

[0098] In the ninth specific implementation, X is CH3-CO-.

[0099] In the tenth specific embodiment, X is a PEG composed of 2-10 repeating ethylene glycol units.

[0100] In the eleventh specific embodiment, X is Ac-Tyr-, preferably wherein X is Ac-(L-Tyr)-.

[0101] In a twelfth specific embodiment, Y is -Arg-Arg-NH2 or -Arg-Arg-Arg-NH2. Even more preferably, Y is –(D-Arg)-(D-Arg)-NH2 or –(D-Arg)-(D-Arg)-(D-Arg)-NH2.

[0102] In the thirteenth specific implementation scheme, R 1 It is selected from methyl, isopropyl, isobutyl, sec-butyl, and n-butyl.

[0103] In the fourteenth specific implementation scheme, R 1 Selected from allyl and propargyl.

[0104] In the fifteenth specific implementation scheme, R 1 It is selected from phenylethyl, benzyloxymethyl and 4-(trifluoromethyl)benzyl.

[0105] It is understood that compounds containing a portion of formula (I) or compounds of formula (II) are preferably amphiphilic.

[0106] Particularly preferred, the compound comprising the portion of formula (I) or the compound of formula (II) is selected from the following compounds or their pharmaceutically acceptable salts:

[0107] and .

[0108] It is understood that the present invention relates particularly to each of the features and embodiments described herein and combinations thereof, including any combination of general and / or preferred features / implementations. In particular, the present invention relates particularly to each combination of the meanings (including general and / or preferred meanings) of the various groups and variables contained in formula (I) or (II).

[0109] The following definitions apply in this specification and the appended claims, unless otherwise specified.

[0110] The term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0111] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (e.g., noncyclic) hydrocarbon group, which can be straight-chain or branched. Therefore, an "alkyl" group does not contain any carbon-carbon double or triple bonds. 1-5 "alkyl" refers to an alkyl group having 1-5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to C14. 1-4 alkyl.

[0112] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chain or branched, and contains one or more (e.g., one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bonds. The term "C..." 2-5 "Alkenyl" refers to an alkenyl group having 2-5 carbon atoms. Preferred exemplary alkenyl groups are vinyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., but-1,3-dien-1-yl or but-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprene). Unless otherwise defined, the term "alkenyl" preferably refers to C 2-4 Alkenyl group.

[0113] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chain or branched, and contains one or more (e.g., 1 or 2) carbon-carbon triple bonds and optionally one or more (e.g., 1 or 2) carbon-carbon double bonds. The term "C..." 2-5 "Alynyl" refers to an alkynyl group having 2-5 carbon atoms. Preferred exemplary alkynyl groups include ethynyl, propynyl (e.g., propynyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to C... 2-4 Alkyne group.

[0114] As used herein, the term "alkylene" refers to an alkanediyl group, such as a divalent saturated acyclic hydrocarbon group, which can be straight-chain or branched. "C" 1-5 "alkylene" refers to an alkylene group having 1-5 carbon atoms, and the term "C" is used to indicate that the alkylene group has 1-5 carbon atoms. 0-3 "alkylene" refers to the presence of a covalent bond (corresponding to option "C0 alkylene") or C 1-3Alkylene. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or CH(CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)- or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless otherwise defined, the term "alkylene" preferably refers to C... 1-4 Alkylenes (including, in particular, straight-chain C) 1-4 Alkylene), more preferably methylene or ethylene, and even more preferably methylene.

[0115] As used herein, the term "carbocyclic" refers to a hydrocarbon cyclic group, including monocyclic and bridging rings, spirocyclic and / or fused ring systems (e.g., consisting of two or three rings), wherein the cyclic group may be saturated, partially unsaturated (e.g., unsaturated but non-aromatic) or aromatic. Unless otherwise defined, "carbocyclic" preferably refers to an aryl, cycloalkyl or cycloalkenyl group.

[0116] As used herein, the term "heterocyclic group" refers to a cyclic group, including monocyclic rings as well as bridging rings, spirocyclic rings, and / or fused ring systems (e.g., consisting of two or three rings), wherein the cyclic group comprises one or more (e.g., 1, 2, 3, 4) cyclic heteroatoms independently selected from O, S, and N, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (e.g., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (e.g., unsaturated but non-aromatic), or aromatic. For example, each of the heteroatom-containing rings may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the respective heteroatom-containing ring is 1-4 and that at least one carbocyclic atom (which may optionally be oxidized) is present in the respective heteroatom-containing ring. Unless otherwise defined, "heterocyclic group" preferably refers to a heteroaryl, heterocyclic alkyl, or heterocyclic alkenyl group.

[0117] As used herein, the term "aryl" refers to an aromatic hydrocarbon cyclic group, including monocyclic aromatic rings and bridging rings and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of 2 or 3 fused rings, wherein at least one of these fused rings is aromatic; or a bridging ring system consisting of 2 or 3 rings, wherein at least one of these bridging rings is aromatic). "Aryl" can refer to, for example, phenyl, naphthyl, dihydronaphthyl (e.g., 1,2-dihydronaphthyl), tetralinyl (e.g., 1,2,3,4-tetrahydronaphthyl), indenyl, indenyl (e.g., 1H-indenyl), anthracene, phenanthryl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6-14 ring atoms, more preferably 6-10 ring atoms, even more preferably phenyl or naphthyl, and most preferably phenyl.

[0118] As used herein, the term "heteroaryl" refers to an aromatic cyclic group, including monocyclic aromatic rings and bridging rings and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of 2 or 3 fused rings, wherein at least one of these fused rings is aromatic; or a bridging ring system consisting of 2 or 3 rings, wherein at least one of these bridging rings is aromatic), wherein the aromatic cyclic group comprises one or more (e.g., 1, 2, 3, 4) cyclic heteroatoms independently selected from O, S, and N, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and additionally wherein one or more carbon ring atoms may optionally be oxidized (e.g., to form oxo groups). For example, each of the aromatic cycloalgides may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring."Heteroaryl" can refer to, for example, thiophenyl, benzo[b]thiophenyl, naphtho[2,3-b]thiophenyl, thianthrenyl, furanyl, benzofuranyl, isobenzofuranyl, benzodihydropyranyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromone, xanthonyl, phenoxathiinyl, pyrroleyl (e.g., 2H-pyrroleyl), imidazoyl, pyrazolyl, pyridyl (e.g., pyridyl; e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyridyl (i.e., pyridyl ... -pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl (e.g., 3H-indoleyl), isoindoleyl, indazoleyl, indazinyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphridinyl, quinoxalinyl, cyclolinyl, pteridinyl, carbazoyl, β-carolinyl, phenanthridineyl, acridineyl, perimidinyl, phenanthridineyl (e.g., [1,10]phenanthridineyl, [1,7]phenanthridineyl or [4,7]phenanthridineyl), phenazinyl, thiazoyl, isothiazinyl, phenothiazinyl, oxazinyl, isoxazinyl, oxadiazinyl (e.g., 1,2,4-oxadiazinyl, 1,2,5-oxadiazinyl (i.e., furazinyl) or 1,3,4-oxadiazinyl), thiazoyl Azolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzo[b]thiophene (i.e., benzothiophene), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazoleyl, 2H-tetrazoleyl, triazinyl (e.g., 1,2,3-triazine) The compounds can be 1,2,4-triazinyl or 1,3,5-triazinyl, furano[2,3-c]pyridyl, dihydrofuranopyridyl (e.g., 2,3-dihydrofurano[2,3-c]pyridyl or 1,3-dihydrofurano[3,4-c]pyridyl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl or imidazo[3,2-a]pyridyl), quinazolinyl, thienopyridyl, tetrahydrothienopyridyl (e.g., 4,5,6,7-tetrahydrothienopyridyl), dibenzofuranyl, 1,3-benzodioxane, benzodioxyl (e.g., 1,3-benzodioxane or 1,4-benzodioxane), or coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic or fused-ring system comprising one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S-ring atoms (if present) and / or one or more N-ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring comprising one or more (e.g., 1, 2, or 3) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S-ring atoms (if present) and / or one or more N-ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized.

[0119] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon cyclic group comprising monocyclic rings as well as bridging rings, spirocyclic rings, and / or fused ring systems (which may consist of, for example, two or three rings; for example, a fused ring system consisting of two or three fused rings). "Cycloalkyl" can refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C14. 3-11 Cycloalkyl, and more preferably C 3-7 Cycloalkyl. Particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3-7 ring atoms (e.g., cyclopropyl or cyclohexyl).

[0120] As used herein, the term "heterocyclic alkyl" refers to a saturated cyclic group, including monocyclic and bridging rings, spirocyclic and / or fused cyclic systems (e.g., consisting of 2 or 3 rings; for example, fused cyclic systems consisting of 2 or 3 fused rings), wherein the cyclic group comprises one or more (e.g., 1, 2, 3, 4) cyclic heteroatoms independently selected from O, S and N, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and wherein one or more carbocyclic atoms may optionally be oxidized (e.g., to form an oxo group). For example, each of the saturated cyclic groups may contain a heteroatom-containing ring comprising 1 or 2 O atoms and / or 1 or 2 S atoms (which may optionally be oxidized) and / or 1, 2, 3, 4 N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the respective heteroatom-containing ring is 1-4, and at least one carbocyclic atom (which may optionally be oxidized) is present in the respective heteroatom-containing ring. "Heterocyclic alkyl" can refer to, for example, aziridine propane, aziridine butane, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, aziridine heptane, diaziridine heptane (e.g., 1,4-diazazidine heptane), oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazazidine heptane, ethylene oxide, and oxygen. Heterocyclic butyl, tetrahydrofuranyl, 1,3-dioxacyclopentyl, tetrahydropyranyl, 1,4-dioxyl, oxacycloheptyl, thiocyclopropane, thiocyclobutyl, tetrahydrothiophene (i.e., thiocyclopentyl), 1,3-dithiocyclopentyl, thiocyclohexyl, 1,1-thiocyclohexyl, thiocycloheptyl, decahydroquinolinyl, decahydroisoquinolinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, “heterocyclic alkyl” preferably refers to a 3-11 member saturated cyclic group, which is a monocyclic or fused cyclic system (e.g., a fused cyclic system consisting of two fused rings), wherein the cyclic group comprises one or more (e.g., 1, 2, 3, 4) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbocyclic atoms are optionally oxidized; more preferably, “heterocyclic alkyl” refers to a 5-7 member saturated monocyclic group comprising one or more (e.g., one, 2, or 3) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbocyclic atoms are optionally oxidized.

[0121] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon cyclic group, including monocyclic and bridged cyclospirocyclic and / or fused cyclic systems (e.g., consisting of 2 or 3 rings; for example, fused cyclic systems consisting of 2 or 3 fused rings), wherein the hydrocarbon cyclic group contains one or more (e.g., 1 or 2) carbon-carbon double bonds and does not contain any carbon-carbon triple bonds. "Cycloalkenyl" can refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 Cycloalkenyl, more preferably C 3-7 Cycloalkenyl. Particularly preferred, “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3-7 ring atoms and containing one or more (e.g., 1 or 2; preferably 1) carbon-carbon double bonds.

[0122] As used herein, the term "heterocyclic alkenyl" refers to an unsaturated alicyclic (i.e., non-aromatic) cyclic group, including monocyclic and bridging rings, spirocyclic and / or fused ring systems (e.g., consisting of 2 or 3 rings; for example, a fused ring system consisting of 2 or 3 fused rings), wherein the cyclic group comprises one or more (e.g., 1, 2, 3 or 4) cyclic heteroatoms independently selected from O, S and N, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., forming an oxo group), and further wherein the cyclic group comprises at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4, and that at least one carbocyclic atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "Heterocyclic alkenyl" can refer to, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolinyl), 3-imidazolinyl or 4-imidazolinyl), tetrahydropyridyl (e.g., 1,2,3,6-tetrahydropyridyl), dihydropyridyl (e.g., 1,2-dihydropyridyl or 2,3-dihydropyridyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocyclic alkenyl" preferably refers to a 3- to 11-membered unsaturated alicyclic cyclic group, which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the cyclic group comprises one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, and wherein the cyclic group comprises at least one cyclic ring between adjacent ring atoms. The double bond does not contain any triple bond between adjacent ring atoms; more preferably, "heterocyclic alkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic cyclic group containing one or more (e.g., 1, 2 or 3) cyclic heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, and wherein the cyclic group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.

[0123] As used in this article, the term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0124] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1–6, more preferably 1–3) halogen atoms, said halogen atoms being independently selected from fluorine, chlorine, bromine, and iodine, preferably all halogen atoms being fluorine atoms. It is understood that the maximum number of halogen atoms is limited by the number of possible attachment sites, and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" can refer to, for example, -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred "haloalkyl" group is -CF3.

[0125] As used herein, the term "alkanoyl" refers to the part of the formula -CO-alkyl, wherein the alkyl group is as defined herein. Preferred examples of alkanoyl groups are acetyl (-CO-CH3), propionyl (-CO-CH2CH3), or butyryl (e.g., n-butyryl, such as -CO-CH2CH2CH3 or isobutyryl, such as -CO-CH(-CH3)2; preferably n-butyryl). Particularly preferred alkanoyl groups are acetyl (-CO-CH3).

[0126] The terms “bond” and “covalent bond” are used synonymously in this document unless otherwise explicitly stated or contradicted by the context.

[0127] The term "hydrophobic moiety" as defined herein refers to a group that does not contain any hydrogen bond donors or acceptors, optionally except for its connection points with the rest of the compound. Therefore, the hydrophobic moiety can be connected to the rest of the compound, for example via -O-, -S-, -NH-, -N(C 1-6 Alkyl), -CO-, -CONH-, -CON(C) 1-6 Alkyl group, -NHCO- or -N(C 1-6 Alkyl)CO-linked. Typical and exemplary hydrophobic groups include (C 1-20 alkyl)-O-, (C 1-20 alkyl)-S-, (C 1-20 alkyl)-NH-, (C 1-20 alkyl)-N(C 1-6 Alkyl), (C 1-20 alkyl)-CO-, (C 1-20 alkyl)-CONH-, (C 1-20 alkyl)-CON(C 1-6 alkyl)-, (C 1-20 alkyl)-NHCO- and (C 1-20 alkyl)-N(C 1-6 Alkyl)CO-. As in formula (II), the hydrophobic moiety is connected to the Z or A moiety via its -NH- group, and the hydrophobic moiety is particularly preferred to be (C 1-20 Alkyl)-CO-.

[0128] An "amphiphilic compound" is a compound that contains both a polar moiety and a hydrophobic moiety. Therefore, an amphiphilic compound is soluble in both polar (e.g., water, ionic liquids, or ethanol) and nonpolar (e.g., hexane or benzene) liquids. If an amphiphilic compound is exposed to a biphase system consisting of a polar phase (e.g., water, ionic liquids, or ethanol) and a nonpolar liquid phase (e.g., benzene, hexane), the amphiphilic compound will accumulate at the phase boundary between the two phases.

[0129] The "polar portion" is preferably characterized by being hydrophilic and having at least two hydrogen bond donors or acceptors. Preferably, the polar portion comprises a charged group, or the polar portion comprises a group selected from -OH, -SH, -COOH (especially in its charged form -COO). - -NH2, -NH(C) 1-5 alkyl), -N(C) 1-5 Alkyl)(C 1-5 Alkyl groups (which can exist in charged form) and -N (C 1-5 Alkyl)(C 1-5 Alkyl)(C 1-5 alkyl) + The group. Another example of a polar part is the PEG moiety, as defined herein.

[0130] "PEG" or "PEG moiety" is a moiety containing at least two repeating units according to the formula -(OCH2CH2)-. Preferably, PEG is according to the formula (C 1-5 Alkyl)-(OCH2CH2) m - part, where m is the number of PEG repeats, preferably 2-20, more preferably 2-10. More preferably, PEG is according to formula (C 1-5 Alkyl)-(OCH2CH2) m The -V- part, where V is selected from -O-, -S-, -NH-, -N(C)-. 1-6 Alkyl), -CO-, -CONH-, -CON(C) 1-6 Alkyl)-, -NHCO-, and -N(C 1-6 Alkyl)CO-, preferably wherein the left side of V is connected to a PEG repeating unit, wherein m is the number of PEG repeats, preferably 2-20, more preferably 2-10.

[0131] As used herein, the terms “optional,” “optionally,” “optionally,” and “may” indicate that the referred feature may be present or may not be present. Whenever the terms “optional,” “optionally,” “optionally,” or “may” are used, the invention specifically relates to two possibilities: for example, the corresponding feature may be present or the corresponding feature may not be present. For example, the statement “X may be optionally replaced by Y” (or “X may be replaced by Y”) means that X is either replaced by Y or not replaced. Similarly, if a component of a composition is indicated as “optional,” the invention specifically relates to two possibilities: for example, the corresponding component may be present (included in the composition) or the corresponding component may not be present in the composition.

[0132] In this specification, various groups are referred to as "optionally substituted". Typically, these groups may have one or more substituents, for example, 1, 2, 3, or 4 substituents. It is understood that the maximum number of substituents is limited by the number of connectable sites on the substituted portion. Unless otherwise defined, a "optionally substituted" group in this specification preferably has no more than two substituents, and in particular may have only one substituent. Furthermore, unless otherwise defined, it is preferred that optional substituents are absent, i.e., the corresponding group is unsubstituted.

[0133] Those skilled in the art will understand that the substituents contained in the compounds of the present invention can be linked to the remainder of the corresponding compound at multiple different positions of the respective specific substituents. Unless otherwise defined, preferred positions of the various specific substituents are shown in the examples.

[0134] In this specification, certain groups are referred to as "optionally substituted". It is understood that a corresponding group can be optionally substituted only if the stated group is present. Therefore, for example, if C is explicitly stated... 0-6 One of the -CH2- units in the alkylene moiety is optionally replaced by -O-, -S-, -NH- or -N(C 1-6 Alkyl) substitution, which means C 0-6 The alkylene moiety can be covalently bonded (corresponding to C0 alkylene) or it can be C 1-6 Alkylene, one of which is a -CH2- unit (C 1-6 The alkylene group may optionally be replaced by one of the aforementioned groups. One of the -CH2- units is replaced by a -O- group. 0-6 Examples of alkylene moieties include, in particular, -O-, -O-CH2-, -CH2-O-, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH2-CH2-, -O-CH(-CH3)-, -CH(-CH3)-O-, -O-CH2-CH2-CH2-, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2- or -CH2-CH2-CH2-O-, especially -CH2-O-CH2-.

[0135] As used herein, unless otherwise expressly stated or contradicted by the context, the terms “a,” “an,” and “the” may be used interchangeably with “one or more,” “at least one,” and “at least one.” Thus, for example, a composition comprising “one” of a compound of formula (I) may be interpreted as a composition comprising “one or more” of compounds of formula (I).

[0136] It should be understood that, regardless of the numerical range provided / disclosed herein, all values ​​and subranges covered by the corresponding numerical range are intended to be covered by the invention. Therefore, the invention specifically and exclusively relates to each value falling within the numerical range disclosed herein, and each subrange covered by the numerical range disclosed herein.

[0137] As used herein, unless otherwise expressly stated or contradicted by the context, the term “comprising” (or “including” or “containing”) means “containing, in particular”, that is, “containing together with other optional elements…”. In addition, the term also includes the narrower meanings of “consistently composed of…” and “composed of…”. For example, the term “A contains B and C” means “A particularly contains B and C”, where A may contain other optional elements (e.g., “A contains B, C, and D” would also be included), but the term also includes the meanings of “A is essentially composed of B and C” and “A is composed of B and C” (i.e., A does not contain any components other than B and C).

[0138] The scope of this invention includes all pharmaceutically acceptable salt forms of compounds comprising the portion of formula (I) or compounds of formula (II), which may be formed, for example, by protonating atoms with lone pairs of electrons that are easily protonated, such as amino groups, with inorganic or organic acids, or as salts of acid groups (such as carboxylic acid groups) with physiologically acceptable cations. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, ethylenediamine, or choline salts; aralkylamine salts such as N,N-dibenzylethylenediamine, benzylamine, and benzophenone; heterocyclic aromatic amine salts, such as pyridine, methylpyridine, quinoline, or isoquinoline; quaternary ammonium salts, such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium, or tetrabutylammonium; and basic amino acid salts, such as arginine, lysine, or histidine. Exemplary acid addition salts include, for example, inorganic acid salts, such as hydrochlorides, hydrobroms, hydroiodates, sulfates (e.g., sulfates or hydrogen sulfates), nitrates, phosphates (e.g., phosphates, hydrogen phosphates, or dihydrogen phosphates), carbonates, bicarbonates, perchlorates, borates, or thiocyanates; and organic acid salts, such as acetates, propions, buties, valerates, hexanoates, heptates, octanoates, cyclopentanepropionates, decanoates, undecanoates, oleates, stearates, lactates, maleates, oxalates, fumarates, tartrates, and malonic acid salts. Fructose, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pyrazine (dihydroxynaphthylate), camphorate, gluconate-heptate, or neopentanoate; sulfonates, such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate (hydroxyethylsulfonate), benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphates; and acidic amino acid salts, such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. Particularly preferred pharmaceutically acceptable salts of compounds comprising a portion of formula (I) or compounds of formula (II) are hydrochloride salts. Therefore, compounds comprising the portion of formula (I) or formula (II), including any of the specific compounds comprising the portion of formula (I) or formula (II) described herein, are preferred in the form of hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate or phosphate, and compounds comprising the portion of formula (I) or formula (II) are particularly preferred in the form of hydrochloride.

[0139] The present invention also specifically relates to compounds of formula (I) or formula (II) in non-salt form, including any of the specific compounds of formula (I) or formula (II) described herein.

[0140] Furthermore, the scope of this invention includes any solvated form of compounds comprising a portion of formula (I) or a compound of formula (II), including solvates with water (i.e., as hydrates) or with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms of compounds comprising a portion of formula (I) or compounds of formula (II), including any amorphous or crystalline form (i.e., polymorphs), are also included within the scope of this invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of compounds comprising a portion of formula (I) or compounds of formula (II) are also included in this invention.

[0141] Furthermore, compounds comprising a portion of formula (I) or compounds of formula (II) may exist in the form of different isomers, particularly stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (especially proton transfer tautomers, such as ketone / enol tautomers or thionone / thiol tautomers). All such isomers of compounds comprising a portion of formula (I) or compounds of formula (II), whether in mixture form or in pure or substantially pure form, are considered part of this invention. As for stereoisomers, this invention includes the isolated optical isomers of the compounds of this invention and any mixtures thereof (especially racemic mixtures / racemates). Racemates can be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates by salting with an optically active acid and then crystallizing. This invention also includes any tautomers of compounds comprising a portion of formula (I) or compounds of formula (II). It should be understood that some compounds may exhibit tautomerism. In such cases, the structural formulas provided herein explicitly describe only one of the possible tautomeric forms. The structural formulas and chemical names provided herein are intended to include any tautomeric form of the corresponding compound, and not only the specific tautomeric form shown in the structural formula or identified by the compound name.

[0142] The scope of this invention also includes compounds comprising a portion of formula (I) or a compound of formula (II) in which one or more atoms are substituted with a specific isotope of the corresponding atom. For example, this invention includes compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are substituted with a deuterium atom (i.e., 2H; also known as "D") is a compound of formula (I) that substitutes for deuterium. Therefore, the present invention also includes compounds containing the portion of formula (I) or formula (II) that are rich in deuterium. Naturally occurring hydrogen is an isotopic mixture containing about 99.98 mol% hydrogen-1 ( 1 H) and approximately 0.0156 mol% deuterium ( 2 The deuterium content at one or more hydrogen sites in compounds comprising the portion of formula (I) or formula (II) can be increased using deuteration techniques known in the art. For example, compounds comprising the portion of formula (I) or formula (II), or reactants or precursors used to synthesize compounds comprising the portion of formula (I) or formula (II), can be subjected to an H / D exchange reaction using, for example, heavy water (D₂O). Other suitable deuteration techniques are described in: Atzrodt J et al. Bioorg Med Chem , 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals , 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem ,79,5861-5868,2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise explicitly stated, compounds containing the portion of formula (I) or compounds of formula (II) are preferably not rich in deuterium. Therefore, naturally occurring hydrogen atoms are preferably present in compounds containing the portion of formula (I) or compounds of formula (II). 1 H hydrogen atom.

[0143] This invention also covers compounds comprising a portion of formula (I) and compounds of formula (II), wherein one or more atoms are replaced by positron-emitting isotopes of the corresponding atoms, such as... 18 F, 11 C, 13 N, 15 O, 76 Br, 77 Br, 120 I and / or 124 I. Such compounds can be used as tracers, tracking agents, or imaging probes in positron emission tomography (PET). Therefore, the present invention includes: (i) wherein one or more fluorine atoms (or, for example, all fluorine atoms) are... 18 Compounds containing a portion of formula (I) and compounds of formula (II) in which one or more carbon atoms (or, for example, all carbon atoms) are replaced by F atoms. 11 Compounds containing a portion of formula (I) and compounds of formula (II) in which C atoms are substituted, and (iii) wherein one or more nitrogen atoms (or, for example, all nitrogen atoms) are... 13Compounds containing a portion of formula (I) and compounds of formula (II) in which an N atom is substituted, (iv) wherein one or more oxygen atoms (or, for example, all oxygen atoms) are... 15 Compounds containing the portion of formula (I) and compounds of formula (II) in which the O atom is substituted, (v) wherein one or more bromine atoms (or, for example, all bromine atoms) are... 76 Compounds containing the portion of formula (I) and compounds of formula (II) in which Br atoms are substituted, (vi) wherein one or more bromine atoms (or, for example, all bromine atoms) are... 77 Compounds containing the portion of formula (I) and compounds of formula (II) in which Br atoms are substituted, (vii) wherein one or more iodine atoms (or, for example, all iodine atoms) are... 120 Compounds containing a portion of formula (I) and compounds of formula (II) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with I atoms, and (viii) compounds in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with I atoms. 124 Compounds containing the portion of formula (I) and compounds of formula (II) with I atoms substituted. Generally, it is preferred that neither the atom in the compound containing the portion of formula (I) nor the atom in the compound of formula (II) is substituted by a specific isotope.

[0144] The compounds of the present invention can be administered as compounds on their own or formulated into pharmaceutical / pharmaceutical compositions. Pharmaceutical / pharmaceutical compositions may optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubilizers.

[0145] The pharmaceutical composition may contain one or more solubilizers, such as polyethylene glycol, including polyethylene glycol with a molecular weight of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400 or PEG 600), ethylene glycol, propylene glycol, glycerin, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., Kolliphor). ®HS 15, CAS 70142-34-6), phospholipids, lecithin, myristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin Dextrin, disaccharismatic-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotrisyl-β-cyclodextrin, maltotrisyl-γ-cyclodextrin, disaccharismatic-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl sulfides, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or any combination thereof.

[0146] The pharmaceutical composition may also contain one or more preservatives, particularly one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methylphenol or 4-chloro-3-methylphenol), benzalkonium chloride, benzyl chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0147] Pharmaceutical compositions can be formulated using techniques known to those skilled in the art, such as those disclosed in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd edition. Pharmaceutical compositions can be formulated into dosage forms for oral, parenteral, intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, sugar lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated chewing gum, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersibles, and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and vaginal suppositories. Dosage forms for nasal application can be administered via inhalation and blowing, such as through a metered-dose inhaler. Dosage forms for topical application include creams, gels, ointments, balms, patches, and transdermal delivery systems.

[0148] The pharmaceutical composition comprising a portion of formula (I) or a compound of formula (II), or the above-described pharmaceutical composition comprising a portion of formula (I) or a compound of formula (II), may be administered to an individual via any convenient route of administration, whether systemic / peripheral or at the desired site of action, including but not limited to one or more of the following: oral (e.g., in tablet, capsule, or absorbable solution form), local (e.g., percutaneous, intranasal, ocular, sublingual, and sublingual), parenteral (e.g., using injection or infusion techniques, and including, for example, by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrathecal, intrasacral, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, or intrasternal injection, or by, for example, implantation into a reservoir, such as subcutaneous or intramuscular implantation), pulmonary (e.g., by inhalation or inhalation therapy, using, for example, aerosols, such as through the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or anterior chamber), rectal, or vaginal administration.

[0149] If the compound or pharmaceutical composition is administered via parenteral administration, examples of such administration include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intramuscular, or subcutaneous administration, and / or administration via infusion techniques. For parenteral administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to pH 3-9). The preparation of suitable parenteral formulations under sterile conditions can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0150] The compound or pharmaceutical composition is administered orally, for example in the form of tablets, capsules, ovules, elixirs, solutions, or suspensions, and may contain flavoring agents or coloring agents, for immediate, delayed, altered, continuous, pulsatile, or controlled release applications.

[0151] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or cassava starch), sodium hydroxyacetic acid starch, croscarmellose sodium, and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl docosanoate, and talc may be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the active agent may be used in combination with various sweeteners or flavoring agents, pigments or dyes, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0152] For oral administration, it is preferred to administer the compound or pharmaceutical composition by oral ingestion, particularly by swallowing. Therefore, the compound or pharmaceutical composition can be administered to enter the gastrointestinal tract through the mouth, which is also known as "oral-gastrointestinal" administration.

[0153] Alternatively, the compounds or pharmaceutical compositions may be administered in the form of suppositories or vaginal suppositories, or topically in the form of gels, hydrogels, lotions, solutions, creams, ointments, or dusting powders. The compounds of the present invention may also be administered transdermally, for example, through the use of skin patches.

[0154] The compounds or pharmaceutical compositions described herein can also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules. Sustained-release matrices include, for example, polylactide, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Therefore, the present invention also relates to liposomes containing compounds of the present invention.

[0155] The compounds or pharmaceutical compositions may also be administered via the pulmonary, rectal, or ocular routes. For ophthalmic use, they may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated as ointments such as petrolatum.

[0156] It is also envisioned to prepare dry powder formulations of compounds comprising the portion of formula (I) or formula (II) for pulmonary application, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that produce substantially amorphous, glassy, ​​or substantially crystalline bioactive powders. Therefore, dry powders of the compounds of the present invention can be prepared according to an emulsification / spray drying method.

[0157] For topical application to the skin, the compounds or pharmaceutical compositions may be formulated as suitable ointments containing an active compound suspended or dissolved in, for example, a mixture of one or more of the following substances: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated as suitable lotions or creams suspended or dissolved in, for example, a mixture of one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, hexadecyl ester wax, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0158] Therefore, this invention relates to the compounds or pharmaceutical compositions provided herein, wherein the respective compounds or pharmaceutical compositions are administered via any of the following routes: oral administration; local administration, including transdermal, intranasal, ocular, buccal, or sublingual routes; parenteral administration using injection or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheathal, intraspinal, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intrasternal, intravenous, intraurethral, ​​or intracranial routes; pulmonary administration, including inhalation or blowing therapy; gastrointestinal administration; intrauterine administration; intraocular administration; subcutaneous administration; ophthalmic administration, including intravitreal or anterior chamber administration; rectal administration; or vaginal administration. Preferred routes of administration are oral or parenteral administration. For each compound or pharmaceutical composition provided herein, oral administration (particularly by oral ingestion) is particularly preferred.

[0159] Typically, a physician will determine the most suitable actual dose for an individual. The specific dose level and frequency of administration for any particular individual can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, age, weight, general health condition, sex, diet, administration pattern and timing, excretion rate, drug combination, severity of the specific condition, and the individual's ongoing treatment.

[0160] The suggested, but not limiting, dose of the compound of this invention for oral administration to a human (approximately 70 kg body weight) may be 0.05-2000 mg per unit dose, preferably 0.1-1000 mg of the active ingredient. The unit dose may be administered, for example, 1 to 3 times daily. The unit dose may also be administered 1 to 7 times weekly, for example, no more than once daily. It should be understood that the dose may need to be routinely varied according to the patient / individual's age and weight, as well as the severity of the condition being treated. The precise dosage and route of administration are ultimately determined by the attending physician or veterinarian.

[0161] This invention relates to pharmaceutical compositions comprising a portion of formula (I) or formula (II) for the treatment or prevention of cancer. Data presented in the examples show significant selectivity of the compounds and compositions of the present invention for cancer cells relative to healthy cells. Importantly, the compounds comprising a portion of formula (I) or formula (II) have also been shown to be effective against chemotherapy-resistant and senescent cancer cells.

[0162] The cancer to be treated or prevented according to the present invention can be a solid tumor or a hematologic cancer. Preferably, the cancer is selected from lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, large cell lung cancer, lung adenocarcinoma, including lung adenocarcinoma or squamous cell carcinoma with EGFR mutation ΔE746-A750), kidney cancer (or renal cancer; e.g., renal carcinoma), gastrointestinal cancer, stomach cancer, colorectal cancer (e.g., colorectal cancer), colon cancer, anal cancer, genitourinary cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), ovarian cancer, etc. Cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian cancer), uterine cancer, prostate cancer (e.g., hormone-refractory prostate cancer), testicular cancer, biliary tract cancer, hepatobiliary duct cancer, neuroblastoma, brain cancer (e.g., glioblastoma), breast cancer (e.g., triple-negative breast cancer, breast cancer or breast adenocarcinoma with BRCA1 and / or BRCA2 gene mutations), head and / or neck cancer (e.g., squamous cell carcinoma of the head and neck), skin cancer, melanoma, Merke L-cell carcinoma (e.g., Merkel cell carcinoma), epidermoid carcinoma, squamous cell carcinoma (or squamous cell carcinoma; including, for example, oral squamous cell carcinoma / squamous cell oral carcinoma, squamous cell skin carcinoma, squamous cell lung carcinoma, squamous cell thyroid carcinoma, squamous cell esophageal carcinoma, or squamous cell vaginal carcinoma), bone cancer (e.g., osteosarcoma or osteoblastoma), fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral cancer, thymoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), Goblet cell carcinoids (e.g., goblet cell carcinoids), hematologic malignancies, leukemias (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia), lymphomas (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma, such as follicular lymphoma or diffuse large B-cell lymphoma), and multiple myeloma. Furthermore, the cancer to be treated (including any of the specific types of cancer mentioned above) may also be chemotherapy-resistant and / or metastatic.

[0163] Compounds comprising a portion of formula (I) or compounds of formula (II), or pharmaceutical compositions comprising a portion of formula (I) or compounds of formula (II), can be administered as a monotherapy (e.g., without the administration of any other therapeutic agent, or without the administration of any other therapeutic agent for the same disease treated or prevented by compound (I)). Therefore, this invention relates to compounds comprising a portion of formula (I) or compounds of formula (II), or corresponding pharmaceutical compositions, for monotherapy in the treatment or prevention of cancer. In particular, this invention relates to the monotherapy administration of compounds comprising a portion of formula (I) or compounds of formula (II), or corresponding pharmaceutical compositions, without the administration of any other anticancer agents.

[0164] However, a pharmaceutical composition comprising a portion of formula (I) or a compound of formula (II), or comprising a portion of formula (I) or a compound of formula (II), may also be administered in combination with one or more additional therapeutic agents. If a portion of formula (I) or a compound of formula (II) is used in combination with a second therapeutic agent active against the same disorder or disease, the dosage of each compound may differ from the dosage when the corresponding compound is used alone; in particular, lower dosages of each compound may be used. A combination of a portion of formula (I) or a compound of formula (II) with one or more additional therapeutic agents may comprise a compound of formula (I) or a compound of formula (II) administered simultaneously / concomitantly and an additional therapeutic agent (in a single pharmaceutical formulation or in separate pharmaceutical formulations) or a compound of formula (I) or a compound of formula (II) or an additional therapeutic agent administered sequentially / separately. If administered sequentially, a portion of formula (I) or a compound of formula (II) or one or more additional therapeutic agents of the present invention may be administered first. If administered concurrently, one or more additional therapeutic agents may be contained in the same pharmaceutical formulation as a compound comprising a portion of formula (I) or a compound comprising formula (II), or they may be administered in two or more different (separate) pharmaceutical formulations.

[0165] Preferably, in the context of treating (or preventing) cancer, one or more additional therapeutic agents administered in combination with the compounds of the present invention are anticancer drugs. One or more anticancer drugs administered in combination with compounds comprising a portion of formula (I) or a compound of formula (II) according to the present invention may be selected, for example, from: tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, or vascular endothelial growth factor receptor kinase inhibitors); cytotoxic drugs (e.g., antimetabolites, such as purine and pyrimidine analog antimetabolites); antimitotic agents (e.g., microtubule stabilizers or antimitotic alkaloids); platinum coordination complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustard or nitrosourea); endocrine agents (e.g., corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists, or somatostatin analogs); or compounds that target enzymes or receptors of specific metabolic pathways overexpressed and / or otherwise involved in deregulation (or misregulation) in tumor cells (e.g., ATP and GTP). Phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (e.g., serine, threonine, and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitors), and various growth factors, their receptors, and corresponding kinase inhibitors (e.g., epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors, and platelet-derived growth factor receptor kinase inhibitors); methionine aminopeptidase inhibitors (e.g., methionine aminopeptidase 2 inhibitors), proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I or topoisomerase II inhibitors), poly-ADP-ribose polymerase inhibitors (PARP inhibitors), and epidermal growth factor receptor (EGFR) inhibitors / antagonists.

[0166] Alkylating agents that can be combined with the compounds of the present invention as anticancer drugs may be, for example, nitrogen mustard (e.g., cyclophosphamide, mechlorethamine, uramustin, melphalan, chloramustin, ifosfamide, bendamustin, or trephosphamide), nitrosourea (e.g., carmustine, streptozotocin, formustine, lomustine, nimustine, prednimustine, ramustine, or semustine), alkyl sulfonates (e.g., busulfan, mannosulfan, or triaziquone), aziridine (e.g., altretamine, triethylmelamine, thioTEPA, carboquinone, or triaziquone); hydrazine (e.g., procarbazine), triazine (e.g., dacarbazine), or imidazotetrazine (e.g., temozolomide).

[0167] Platinum coordination complexes that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, saxaplatin, or triplatintetranitrate.

[0168] Cytotoxic agents that can be used in combination with the compounds of the present invention as anticancer drugs can be, for example, antimetabolites, including folic acid analog antimetabolites (e.g., aminopterin, methotrexate, pemetrexed or raltitrexed), purine analog antimetabolites (e.g., cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin or 6-thioguanine) and pyrimidine analog antimetabolites (e.g., cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), fluorouracil, gemcitabine, enoxabin or sapattabine).

[0169] Antimitotic agents that can be combined with the compounds of the present invention for use as anticancer drugs can be, for example, taxanes (e.g., docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel) or albumin-bound paclitaxel (e.g., abraxane). ® Vinca alkaloids (e.g., vincristine, vinblastine, vinflunine, vindesin, or vinorelbine), epothilones (e.g., epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or epothilone B analogues (e.g., ixaprone / azaepothilone B).

[0170] Antitumor antibiotics that can be combined with the compounds of the present invention as anticancer drugs can be, for example, anthracyclines (e.g., arubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, pentorubicin or zorubicin), anthraquinones (e.g., mitoxantrone or pinoxantrone), or antitumor antibiotics isolated from Streptomyces (e.g., actinomycins (including actinomycin D), bleomycin, mitomycin (including mitomycin C) or plicamycin).

[0171] Tyrosine kinase inhibitors that can be combined with the compounds of the present invention as anticancer drugs may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib, or vemurafenib.

[0172] The topoisomerase inhibitors that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin, beloteccan, rubitecan, or lamellarin D) or topoisomerase II inhibitors (e.g., acridine, etoposide, etoposide phosphate, teniposide, or doxorubicin).

[0173] PARP inhibitors that can be used as anticancer drugs in combination with the compounds of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP 9722, MK 4827, E7016 or 3-aminobenzamide.

[0174] EGFR inhibitors / antagonists that can be used in combination with the compounds of the present invention as anticancer drugs may be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, poziotinib, ABT-414, AV-412, PD 153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.

[0175] Other anticancer drugs can also be used in combination with the compounds of this invention. Anticancer drugs may include biological or chemical molecules such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, acridine, bexarotene, estradiol, irofulven, trabectedin, cetuximab, panitumumab, tosimomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, avozid, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, and porfimer. sodium), tarapofen, temopofen, vertepofen, retinoic acid, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmoflu, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, londamine, lucanthone, masrophenol The following drugs are listed: oprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omaxetine, stitimagene, ceradenovec, tegafur, testosterone, thiazoflurin, tipifarnib, vorinostat, iniparib, or copanlisib.

[0176] Biologics targeting tumor markers / factors / cytokines in cancer or proliferative diseases, such as antibodies, antibody fragments, antibody constructs (e.g., single-chain constructs), and / or modified antibodies (e.g., antibodies with CDR transplantation, humanized antibodies, "fully human" antibodies, etc.), may also be used in co-treatments with the compounds of this invention. Examples of such biomolecules are anti-HER2 antibodies (e.g., trastuzumab, Herceptin). ® Anti-CD20 antibodies (such as rituximab, Rituxan) ® MabThera ® Reditux ®Anti-CD19 / CD3 constructs (see, for example, EP1071752) and anti-TNF antibodies (see, for example, Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328). Additional antibodies, antibody fragments, antibody constructs, and / or modified antibodies used in conjunction with the compounds of the present invention for co-treatment methods can be found, for example, Taylor PC. Curr Opin Pharmacol , 2003, 3(3): 323-328; or RoxanaA, Maedica , 2006, 1(1): 63-65.

[0177] Anticancer agents that can be used in combination with the compounds of the present invention may be, in particular, immuno-oncology therapeutics targeting any one of CTLA-4, PD-1, PD-L1, TIM3, LAG3, OX40, CSF1R, IDO, or CD40 (e.g., antibodies (e.g., monoclonal or polyclonal antibodies), antibody fragments, antibody constructs (e.g., single-chain constructs), or modified antibodies (e.g., CDR-transplanted antibodies, humanized antibodies, or “fully human” antibodies). Such immuno-oncology therapeutics include, for example, anti-CTLA-4 antibodies (particularly antagonistic or pathway-blocking anti-CTLA-4 antibodies; e.g., ipilimumab or trimemumab), and anti-PD-1 antibodies (particularly antagonistic or pathway-blocking anti-PD-1 antibodies; e.g., nivolumab (BMS-936558), pembrolizumab (MK-3475), pildizumab (CT-011), AMP-224, or APE02058). Anti-PD-L1 antibodies (especially pathway-blocking anti-PD-L1 antibodies; such as BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, or MEDI6469), anti-TIM3 antibodies (especially pathway-blocking anti-TIM3 antibodies), anti-LAG3 antibodies (especially antagonistic or pathway-blocking anti-LAG3 antibodies; such as BMS-986016, IMP701, or IMP731), anti-OX40 antibodies (especially agonistic anti-OX40 antibodies; such as MEDI0562), anti-CSF1R antibodies (especially pathway-blocking anti-CSF1R antibodies; such as IMC-CS4 or RG7155), anti-IDO antibodies (especially pathway-blocking anti-IDO antibodies), or anti-CD40 antibodies (especially agonistic anti-CD40 antibodies; such as CP-870, 893, or Chi Lob 7 / 4). Furthermore, immuno-oncology therapeutic agents are well-known in the art and described in references such as Kyi C et al. FEBS Lett , 2014, 588(2): 368-76; Intlekofer AM et al., J Leukoc Biol, 2013, 94(1): 25-39; Callahan MK et al., J Leukoc Biol , 2013, 94(1): 41-53; NgiowSF et al., Cancer Res , 2011, 71(21): 6567-71; and Blattman JN et al., Science , 2004, 305(5681): 200-5.

[0178] The combinations described above can be conveniently used in the form of pharmaceutical formulations. The individual components of such combinations can be administered sequentially or simultaneously / concomitantly in pharmaceutical formulations, either alone or in combination, by any convenient route. When administered sequentially, the compounds of the present invention (i.e., compounds comprising a portion of formula (I), compounds of formula (II), or pharmaceutically acceptable salts thereof) or additional therapeutic agents can be administered first. When administered simultaneously, the combinations can be administered in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it should be understood that the two or more compounds must be stable and compatible with each other and with the other components of the formulation. When formulated individually, they can be provided in any convenient formulation.

[0179] The present invention also relates to a method of treating cancer in an individual as described herein, the method comprising administering a compound comprising a portion of formula (I) or a compound of formula (II), or a pharmaceutical composition comprising a portion of formula (I) or a compound of formula (II). Administration is preferably as described herein.

[0180] The present invention also relates to the use of a compound comprising a portion of formula (I) or a compound of formula (II), or a pharmaceutical composition comprising a portion comprising formula (I) or a compound of formula (II), in the preparation of an anticancer medicament, as described herein.

[0181] According to the present invention, the individual or patient to be treated can be an animal (e.g., a non-human animal). Preferably, the individual / patient is a mammal. More preferably, the individual / patient is a human (e.g., male or female) or a non-human mammal (e.g., guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig). Most preferably, according to the present invention, the individual / patient to be treated is a human.

[0182] As used herein, the term “treatment” for a disorder or disease is well known in the art. “Treatment” for a disorder or disease means that the disorder or disease is suspected or has been diagnosed in a patient / individual. Patients / individuals suspected of having a disorder or disease typically exhibit specific clinical and / or pathological symptoms that can be readily attributed by a technician to a specific pathological condition (i.e., a diagnosis of disorder or disease).

[0183] "Treatment" of a disorder or disease can, for example, result in the cessation of the progression of the disorder or disease (e.g., no worsening of symptoms) or a delay in the progression of the disorder or disease (in cases where the cessation of progression is only temporary). "Treatment" of a disorder or disease can also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) in an individual / patient suffering from the disorder or disease. Therefore, "treatment" of a disorder or disease can also refer to an improvement in the disorder or disease, which can, for example, result in the cessation of the progression of the disorder or disease or a delay in its progression. Such partial or complete responses may be followed by relapse. It should be understood that an individual / patient can experience a broad response to treatment (e.g., the exemplary response described above). Treatment of a disorder or disease can, in particular, include curative treatment (preferably resulting in a complete response and ultimately curing the disorder or disease) or palliative treatment (including symptom relief).

[0184] As used herein, the term "prevention" of a disorder or disease is well known in the art. For example, patients / individuals suspected of being susceptible to a disorder or disease may particularly benefit from prevention of the disorder or disease. Individuals / patients may have a susceptibility or predisposition to a disorder or disease, including but not limited to a genetic predisposition. Such a predisposition can be determined by standard methods or assays, using, for example, genetic markers or phenotypic indicators. It should be understood that the disorder or disease to be prevented according to the present invention has not yet been diagnosed or cannot be diagnosed in the patient / individual (e.g., the patient / individual does not exhibit any clinical or pathological symptoms). Therefore, the term "prevention" includes the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and / or pathological symptoms, or prior to a diagnosis or determination by a physician.

[0185] As used herein, the term "treatment or prevention" preferably refers to "treatment". Therefore, different grammatical forms of the same term, i.e., "treatment or prevention" as used herein, preferably refer to "treatment".

[0186] The compounds of the present invention, such as those comprising a portion of formula (I) or formula (II), also exhibit antibacterial properties. Therefore, in another embodiment, the present invention relates to a compound comprising a portion of formula (I) or formula (II), or a pharmaceutical composition comprising a compound comprising a portion of formula (I) or formula (II) for the treatment or prevention of bacterial infectious diseases, and relates to the use of a compound comprising a portion of formula (I) or formula (II) as an antibacterial agent, preferably wherein such use is cosmetic and / or non-therapeutic.

[0187] The present invention will now be described with reference to the following embodiments, which are illustrative only and should not be construed as limiting the scope of the invention.

[0188] Example

[0189] If only hydrophobic cyclic and acyclic building blocks are used, the development of amphiphilic β-heteromeric oligomers starting from cyclic and acyclic building blocks with different secondary structure tendencies inevitably results in hydrophobic structures. These hydrophobic β-heteromeric oligomers can be conjugated with hydrophobic elements to form amphiphilic water-soluble molecules. Simultaneously, the tendency for self-association and interaction with other amphiphilic molecules / systems increases. The hydrophilic elements can have different chemical properties and can carry polar or basic groups, preferably polar neutral groups and basic groups. Scheme 2 provides an example of an amphiphilic, isochiral β-heteromeric oligomer based on cyclic and acyclic building blocks.

[0190] Option 2

[0191]

[0192] synthesis

[0193] The β-peptides in Schemes 2 and 3 consist of commercially available cyclic and acyclic building blocks. They were assembled via solid-phase synthesis using Fmoc Chemistry and standard protocols. The peptide in Scheme 2 was prepared in-house. Peptide 1aR and its analogues reported in Scheme 3 (1aR-iBu3, 1aR-Me3, (CF3)5, 1aR-Me3, (CF3)8, 1aR-Me3,5, 1aR-Me6,8, and 1aR-mix1-3) were resynthesized and synthesized at GenicBio (China), respectively, provided with trifluoroacetic acid or chloride peptide salts of at least 95% purity. The materials and methods for in-house synthesis are described below. Fmoc-L-β 3 -valine-OH, Fmoc-L-β 3 -Leucine-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-Rink-amide-MBHA resin, N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), Et2O, N,N-diisopropylethylamine (DIPEA), and piperidine were purchased from Iris Biotech GmbH (Germany). Fmoc-β-alanine-OH and N,N'-diisopropylcarbodiimide (DIC) were purchased from Novabiochem-Merck Millipore (Germany). trans-(1s, 2s)-ACPC-OH was purchased from Chem-Impex International (USA). 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBt) were purchased from Biosolve (The Netherlands). 1,2-Ethylenedithiol (EDT), anisole sulfide (TIA), and 5,6-carboxyfluorescein (FAM) were purchased from Fluka (Germany). Trifluoroacetic acid (TFA) for HPLC was purchased from Alfa Aesar (Thermo Fisher Scientific, Germany). Triisopropylsilane (TIS), acetic anhydride, acetonitrile, MeOH, and N,N-dimethylformamide (DMF) for HPLC (ACN) were purchased from Sigma-Aldrich (Merck, Germany). D2O and deuterated solvents were purchased from Armar GmbH (Germany).

[0194] Solid-phase peptide synthesis of 1b, 1_ALA, and 1a was performed manually. Fmoc-Rink-amide-MBHA resin was swelled in 500 μL DMF / NMP (80:20 v / v) for 30 min, then the solvent was removed. The Fmoc-protecting group was cleaved by adding 500 μL of 40% piperidine to DMF / NMP (80:20 v / v), shaking for 3 min, and removing the solution. Then, 500 μL of 20% piperidine to DMF / NMP (80:20 v / v) was added, shaking for 12 min, and the solution was removed. The resin was washed five times with DMF. For dual coupling, each Fmoc-amino acid (3 equivalents for β-amino acids, 5 equivalents for α-amino acids) was dissolved in DMF / NMP (80:20 v / v) containing 3 or 5 equivalents of HOBt, added to the resin, followed by 2.8 or 4.8 equivalents of HBTU and 6 or 10 equivalents of DIPEA, and the suspension was shaken for 1 hour. The reaction mixture was aspirated, and the resin was washed with DMF. The coupling process was repeated. At the end of chain elongation, acetylation was performed in 600 μL of DMF / NMP (80:20 v / v) using 10 equivalents of DIPEA and 10 equivalents of acetic anhydride. For FAM labeling, the N-terminus of the resin-bound peptide was acylated for 45 minutes with 5 equivalents of FAM in the presence of HOBt / DIC (5 equivalents each). The acylation process was repeated, followed by treatment with 20% piperidine in DMF (2 × 30 minutes). Finally, the resin was washed five times each with DMF, DCM, and Et2O. For cleavage, 800 μL of a TIS / EDT / TIA / H2O / TFA (3:3:3:1:90 v / v) mixture was added to the peptide-resin, and the suspension was shaken for 3.5 h. The resin was removed by filtration, and then ice-cold Et2O was added to the filtrate to precipitate the peptide. After 10 min at -20 °C, the suspension was centrifuged at 8 °C for 5 min, and then the ether was removed by decantation. The washing and centrifugation steps with ice-cold ether were repeated three times. The precipitate was dried under a nitrogen stream. The homogeneity (85-90%) and identity of the peptides were confirmed by reversed-phase HPLC (Thermo Fisher Scientific Dionex, UltiMate 3000, using a Syncoris C18 column, 100 Å, 5 μm, 250 × 4.6 mm) and MALDI-TOF-MS (Bruker Daltonics, Autoflex Speed) using α-cyano-4-hydroxycinnamic acid as a matrix (Table 1).

[0195] Table 1. Analysis and characterization of internally synthesized peptides.

[0196]

[0197] NMR spectroscopy

[0198] Equipped with QXI ( 1 H / 13 C / 15 N / 31 NMR spectra were recorded on a Bruker (Germany) AVANCE III HD 600MHz spectrometer with a P probe. NMR peptide samples (1.1–1.8 mM, 500 μL in water containing 7% D₂O) were determined at 298 K in standard 5-mm TA tubes (Armar, Germany). Bruker standard samples were used with 2 mM sucrose and 0.5 mM DSS (4,4-dimethyl-4-silylpentane-1-sulfonic acid). 1 H-calibrate the spectrum. Indirect calibration is performed using the recommended scaling factor of 0.25144953. 13 C frequency. The following 2D NMR experiments were performed: 1 H- 1 H TOCSY (4 scans, 1024x256 complex points, 12ms and 120ms mixing time, 8.33 ppm F1 spectral width, 1s cycle delay); 1 H- 1 H ROESY (80 scans, 1024x350 complex points, 200 ms mixing time, 8.33 ppm F1 spectral width, 1.2 s cycle delay); 1 H- 13 C HSQC (128 scans, 512x128 complex points, 77 ppm F1 spectral width, 1.5s cycle delay); 1 H- 13 C HSQCaro (128 scans, 512x50 complex points, 44.2 ppm F1 width, 1.5s cycle delay); 1 H- 13 CHMBC (80 scans, 1024x128 complex points, 222.4 ppm F1 width, 2s cycle delay); 1 H- 13 C HSQC-TOCSY (80 scans, 1024x128 complex points, 55.2 ppm F1 width, 2 s cycle delay). NMR data were processed using Bruker Top Spin version 3.6.1. NMR data were analyzed and assigned using TopSpin and Sparky (TD Goddard and DG Kneller, SPARKY3; University of California, San Francisco) (Table 2-11).

[0199] Table 2. 1b in water13 C belongs to.

[0200]

[0201] Table 3. 1b in water 1 H NMR attribution.

[0202]

[0203] Table 4. 1-ALA in water 13 C NMR attribution.

[0204]

[0205] Table 5. 1-ALA in water 1 H NMR attribution.

[0206]

[0207] Table 6. 1a in water 13 C NMR attribution.

[0208]

[0209] Table 7. 1a in water 1 H NMR attribution.

[0210]

[0211] Table 8. Continuous and short-range NOE cross peaks of 1b in water.

[0212]

[0213] Table 9. Continuous NOE cross peaks of 1-ALA in water.

[0214]

[0215] Table 10. Continuous NOE cross peaks of 1a in water.

[0216]

[0217] Table 11. 1-ALA (1.1 mM, in water) at 25 °C 3 J HNHβ Coupling constant, temperature coefficient, and amide proton chemical shift. Estimated values ​​affected by overlapping peaks

[0218]

[0219] CD spectrum

[0220] Circular dichroism (CD) measurements were recorded at 23°C using a Chirascan-plus CD spectrometer (Applied Photophysics, UK) with a 1 mm quartz cell (Hellma Analytics, Germany). Peptides were dissolved in water, TFE (2,2,2-trifluoroethanol, Iris Biotech GmbH), MeOH, ACN, and 10 mM phosphate buffer (pH 7.3), containing or without POPC (1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine, Sigma-Aldrich) vesicles. The latter was prepared as follows: dried POPC was suspended in phosphate buffer and incubated at room temperature for 1 hour, followed by vigorous vortexing to obtain a homogeneous, milky POPC suspension. The suspension was then sonicated until its appearance changed from milky to almost transparent (maximum sonication time 30 minutes). The peptide concentration was determined spectrophotometrically using a Cary 60 UV-Vis spectrophotometer (Agilent Technologies, Germany), with Tyr showing UV absorbance at approximately 280 nm and a molar extinction coefficient of 1480 M. -1 cm -1 (H.Mach, CR. Middaugh, RV. Lewis, Anal Biochem 1992, 200, 74-80). Peptide concentrations were as follows: 1b: 0.19 mM aqueous solution, 0.12 mM methanol solution; 1_ALA: 0.23 mM aqueous solution, 0.14 mM methanol solution; 1a: 0.39 mM aqueous solution, 0.34 mM methanol solution. For each CD spectrum, three scans were performed using a 1 nm step resolution, a 1 nm bandwidth, and a time-per-point interval of 1 s. The CD spectrum after subtracting the solvent was differentially spectrally normalized to represent the ellipticity, and the average molar ellipticity of residues was divided by 10. 3 And represented as [θ] in the diagram. R x 10 -3 (deg cm 2 dmol -1 ).

[0221] Secondary structure

[0222] The secondary structure of the β-peptide in Scheme 2 in water and methanol was studied using CD spectroscopy. Figure 1Two β-peptides with a cyclic-acyclic arrangement showed a maximum at 223 nm, a minimum at 204 nm, and zero crossover at 215 nm. The min. / max. ratio of the shorter β-peptide 1b was 4.6, and that of the longer β-peptide 1_ALA was 7.6. The CD signal was L-12 (=2.5). 12 The image of the CD signal of the helical structure shows that cyclic building blocks are preferred over non-cyclic building blocks, and the preferred secondary structure of 1b and 1_ALA is mainly right-handed 12 (=2.5). 12 -- Helical. The β-peptide with an acyclic-cyclic-acyclic arrangement (1a) shows a maximum at 222 nm, a minimum at 204 nm, and a zero crossover at 214 nm. The min. / max. ratio is 3.5. Compared to the CD spectra of 1b and 1_ALA, the maximum value and therefore the zero crossover of 1a are shifted to shorter wavelengths. This is due to the observed shorter and therefore less stable 12 (=2.5). 12 The displacement of the helix towards shorter wavelengths is assumed by 1a to be less certain or more distorted, resulting in 12 (=2.5). 12 )-helix. However, other secondary structures cannot be ruled out, as β-helical structures have been reported. 2 -amino acids and β 3β-peptides composed of amino acid mixtures can form 10 / 12-helices, and the CD feature shows a maximum width at 205 nm (D. Seebach, S. Abele, K. Gademann, G. Guichard, T. Hintermann, B. Jaun, JL Matthews and JV Schreiber, Helv Chim Acta, 1998, 81, 932-982; D. Seebach, JV Schreiber, S. Abele, X. Daura and WF van Gunsteren, Helv Chim Acta, 2000, 83, 34-57). Furthermore, short oligomers of trans-ACBC have been reported to tend to adopt an 8-helix (E. Gorrea, G. Pohl, P. Nolis, S. Celis, KK Burusco, V. Branchadell, A. Perczel, and RM Ortuno, J OrgChem, 2012, 77, 9795-9806; E. Torres, E. Gorrea, E. Da Silva, P. Nolis, V. Branchadell, and RM Ortuno, Org Lett, 2009, 1, 2301-2304). In water, the CD spectra of the β-peptides show curves similar to those in methanol, but with lower intensity. Similarly, the CD spectrum of 1a differs from that of 1b and 1_ALA (a left shift, as already observed in methanol). It is believed that the β-peptides are less structured in water than in methanol. This suggests that these peptides adopt a more defined structure in less polar environments (e.g., within cell membranes).

[0223] Therefore, β-peptides with cyclic-acyclic arrangements (Examples 1b and 1_ALA) tend to adopt a dextrorotatory 12 (=2.5) moiety. 12 β-helices. Particularly preferred in low-polarity environments. β-peptides with an acyclic-cyclic-acyclic arrangement (examples 1a and 1aR) tend to adopt a dextrorotatory 12 (=2.5) helix. 12 The secondary structures are more uncertain and may be twisted and / or in equilibrium with other secondary structures (due to the weak negative circular dichroism signal below 218 nm, it is speculated that they may be in dynamic equilibrium with right-handed 10 / 12-helices). The formation of these secondary structures is particularly favorable in environments with lower polarity.

[0224] Cell Research

[0225] The following materials were used in the cell studies described in this article: ethanol (VWR, Austria), Hoechst 33342 (Fluka), annexin V-APC (Immunotools), and Lumit. TM uman IL-1β immunoassay (Promega), CellTiter-Glo ® 3D (Promega), LDH-Cytox TM Lactate dehydrogenase (LDH) Assay Kit (Biolegend), ROS, 20% triton-X, doxorubicin (Selleckchem), formaldehyde (Merck), glutaraldehyde (Fisher Scientific), citrate (Merck), hexacyanoferrate (Merck), magnesium chloride (Merck), sodium chloride (Merck), X-gal (Invitrogen), FLICA 660 Caspase-1 Assay Kit ® (Biorad), MTT (3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide), RNase, Accutase ® Solution, propidium iodide, fetal bovine serum, penicillin-streptomycin and L-glutamate were purchased from Sigma-Aldrich (Austria).

[0226] Dulbecco's modified Eagle's medium (DMEM) – high glucose and Roswell Park Memorial Institute (RPMI) 1640 medium and 1X Dulbecco phosphate-buffered saline (DPBS) were purchased from Szabo-Scandic (Austria). DMSO (dimethyl sulfoxide) was purchased from VWR (Austria). Primary human lung fibroblasts were donated by Dr. Jutta Horejs-Höck, University of Salzburg, Austria. The MCF-7 cell line was donated by Dr. Barbara Krammer, University of Salzburg, Austria. The HT1975, A427, and SKLU-1 cell lines were donated by Dr. Emilio Casanova, Medical University of Vienna, Austria. A549 (ATCC: CLL-185), H460 (ATCC: HTB-177), H520 (ATCC: HTB-182), and HCC827 (ATCC: CRL-2868) cell lines were purchased from ATCC. The platinum-resistant A549 (ddA549) cell line was purchased from Szabo Scandic. (MitoView) TM720 and MemBrite TM Fix660 / 680 were purchased from Biotium, and dihydrorhodamine 123 (DHR 123) was purchased from Sigma.

[0227] Cell culture

[0228] Primary human lung fibroblasts and the MCF-7 cell line were cultured in DMEM-high glucose medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, and 1% L-glutamate. All other cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, and 1% L-glutamate. Cells were grown in a humidified incubator at 37°C and 5% CO2. Cells at 80% confluence were used in all experiments.

[0229] Vitality Measurement

[0230] Cells in complete growth medium (1×10 4 Cells were seeded per well in 96-well plates. The following day, the culture medium was replaced with serum-free medium containing different concentrations of peptides. After incubation for 24 hours, 10 μL of MTT solution (5 mg / mL in DPBS) was added to both the treated and untreated control groups, and the cells were incubated at 37°C in the dark for 2 hours to determine cell viability. The culture medium was then aspirated, and the cells were lysed with 100 μL of DMSO. The absorbance of the formazan product obtained in viable cells was measured at 550 nm using a GloMax® multi-functional microplate reader. At least three independent experiments were performed (each sample was repeated three times), and cell viability was normalized to the untreated control group.

[0231] Cellular uptake and colocalization of peptide 1aR

[0232] Cells (3×10) 4Cells were cultured overnight in 8-well chamber µ-slides (Ibidi). The next day, the medium was replaced with serum- and phenol red-free medium (control group) or 5 µM FAM-1aR. Cell membranes were stained with MemBrite™ Fix 660 / 680 (Biotium), and nuclei were stained with 1 μg / mL Hoechst 33342 (Fluka). For mitochondrial colocalization analysis, 100 nM MitoView™ 720 (Biotium) was added and incubated at 37°C for 15 min. Colocalization imaging was performed using an Olympus IX73 inverted microscope, while live-cell imaging was performed using an LSM 700 laser scanning confocal microscope from Carl Zeiss. The FITC channel was used for FAM-1aR (excitation = 494 nm, emission = 518 nm), and the CY7 channel was used for MitoView. TM 720 (excitation = 550 nm, emission = 565 nm), MemBrite TM Fix 660 / 680 (excitation = 663 nm, emission = 682 nm), while the DAPI channel is used for Hoechst33342 (excitation = 345 nm, emission = 455 nm).

[0233] lactate dehydrogenase release assay

[0234] Cells in complete growth medium (1×10 4 Cells (peptide / well) were seeded into 96-well plates. The following day, the medium was replaced with serum-free medium containing 20 μM 1aR. After incubation for 1 hour, 2 hours, 4 hours, and 24 hours, the plates were centrifuged at 300 rpm for 5 minutes to remove any cell debris from the supernatant. Subsequently, 50 μL of the supernatant was transferred to a new 96-well plate, and 50 μL of LDH working solution was added. The plates were incubated at room temperature in the dark for 30 minutes. 25 μL of stop solution was added to terminate the reaction, and the absorbance of LDH released by the cells was measured at 490 nm using a GloMax® multi-functional microplate reader. At least three independent experiments were performed (each sample was repeated three times). Cytotoxicity was calculated using the following formula: Cytotoxicity (%) = ((peptide - low control) / (high control - low control)) 100

[0235] Propidium iodide (PI) staining is used to observe peptide-induced cell membrane damage.

[0236] Cells (3×10) 4Cells were cultured overnight in 8-well chamber slides (Ibidi). The next day, the medium was replaced with serum-free medium (control group) or 10 μM 1aR. Cells were incubated for 1 hour and 24 hours, respectively, followed by staining with propidium iodide (PI) and Hoechst 33342 for 10 minutes. After washing twice with DPBS, fluorescence images were acquired using an Olympus IX73 inverted microscope. The CY3 channel was used for PI staining (excitation = 550 nm, emission = 565 nm), and the DAPI channel was used for the nuclear marker Hoechst 33342 (excitation = 345 nm, emission = 455 nm).

[0237] Annexin V / PI assay

[0238] Cells in complete growth medium (1×10 5 Cells were seeded (number per well) in 12-well plates. The following day, the medium was replaced with serum-free medium containing different concentrations of peptides. After incubation for 1 hour and 24 hours, the supernatant was collected and transferred to 2 mL Eppendorf tubes. Cells were digested with 500 μL Accutase® solution, added to the corresponding supernatant, and then the suspension was centrifuged at 1500 rpm for 5 minutes. After removing the supernatant, the cell pellet was washed twice with 1 mL DPBS and resuspended in 98.5 µL of 1× Annexin V buffer containing 1 µL annexin V-APC and 0.5 µL 1 mg / mL PI. After incubation at room temperature in the dark for 15 minutes, 200 μL of 1× Annexin V buffer was added, followed by analysis using a CytoFLEX flow cytometer. At least three independent experiments were analyzed using Kaluza 1.5a flow cytometry software (Beckman Coulter).

[0239] Cell cycle analysis

[0240] Cells in complete growth medium (5 × 10⁻⁶) 5Cells were seeded (number per well) in 35 mm cell culture dishes. The following day, the culture medium was replaced with serum-free medium containing different concentrations of peptides. After incubation for another 24 hours, the supernatant was collected and transferred to 2 mL Eppendorf tubes. Cells were digested with 500 μL of Accutase® solution, added to the corresponding supernatant, and the suspension was centrifuged at 1500 rpm for 5 minutes. After removing the supernatant, the cell pellet was resuspended in 200 μL of DPBS. For fixation, 2 mL of ice-cold 70% ethanol was added to the suspension with gentle stirring. After freezing at -20 °C for at least 1 hour, the cell suspension was centrifuged at 1500 rpm for 5 minutes and washed twice with 2 mL of DPBS. The cells were then stained with a solution of 25 μL 0.4 mg / mL PI, 25 μL 1 mg / mL RNase, and 450 μL DPBS. After incubation at 37°C in the dark for 15 minutes, the fluorescence of DNA-bound PI was measured using a CytoFLEX flow cytometer. Cell cycle data from at least three independent experiments were analyzed using Kaluza 1.5a flow cytometry software (Beckman Coulter).

[0241] Determination of dihydrorhodamine 123 (DHR 123)

[0242] Cells in complete growth medium (1×10 4 Cells were seeded at 10 μM / well in 96-well plates. The following day, the medium was replaced with serum-free medium, and the cells were stained with 10 μM DHR 123 for 30 minutes. After treatment with 10 µM 1aR, ROS induction levels were measured using a GloMax® multi-functional microplate reader.

[0243] Caspase-1 assay

[0244] Cells in complete growth medium (1x10) 5Cells (number per well) were seeded in 12-well plates. The following day, the medium was replaced with serum-free medium containing different concentrations of peptides. After incubation for 1 hour, 4 hours, and 24 hours, the supernatant was collected and transferred to 2 mL Eppendorf tubes. Cells were digested with 500 μL of Accutase® solution and added to the corresponding supernatant. The suspension was then centrifuged at 1500 rpm for 5 minutes. After removing the supernatant, the cell pellet was stained with 1.6 μL of FLICA working solution (in 98.4 μL of medium). After incubation at 37°C in the dark for 20 minutes, 0.5 μL of 1 mg / mL PI was added, followed by an additional 10 minutes of incubation. Cells were washed twice with 2 mL of FLICA washing buffer and then resuspended in 300 μL of FLICA washing buffer for analysis using a CytoFLEX flow cytometer. At least three independent experiments were analyzed using Kaluza 1.5a flow cytometry software (BeckmanCoulter).

[0245] IL1-β assay

[0246] Cells in complete growth medium (1x10) 4 (Number of cells / well) were inoculated into 96-well plates. The following day, the medium was replaced with serum-free medium containing 10 μM IL-1β and treated for 24 hours. IL-1β release was measured according to the manufacturer's protocol. At least three independent experiments were analyzed.

[0247] Scanning electron microscope

[0248] Cells were fixed in 2.5% glutaraldehyde in 0.1 M PBS for 30 minutes. Subsequently, the cells were washed three times in 0.1 M PBS for 10 minutes each time. The samples were dehydrated in a series of fractionated ethanol solutions. After being placed in 100% ethanol, the cells were dried using a critical point desiccator (EM-CPD300, Leica microscopy system), followed by 5 nm platinum coating using a sputter coater (EM-ACE600, Leica microscopy system). Finally, coverslips containing dried cells were imaged using a scanning electron microscope (FE-SEM Merlin compact VP, Carl Zeiss) at 5 kV with a secondary electron detector.

[0249] spherical formation

[0250] 1x10 4Cells were seeded in BIOFLOAT FLEX (faCellitate) coated, TC-free U-bottom 96-well plates. The plates were then centrifuged at 1500 rpm for 5 minutes to encourage cell aggregation in the center of the wells, promoting globule formation. After 4 days of incubation, the globules were treated with escalating concentrations of the compound in FCS-free medium. Cell viability was measured using the CellTiter-Glo® 3D Cell Viability Assay (Promega) 48 hours later, and the globules were transferred to opaque white 96-well plates according to the manufacturer's protocol.

[0251] Age-induced

[0252] Human lung adenocarcinoma cells A549 were treated at a rate of 1x10⁻⁶. 5 Cells were seeded at a concentration of 0.1 µg / mL in senescence-inducing flasks in fully replenished RPMI 1640 containing 0.1 µg / mL doxorubicin. The RPMI 1640 medium containing 0.1 µg / mL doxorubicin was replaced every 48 hours until the cells reached 60% confluence.

[0253] Assay of aging-related β-galactosidase activity

[0254] A549 cells were cultured at a concentration of 1.25 x 10⁻⁶. 5 Cells were seeded at a concentration of [missing value] mL in 6-well plates and incubated at 37°C for 18 hours. Subsequently, cells were washed with PBS and fixed at room temperature (2% formaldehyde and 0.25% glutaraldehyde) for 2 minutes. After a second wash with PBS, cells were incubated with freshly prepared staining solution (40 mM citric acid, 5 mM hexacyanoferrate, 2 mM magnesium chloride, 150 mM sodium chloride, and 1 mg / mL X-gal (5-bromo-4-chloro-3-indolyl-β-galactopyranoside), pH 6.0) at 37°C in the dark for 18 hours. Afterward, the staining solution was aspirated, cells were washed with PBS, incubated in methanol for 1 minute, and then observed under an inverted bright-field microscope.

[0255] Cytotoxicity

[0256] The β-peptides in Protocol 2 were tested in cancer cell lines. β-peptides with acyclic-cyclic-acyclic arrangements (1a and 1aR) exhibited a variety of biological effects, with 1aR being more effective than 1a. In contrast, β-peptides with cyclic-acyclic arrangements (1b and 1_ALA) showed only weak cytotoxic effects (Table 12).

[0257] Since these two groups of β-peptides contain the same building blocks but with different arrangements, it is reasonable to hypothesize that the biological effects of compounds 1a and 1aR are attributed to the unique secondary structure characteristics of the hydrophobic β-peptide moiety. Therefore, the two groups of β-peptides exhibit different CD characteristics. Furthermore, the amphiphilicity of the individual β-peptides 1a and 1aR cannot explain their effects, as the inactive β-peptides 1b and 1_ALA are also amphiphilic.

[0258] Table 12. Cytotoxicity of β-peptides, as determined by MTT assay after incubation with different concentrations of β-peptides for 24 hours (nr, not reached).

[0259]

[0260] Other cell research

[0261] The highly efficient and specific anticancer properties of peptide 1aR of the present invention have been demonstrated as follows.

[0262] The effects of this peptide on the viability of various human cancer cell lines were analyzed using MTT assay and annexin V / PI staining. The IC50 values ​​of various human lung cancer cell lines after 24 hours of peptide treatment were also analyzed. 50 The IC50 value was higher than that of the healthy lung fibroblast cell line MRC-5 and the healthy human bronchial epithelial cell line BEAS-2B. 50 The value is 3.5 to 12 times lower. The corresponding IC... 50 The values ​​are summarized in Table 13.

[0263] Table 13. Effect of 1aR on the viability of human cell lines after 24 hours of 1aR treatment. 50 The values ​​were calculated using GraphPadPrism 6 software based on at least three independent experiments.

[0264]

[0265] To further determine its effect on cell death, annexin V / propidium iodide (PI) staining was performed. After treatment with 20 µM1aR, 94.02% (lung adenocarcinoma A549) and 91.43% (with EGFR mutation) showed positive results. Cell death occurred in 92.12% of lung adenocarcinoma (HCC827) and lung squamous cell carcinoma (SCC) (H520) cells (percentage of cells not double-negative for Annexin V and PI). In contrast, untreated control cultures contained only 4.56–26.09% dead cells. Furthermore, the healthy lung fibroblast cell line MRC-5 was largely insensitive to the treatment, showing only 8.15% cell death induced compared to untreated cells. Figure 2A). Interestingly, 63.46% of the cells died within one hour of treatment, and most of these dead cells were double-positive for annexin V and PI. Figure 2 B). This indicates that the induced cell death pattern is not apoptosis, but rather necrosis or pyroptosis.

[0266] Peptide 1aR exhibits good cell permeability, as confirmed by intracellular uptake experiments of a fluorescently labeled analog of 5,6-carboxyfluorescein (FAM-1aR) carrying an N-terminal acetyl group, demonstrating its uniform distribution within the mitochondrial network. Figure 3 As shown, in A549 cells, the green fluorescence of FAM-1aR overlapped with the red fluorescence of the mitochondrial probe MitoView™ 720. Furthermore, peptide uptake was energy-independent, as peptide accumulation was observed intracellularly after incubation at both 37°C and 4°C. Figure 4 The specificity of 1aR for cancer cells does not appear to be due to its low uptake. Figure 5 Furthermore, 1aR induces significant morphological changes in cancer cell lines. Cells become swollen and exhibit prominent large vesicles emerging from the plasma membrane, a characteristic feature of pyroptosis. Figure 6 , 14 And 15). In contrast, the healthy lung fibroblast cell line MRC-5 did not undergo morphological changes ( Figure 6 ).

[0267] Peptide 1aR can also induce pyroptosis. Pyroptosis is a gasdermin (GSDM)-mediated programmed cell death process. GSDM family members (GSDMA-E) can be cleaved by inflammatory caspases (caspase-1, -4, -5, and -11) and apoptosis-associated caspases (caspase-3, -6, -7, and -8). After cleavage, the N-terminal domain (GSDM-N) executes pyroptosis by creating pores in the cell membrane, leading to characteristic morphological changes and the release of pro-inflammatory mediators such as interleukin-18 (IL-18) and interleukin-1β (IL-1β) into the extracellular environment, thereby amplifying the systemic immune response. To confirm membrane leakage, lactate dehydrogenase (LDH) assays were performed. LDH is abundant in the cytoplasm and can only be released and detected when the cell membrane is damaged. Indeed, after 1aR treatment, the LDH level in A549 cultures increased by up to 120 times compared to the untreated control group, while in the non-cancer cell line MRC-5, no increase in LDH was detected either 1 hour or 24 hours after treatment. Figure 7 These observations are consistent with PI staining results 30 minutes after treatment (10 μM 1aR) (e.g. Figure 8As shown in the image, this indicates rapid cell membrane damage, as PI can only enter the cell when cell membrane permeability increases. In MRC-5 cells, no red fluorescence was detected after either 30 minutes or 24 hours of treatment, indicating that the cell membranes remained intact. Another characteristic of pyroptosis is that the cell nucleus remains intact, even after 24 hours of treatment. Figure 3 , 6 (8, 11, 14, and 15). To further demonstrate the disruption of the cell membrane, scanning electron microscopy was performed, showing that A549 cells exhibited significant membrane perforation after 1 hour of treatment with 10 μM 1aR, while MRC-5 cells showed no changes after either 1 hour or 24 hours of treatment. Figure 9 ).

[0268] The induction of pyroptosis was further confirmed by the assay of human IL-1β and caspase-1, showing that compared with the control group and healthy MRC-5 cells, the treated A549 cells showed significant induction of active caspase-1 and IL-1β. Figure 10 ).

[0269] Cleaved GSDMD and GSDME can create pores within the mitochondrial membrane, leading to decreased permeability, dissipation of mitochondrial membrane potential, fragmentation of the mitochondrial network, and the generation of mitochondrial reactive oxygen species (ROS) (doi: 10.1073 / pnas.1414859111, https: / / doi.org / 10.1038 / s41467-019-09397-2, doi: 10.1080 / 23723556.2019.1621501). Therefore, the effects of 1aR on mitochondria were analyzed. A549 cell treatment did indeed induce mitochondrial membrane depolarization (…). Figure 11 The production of reactive oxygen species increased by approximately 18 times. Figure 12 ).

[0270] Treatment-induced senescence (TIS) is associated with tumor growth slowdown and contributes to chemotherapy resistance in cancer cells. However, while TIS is associated with tumor growth slowdown, TIS and spontaneously senescent cancer cells can reactivate their proliferative potential, leading to cancer recurrence and increased invasiveness. Therefore, improved treatments are needed, either to avoid inducing TIS or to target senescent or other chemotherapy-resistant cancer cells. Recent studies have shown that pyroptosis induction remains effective against cisplatin-resistant A549 (ddA549) cancer cells, with an IC50 concentration of [missing information]. 50 The value was 7.91 ± 0.9. Consistent with this, preliminary experiments showed that 1aR treatment resulted in approximately 80% death of senescent A549 cancer cells. Figure 13 ).

[0271] Results of other related cell experiments, such as Figure 14 –16 is shown.

[0272] Other peptide analogs of 1aR

[0273] By synthesizing the 1aR analogues reported in Scheme 3, we can explore the R of the building block "A". 1 The chemical diversity of functional groups (such as those of formulas (I) and (II)). In particular, the following R groups are selected. 1 Group substitutions for isopropyl and isobutyl in 1aR:

[0274] • Methyl (alkyl group, very low hydrophobicity and very low steric hindrance compared to isopropyl and isobutyl).

[0275] • Allyl (unbranched alkenyl group, low hydrophobicity and lower steric hindrance compared to isobutyl).

[0276] • Prolyl (unbranched alkynyl group, low hydrophobicity and lower steric hindrance compared to isobutyl).

[0277] • sec-butyl (branched alkyl group, structural isomer of isobutyl).

[0278] • n-Butyl (a non-branched alkyl group, a structural isomer of isobutyl, which is more hydrophobic than isopropyl and isobutyl).

[0279] ·2-Phenylacetyl (an aromatic group, which is more hydrophobic and has greater steric hindrance than isopropyl and isobutyl).

[0280] ·Benzyloxymethyl (an aromatic group, which is more hydrophobic and sterically hindered than isopropyl and isobutyl).

[0281] ·4-(trifluoromethyl)-benzyl (aromatic and fluorinated group, which is more hydrophobic and has greater steric hindrance than propyl and isobutyl).

[0282] As mentioned in the "Synthesis" section above, the 1aR peptide analog in Scheme 3 has been prepared at GenicBio (China) using a standard scheme based on Fmoc solid-phase chemistry.

[0283] Scheme 3. Chemical structure of 1aR peptide analog (synthesized, purified and characterized by HPLC and MS analysis at GenicBio (China).

[0284]

[0285] R in the synthesized peptide 1Group combinations, including the lead peptide 1aR, are shown below ("pos." = position) (each selected R 1 The chemical structures of the functional groups are shown in Table 14.

[0286] ·R in 1aR 1 : Isopropyl (position 3), Isobutyl (positions 5, 6, and 8).

[0287] ·R in 1aR-Me3,(CF3)8 1 : Methyl (3 position), isobutyl (5 and 6 positions), 4-(trifluoromethyl)-benzyl (8 position).

[0288] ·R in 1aR-iBu3 1 : Isobutyl (positions 3, 5, 6, and 8).

[0289] The R in 1aR-mix1 1 : Allyl (3 position); Butyl (5 position), Benzyloxymethyl (6 position), Methyl (8 position).

[0290] ·R in 1aR-mix2 1 : propargyl (3 position); butyl (5 position); benzyloxymethyl (6 position); methyl (8 position).

[0291] ·1aR-Me3, (CF3)5 in R 1 : Methyl (3 position); 4-(trifluoromethyl)-benzyl (5 position), isobutyl (6, 8 positions).

[0292] The R in 1aR-mix3 1 : Methyl (3 position), 2-phenylethyl (5 position), butyl (6 position), sec-butyl (8 position).

[0293] ·R in 1aR-Me3,5 1 : Methyl (3, 5 positions), isobutyl (6, 8 positions).

[0294] ·R in 1aR-Me6,8 1 : Isopropyl (3 position), Isobutyl (5 position), Methyl (6 and 8 positions).

[0295] Table 14. R in 1aR and its peptide analogs 1 Chemical structure of the group (“pos.” = position; “m=1” indicates the presence of cyclic residues based on cyclopentane).

[0296]

[0297] Reflecting the selected R 1 Peptides with combined functional groups have been characterized for the following properties:

[0298] IC in A549 cancer cells 50 value.

[0299] IC50 in MRC-5 cells 50 value.

[0300] These data have been based on their IC50 with the lead peptide 1aR 50 The value ratios are evaluated (Table 15).

[0301] The IC50 of novel peptides in A549 cancer cells 50 Values ​​can be categorized as follows:

[0302] • Comparable to 1aR (at most 1:2)

[0303] Slightly higher than 1aR (at most 1:4)

[0304] • Moderately higher than 1aR (up to 1:12)

[0305] • Significantly higher than 1aR (at most 1:28)

[0306] Table 15. IC50 of 1aR and its analogues on A549 cancer cells and MRC-5 cells 50 Value Comparison (IC) 50 The values ​​are also shown in Table 16.

[0307]

[0308] Importantly, all peptides (including the lead peptide 1aR) showed IC50 efficacy against A549 cancer cells. 50 The values ​​all fall within a narrow range (4-111 mM), indicating that R 1 The functional group exhibits good to excellent tolerance to chemical moieties with varying degrees of hydrophobicity and steric hindrance. However, the following points should be considered:

[0309] Overall hydrophobicity and steric hindrance of peptide chains: R 1 The balance between intergroup hydrophobicity and steric hindrance seems to be related to better IC. 50 Values ​​are related, as observed below:

[0310] • The significant reduction in the overall hydrophobicity and steric hindrance of the lead peptide 1aR and IC 50 Values ​​were categorized as significantly higher than those associated with 1aR (up to 1:28), as shown for peptides 1aR-Me3,5 and 1aR-Me6,8.

[0311] • A moderate increase in the overall hydrophobicity and steric hindrance of the lead peptide 1aR is associated with IC 50 The value is classified as being comparable to 1aR (at most 1:2), as shown in peptide 1aR-iBu3, which contains an isobutyl group at position 3 that is moderately hydrophobic and slightly sterically hindered compared to isopropyl.

[0312] Conversely, at the more lateral positions 3 and 8 of the lead peptide 1aR, the balance between the decrease / increase in hydrophobicity and steric hindrance is related to IC50. 50 The values ​​are classified as being comparable to 1aR (at most 1:2), as shown in peptide 1aR-Me3, (CF3)8.

[0313] However, the balance between decreasing / increasing hydrophobicity and steric hindrance is not entirely independent of position along the peptide chain, as shown in peptide 1aR-Me3,(CF3)5, whose IC50... 50 The value is classified as moderate to higher than 1aR (at most 1:12).

[0314] • Moderate sensitivity at position 5: The significantly increased hydrophobicity (and / or aromaticity) and steric hindrance at position 5 of the lead peptide 1aR are both related to IC50. 50 Values ​​were categorized as moderately higher than 1aR (up to 1:12), as shown for peptides 1aR-Me3, (CF3)5, and 1aR-mix3.

[0315] • Slight sensitivity at position 6: The significantly increased hydrophobicity (and / or aromaticity) and steric hindrance at position 6 of the lead peptide 1aR are both related to IC50. 50 The values ​​were categorized as slightly higher than 1aR (up to 1:4), as shown for peptides 1aR-mix1 and 1aR-mix2.

[0316] IC50 of 1aR peptide analogs in A549 and MRC-5 cell lines after treatment with peptide at concentrations up to 200 μM for 24 hours. 50 The values ​​are shown in Table 16 below.

[0317] Table 16. IC50 of 1aR peptide analogs after 24 hours of treatment with peptide at concentrations up to 200 μM in A549 and MRC-5 cell lines. 50 value

[0318]

[0319] Other peptide analogs of 1aR, wherein the Z subunit is characterized by m=0

[0320] The proposed variant of the lead peptide 1aR containing the cyclobutane-based building block "Z" is as follows:

[0321]

[0322] The substitution of the lead peptide 1aR by 1aR-Cbu is as follows:

[0323] · Take the 3 bits of R in 1aR 1 The isopropyl group is replaced with R, which moderately increases hydrophobicity and steric hindrance. 1 Isobutyl group.

[0324] • Replace the cyclopentane-based building blocks “Z” (m=1) at positions 4 and 7 in 1aR with cyclobutane-based building blocks “Z” (m=0) that have moderately reduced hydrophobicity and steric hindrance.

[0325] As mentioned in this article, the cyclic β-amino acid trans-2-aminocyclopentanecarboxylic acid ([trans-ACPC)) n=6.8 (DH Appella, LA Christianson, DA Klein, DR Powell, XL Huang, JJ Barchi and SH Gellman, Nature, 1997, 387, 381-384) and trans-2-aminocyclobutanecarboxylic acid ([trans-ACBC)) n=6.8 (C. Fernandes, S. Faure, E. Pereira, V. Thery, V. Declerck, R. Guillot and D. J. Aitken, Org Lett, 2010, 12, 3606-3609) Homopolymers can form so-called 12 (=2.5) in both solution and crystals. 12 )-Helix (RP Cheng, SH Gellman and WF DeGrado, Chem Rev, 2001, 101, 3219-3232) (Scheme 1).

[0326] The substitution of the cyclic subunit “Z” in formulas (I) and (II), based on the cyclopentane ring (m=1) in the lead peptide 1aR and its peptide analogue shown in scheme 3, with a cyclic homologue based on the cyclobutane ring (m=0) is considered tolerable.

[0327] The cyclobutane-based building block “Z” (m=0) exhibits moderately reduced hydrophobicity and steric hindrance compared to the cyclopentane-based building block “Z” (m=1), which leads to reduced hydrophobicity of the -[AZA]- segment.

Claims

1. Compounds containing a portion of formula (I): -[AZA] n - (I) in: Each A is independently a group of the following formula: Each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety in the alkylene group and the -(C 0-6 In each of the alkylene-heterocyclic groups, the heterocyclic moiety is optionally substituted by one or more groups, said groups being independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl and heterocycloalkyl, wherein -(C 0-6 alkylene)-carbocyclic or the -(C 0-6 C in alkylene-heterocyclic group 0-6 One of the -CH2- units in the alkylene moiety is optionally replaced by -O-, -S-, -NH- or -N(C 1-6 Alkyl)-substitution; Each Z is independently a group of the following formula: Each m is independently 0 or 1; and n is 2, 3, or 4; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein each R 1 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(C 0-6 alkylene)-carbocyclic or -(C 0-6 alkylene)-heterocyclic group, wherein -(C 0-6 The carbocyclic moiety in the alkylene group and the -(C 0-6 In each of the alkylene-heterocyclic groups, the heterocyclic moiety is optionally substituted by one or more groups, said groups being independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OH, -O(C) 1-6 alkyl), -O(C) 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 Alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 Alkyl), -NH-OH, -N(C 1-6 alkyl)-OH, -NH-O(C 1-6 alkyl), -N(C) 1-6 alkyl)-O(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Halogenated alkyl groups, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 Alkyl), -CO-O-(C 1-6 Alkyl), -O-CO-(C 1-6 Alkyl groups), -CO-NH2, -CO-NH(C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-(C 1-6 Alkyl), -NH-CO-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO-O-(C 1-6 Alkyl), -O-CO-NH-(C 1-6 Alkyl), -O-CO-N(C 1-6 alkyl)-(C 1-6 Alkyl groups), -SO2-NH2, -SO2-NH(C 1-6 Alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-SO2-(C 1-6 alkyl), -SO2-(C 1-6 alkyl), -SO-(C 1-6 Alkyl), cycloalkyl, and heterocyclic alkyl.

3. The compound of claim 1 or 2, wherein n is 2.

4. The compound of any one of claims 1-3, wherein each R 1 Independently for C 2-5 Alkyl groups, preferably each R 1 Independently for C 3-4 Alkyl groups, more preferably each R 1 It is either isopropyl or isobutyl.

5. The compound of any one of claims 1-4, wherein m is 1.

6. The compound according to any one of claims 1-5, wherein: - Each A has the following configuration: ; and / or - Each C has the following configuration: .

7. The compound of any one of claims 1-6, wherein the compound is a compound of formula (II): X-[Z] p -[A-Z-A] n -Y (II) in: A, Z and n are as defined in any one of claims 1-6; p is 0 or 1; X is an amino acid sequence of 1-5 hydrophobic amino acid residues, wherein X is connected to the remainder of the compound of formula (II) via its C-terminus, and optionally, wherein X has an alkanoyl group at its N-terminus; and Y is an amino acid sequence of 1-5 polar amino acid residues, preferably a combination of basic amino acid residues or a combination of basic and polar neutral amino acid residues, wherein Y is connected to the remainder of the compound of formula (II) via its N-terminus, and optionally, wherein the C-terminal COOH group of Y is replaced by -CONH2 or -CH2OH. Or its pharmaceutically acceptable salt.

8. The compound of claim 7, wherein each of the hydrophobic amino acid residues is independently selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Met and Trp, preferably from Val, Leu, Ile, Phe, Tyr and Trp, and more preferably from Phe, Tyr and Trp.

9. The compound of claim 7 or 8, wherein the polar amino acid residues are each independently selected from Arg, Lys and His, preferably from Arg and Lys.

10. The compound of any one of claims 7-9, wherein p is 1.

11. The compound of any one of claims 7-10, wherein X is alkyl-Tyr-, preferably wherein X is alkyl-(L-Tyr)-. and / or Wherein Y is -Arg-Arg-NH2 or -Arg-Arg-Arg-NH2, preferably where Y is –(D-Arg)-(D-Arg)-NH2 or –(D-Arg)-(D-Arg)-(D-Arg)-NH2.

12. The compound of any one of claims 1-11, wherein the compound is amphiphilic.

13. The compound of claim 1 or 7, wherein the compound is selected from any one of the following compounds: and Or its pharmaceutically acceptable salt or any compound.

14. The compound of claim 1 or 7, wherein the compound is selected from any one of the following compounds: Or its pharmaceutically acceptable salt or any compound.

15. A pharmaceutical composition comprising a compound of any one of claims 1-14 and a pharmaceutically acceptable carrier.

16. The compound of any one of claims 1-14 or the pharmaceutical composition of claim 15, used as a pharmaceutical agent.

17. The compound of any one of claims 1-14 or the pharmaceutical composition of claim 15, for the treatment or prevention of cancer.

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