Inhibitors of oxidative phosphorylation and a pharmaceutical composition comprising these

Abstract

The present invention concerns a compound according to a formula 1 configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, and a pharmaceutical composition comprising said compound, as well as uses thereof for inhibition of oxidative phosphorylation.

Description

[0001] INHIBITORS OF OXIDATIVE PHOSPHORYLATION AND A PHARMACEUTICAL COMPOSITION COMPRISING THEREOF

[0002] TECHNICAL FIELD

[0003] The present disclosure generally relates to a compound, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof. The disclosure relates particularly, though not exclusively, to a compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, and a pharmaceutical composition comprising said compound, and a use of said compound.

[0004] BACKGROUND

[0005] This section illustrates useful background information without admission of any technique described herein representative of the state of the art.

[0006] Oxidative phosphorylation (OXPHOS) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. Several well-known drugs and toxins that inhibit oxidative phosphorylation exist. Such drugs commonly inhibit only one enzyme in the electron transport chain, and inhibition of any step in this process will halt the rest of the process. Compounds that inhibit oxidative phosphorylation of mitochondrial respiration are useful in the treatment of various diseases. Such medicines target the mitochondria, to disrupt the energy production process. By inhibiting OXPHOS, these drugs effectively reduce the energy supply to cells, thereby inhibiting their growth and proliferation. This approach is particularly beneficial in treating tumors that rely heavily on mitochondrial respiration for their energy needs.

[0007] While Complex I inhibitors offer a promising avenue for various therapies, the existing inhibitors sometimes possess significant adverse effects in patients, such as lactic acidosis which can be even life-threatening, cardiotoxicity, and neurotoxicity including cognitiveimpairment and neuroinflammation. Therefore, safer and better tolerated alternative inhibitors of OXPHOS are needed to avoid these harmful or even life-threatening side effects, without compromising the inhibitor efficacy.

[0008] Systemic treatment of cancer is based on cytotoxic or cytostatic therapy. On one hand, the problem of current cytotoxic treatments like chemotherapies is that they do not differentiate between cells, and the toxic effect against healthy cells often leads to unmanageable adverse effects. On the other hand, cancers can develop resistance to existing treatment strategies. Thus, cytostatic treatments may control tumor development for a while, but the surviving clones can eventually give rise to drug resistant clones in cancer and relapse will eventually occur. Therefore, novel and effective cancer treatments alongside chemotherapies are needed.

[0009] Contrary to earlier understanding of cancer metabolism, cancer cells can be highly dependent on mitochondrial respiration, which serves the needs of cancer cells for bioenergy and anabolic metabolism. The research has shown, pharmacological inhibition of mitochondrial respiration can be cytostatic or cytotoxic particularly for cancer cells. Chemical compound Metformin (commercially known as Glucophage) is primarily utilized as antidiabetic drug. This compound inhibits complex I of the mitochondrial respiration chain. Metformin has demonstrated weak anti-tumor efficacy in animal models of human cancer and in clinical trials, as demonstrated by El-Khayat et al. 2022, Serageldin et al 2023 and Bakry et al. 2023. However, the therapeutic window and systemic toxicity associated with such complex I inhibitors necessitate the development of more selective and safer inhibitors. Therefore, there is a need for improved inhibitors of complex I of the mitochondrial respiration chain that potentially exhibit enhanced anti-tumor efficacy.

[0010] Cancer cells adopt a mechanism of uncontrolled cell division, allowing them to proliferate unchecked. This unregulated growth can result from mutations in oncogenes or tumor suppressor genes, such as p53, leading to the activation of signalling pathways that drive proliferation and inhibit cell death. These changes enable cancer cells to proliferate and grow incessantly without normal regulatory controls.

[0011] Therapeutic strategies for aggressive cancers, including breast cancer, often focus on disrupting key pathways involved in cell cycle regulation, metabolism and survival. Some approaches target specific oncogenes like Myc, though this has proven challenging due to its structure and function. Alternatively, therapies may aim at modulating pathways that interact with Myc or leveraging synthetic lethal interactions, where inhibiting a secondarypathway selectively eliminates cancer cells while sparing normal ones. More effective yet safe treatments for cancers with dysregulated growth signaling are needed.

[0012] SUMMARY

[0013] The appended claims define the scope of protection. Any examples and technical descriptions of apparatuses, products and / or methods in the description and / or drawings not covered by the claims are presented not as embodiments of the invention but as background art or examples useful for understanding the invention.

[0014] According to a first example aspect there is provided a compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof,

[0015]

[0016] wherein,

[0017] - (A) is selected from formula 2 or 3:

[0018]

[0019] wherein,

[0020] • the (A) according to the formula 2 comprises Xi -X3, wherein each of the Xi - X3 is independently selected from (CH), (CF), and nitrogen (N);

[0021] • the (A) according to the formula 3 comprises Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5, is independently selected from (N), (NH), (S) and (O), and wherein at least two of the Z1 - Z5, are independently selected from carbon (C) and (CH); and wherein• both in the formula 2 and in the formula 3, R1 is selected from R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop- 1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop- 1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2- methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0022] • both in the formula 2 and in the formula 3, R2 is selected from R2 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0023] - R3 is selected from R3 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0024] - R4 is selected from R4 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F) - R5 is selected from R5 substituents hydrogen- (H), methyl- (CH3), ethyl- (CH3CH2), isopropyl- ((CH3)2CH); and

[0025] - R6 is selected from R6 substituents hydrogen- (H) and methyl- (CH3),

[0026] and wherein the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0027] Sometimes, cancer cells have metabolic activity, e.g., Krebs cycle and oxidative phosphorylation (OXPHOS) activity, that is unique from the metabolic activity, e.g., Krebs cycle and OXPHOS activity, of non-cancer cells. The compound according to the formula 1 is advantageous, as it is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, thereby being an OXPHOS inhibitor. As used herein, the “configured to” means the compound is configured to perform the indicated function, e.g. based on its physical structure, instead of just being suitable for performing the indicated function. The present compound is advantageous as it shows selective inhibition of the oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, suchas selective inhibition in cancerous cells over non-cancerous cells. The present compound is advantageous as it shows improved selective inhibition of OXPHOS inside a cell, when compared to at least some of the existing OXPHOS inhibitors. The present compound according to the formula 1 is advantageous, as it is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, based on its physical structure. In an embodiment, the present compound according to the formula 1 is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as it has a high binding affinity to Complex I (NADH dehydrogenase (ubiquinone) of the electron transport chain, therefore preventing the transfer of electrons from NADH to ubiquinone (coenzyme Q10), and the production of ATP through oxidative phosphorylation. In an embodiment, the present compound according to the formula 1 is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as it has a high binding affinity to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or to NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I. The present compound according to the formula 1 is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as measured with the Seahorse XF Mito Tox Assay Kit, and by measuring of the OCR changes as described by Pratibha Sharma et al. 2024.

[0028] The present compound is further advantageous as it shows selective cytotoxicity towards cancer cells, over healthy, non-cancerous cells in vitro. The cytotoxicity of the present compound, especially cancer-targeted cytotoxicity, can be utilized therapeutically with high anti-cancer effect and with less adverse effects of patients. The present compound is therefore advantageous as it provides a targeted cytotoxicity to specific cell types such as cancer cells having increased energy needs relying on mitochondrial respiration. The present compound is therefore advantageous as it has less off-target effects in other cell types, such as normal, non-cancerous cells. Targeting the unique metabolic activity of cancer cells allows the present compound to selectively kill cancer cells over non-cancer cells.

[0029] According to an alternative example aspect there is provided a compound according to the formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the R1 is selected from R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CHs^CH), isobutyl-((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O),methylamino- (CH3NH), dimethylamino- ((CHs^N), ethylamino- (CH3CH2NH), diethylamino-((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio-((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CHs^CCH), 3-methylbut-2-en-1-yl-((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CHs^CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CHs^CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F), or R1 is absent.

[0030] According to a second example aspect there is provided a pharmaceutical composition comprising the compound of the first aspect as an active ingredient, and at least one further component selected from a pharmaceutically acceptable carrier, excipient and / or adjuvant. The pharmaceutical composition is advantageous as it is configured to inhibit oxidative phosphorylation of mitochondrial respiration inside a cell, and thus, it can be used in a treatment of various medical conditions or diseases by inhibiting oxidative phosphorylation of mitochondrial respiration. The pharmaceutical composition is advantageous as it can be used in the treatment of various medical conditions or diseases by selectively inhibiting oxidative phosphorylation of mitochondrial respiration. The pharmaceutical composition is advantageous as it can be used in a treatment of various medical conditions by selectively targeting tissues and cells, e.g. selectively targeting cancerous cells.

[0031] According to a third example aspect, there is provided a use of the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. The use of the compound, or the pharmaceutical composition for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell is advantageous, as it can be used in research to improve the treatment of diseases.

[0032] According to a fourth example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in inhibiting oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, preferably for use in therapeutics, more preferably for use in treatment of a patient, more preferably for use in treatment of a cancer, even more preferably for treatment of a breast cancer. The use of the compound, or the pharmaceutical composition for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell is advantageous, as it can be used in treating diseases wherein inhibition of mitochondrial respiration is therapeutic. The use of the present compound is also advantageous, as it has growth inhibitory effects already at low concentrations.According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use as a medicament. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in treatment of cancer. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in treatment of breast cancer and / or lymphoma. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in treatment of breast cancer and / or lymphoma, wherein the treatment comprises inhibiting mitochondrial oxidative phosphorylation (OXPHOS) in cells. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in treatment of cancer expressing elevated levels of Myc. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, for use in treatment of breast cancer and / or lymphoma expressing elevated levels of Myc. According to a further example aspect, there is provided the compound of the first example aspect, or the pharmaceutical composition of the second example aspect, wherein the compound specifically binds to ND1 and / or NDLIFS7 of the mitochondrial complex I, for use in treatment of cancer. According to a further example aspect, there is provided a use of the compound of the first example aspect, for preparation of a medicament for a treatment of a cancer.

[0033] Different non-binding example aspects and embodiments have been illustrated in the foregoing. The embodiments in the foregoing are used merely to explain selected aspects or steps that may be utilized in different implementations. Some embodiments may be presented only with reference to certain example aspects. It should be appreciated that corresponding embodiments may apply to other example aspects as well. In particular, the embodiments described in the context of the first aspect are applicable to each further aspect. Any appropriate combinations of the embodiments may be formed.

[0034] BRIEF DESCRIPTION OF THE FIGURES

[0035] Some example embodiments will be described with reference to the accompanying figures, in which:

[0036] Fig. 1 shows exemplary possible tautomers (l)-(VI II) of the compound according to the formula 1.Fig. 2 shows exemplary possible tautomers (l)-(IV) of the R1 substituents of the compound according to the formula 1. Each of the (l)-(IV) represent a tautomer pair of alternative tautomers of the R1 substituents;

[0037] Fig. 3 (a) shows a schematic view of the synthesis scheme of the compound KLC-004 (5(l )) , as explained in the Example 3; and (b) shows a schematic view of the synthesis scheme of the compound KLC-005 (7(l)), as explained in the Example 4.

[0038] Fig. 4 Shows a schematic view of the synthesis scheme of the compound KLC-051 in scheme 1; KLC-048 in scheme 2; and KLC-049 in scheme 3, as explained in the Example 6.

[0039] Fig. 5 Shows a schematic view of the synthesis scheme of the compound KLC-050 in scheme 4; KLC-052 in scheme 5; and KLC-053 in scheme 6, as explained in the Example 6.

[0040] Fig. 6 Shows the results of a target engagement study measuring mitochondrial respiration, measured as Oxygen Consumption Rate (OCR), as explained in the Example 7. The cells used in the in vitro experiment were BT549, a triple-negative breast cancer (TNBC) cells, expressing high levels of endogenous Myc. Before the start of the experiment the cells were treated overnight with 0,5% DMSO (indicated with triangles), or KLC-004 at concentrations 1pM (indicated with crosses), or 5pM (indicated with circles) or 10 pM (indicated with squares). The oxygen consumption rate (OCR) is shown in pmol / min / 1000 cells is shown on the y-axis, and its changes are monitored at an injection series. X-axis shows time in minutes. (A) represents the time point shown in x-axis, wherein oligomycin (2 pM) is injected in the cell culture. (B) represents the time point shown in x-axis, wherein FCCP (1 pM) is injected in the cell culture. (C) represents the time point shown in x-axis, wherein a mixture of rotenone and antimycin A (0.5 pM) is injected in the cell culture. The data are presented as means ± SD. This data shows that the compound KLC-004 efficiently reduces OCR. As used herein, the terms KLC4 and KLC0004 refer to KLC-004. The corresponding nomenclature applies to other compounds according to formula 1 described herein, such as compound KLC-005 and compounds KLC-048 to KLC-057, as shown in the figures below.

[0041] Fig. 7 Shows the same experiments as in the Fig. 6 and as explained in the Example 7, with the difference that it is conducted with MDAMB231 cells, which are TNBC cells expressing low levels of endogenous Myc.

[0042] Fig. 8 Shows cytotoxicity assay dose-response curve illustrating the effect of KLC-004 on cell proliferation in two doxycycline-inducible isogenic Hs578T triple-negative breast cancer(TNBC) cells, as explained in the Example 8. Human Hs578T cell lines used were Myc-high (Mychi, closed grey squares) expressing high levels of Myc, and Myc-low (Mycl0, closed black circles) expressing non-induced levels of Myc. The cell proliferation is shown as cell proliferation in percentual growth (% Growth). The log-concentration of KLC-004 is shown in pM on the x-axis.

[0043] Fig. 9 shows cytotoxicity assay dose-response curve illustrating the effect of KLC-004 on cell proliferation in doxycycline-inducible MDA-MB-157 triple-negative breast cancer (TNBC) cells, as explained in the Example 8. MDA-MB-157 cell lines used herein are Myc-high (Mychi, closed grey squares), expressing high levels of Myc, and Myc-low (Myc10, closed black circles) expressing non-induced levels of Myc. The cell proliferation is shown as cell proliferation in percentual growth (% Growth). The log-concentration of KLC-004 is shown in pM on the x-axis.

[0044] Fig. 10 Shows a dose-response curve illustrating the effect of KLC-004 in a panel of breast cancer cell lines, and two normal mammary epithelial cell lines (HMEC, MCF10A) shown as % of proliferation on the y-axis, as explained in the example 11. The experimental panel was divided into categories of endogenous Myc high cell lines (T47D, HCC1395, BT549, HCC1937) expressing high levels of Myc; Myc low cell lines (Hs578T, MDAMB157, MDAMB231, MCF7) expressing low levels of Myc, intermediate Myc-level cells (BT474) expressing intermediate levels of Myc, and normal transformed breast cell lines (HMEC and MCF10A). The log-concentration of KLC-004 is shown in pM on the x-axis, and the cell proliferation is shown on the y-axis as percentual cell proliferation (% proliferation).

[0045] Fig. 11 Shows a graph depicting the long term survival of breast cancer cells in a colony formation assay after treatment with KLC-004 (light grey bar / open circle, 3 pM) and control substance DMSO (black bar / open squares, 0.5 vol-%) in endogenous Myc-high breast cancer cell lines BT549, HCC1937, HCC1395, T47D (shown in a)); or in endogenous Myc-low breast cancer cell lines Hs578T, MDA-MB-157, MDA-MB-231 (shown in b)). The cells were treated respectively for the duration of 14 days, prior to assessment of the colony formation. The p values shown are: <0.001=***, and ns=not significant. The colony formation of the cells is shown on the y-axis as %, and the experiment is further explained in the Example 12.

[0046] Fig. 12 Shows the pharmacokinetic profile of CD-1 mice, after KLC-004 administration in both oral (Per Os, PO, closed grey squares) and Intraperitoneal (IP, closed black circles) routes at 10 mg / kg dose, as explained in the example 14. Both groups of mice were administered with KLC-004 at the indicated time points on the x-axis (in min), each of the measured time point treatment groups included 3 animals, The concentration of KLC-004in plasma of the studied mice is shown on the y-axis as ng / ml, measured in the time points (min) as indicated on the x-axis.

[0047] Fig. 13 a) shows in vivo results of KLC-004 -treated mouse Xenograft models, measured as tumor volume and indicating the anti-tumor efficacy of KLC-004. a) shows the measured tumor volume (mm3on y-axis) at different time points (days on x-axis) from BT549 Cell Line-Derived subcutaneous Xenograft (CDX) model mice. Tumor-bearing female NOD-SCID mice were intraperitoneally (i.p.) treated with either 10 mL / kg control vehicle (2HPpCD:Saline (20%:80%, w / v); i.p., OD; n = 8) shown as closed black circles, or with 10 mg / kg KLC-004 (i.p., OD; n = 7) shown as closed grey triangles, or with 30 mg / kg KLC-004 (i.p., OD; n = 7) shown as closed grey squares. Said treatments were administered for 21 days, once daily (OD) (indicated by the area of the grey box), and tumor volumes (in mm3) were measured at time points (in days, d) as indicated on the x-axis. The p value shown is: <0.0001=****.

[0048] Fig. 13 b) shows data from human patient-derived subcutaneous Xenograft (PDX) model mice, wherein tumor-bearing female NOD-SCID mice were intraperitoneally (i.p.) treated with either 10 mL / kg control vehicle (2HPpCD:Saline (20%:80% w / v); i.p., BID; n = 6) shown as closed grey circles, or with 30 mg / kg KLC-004 (i.p., BID; n = 6) shown as closed grey triangles. Said treatments were administered for 21 days twice daily (BID), and tumor volumes (in mm3), as shown in the y-axis were measured at time points (in days, d) as indicated on the x-axis. The p value shown is: <0.01=**.

[0049] Fig. 14 shows the structural (skeletal) formulas for synthesized compounds KLC-054 (a), KLC-055 (b), KLC-056 (c) and KLC-057 (d), all of which are compounds according to formula 1. Said compounds were synthesized in a similar manner as compounds KLC-040-KLC-053 as further described in Example 6. All compounds KLC-054 to KLC-057 were obtained as HCI salts.

[0050] Fig. 15 a) Shows the results of a target engagement study measuring mitochondrial respiration, measured as Oxygen Consumption Rate (OCR), as also explained in the Example 16. The cells used in the in vitro experiment were BT549, a triple-negative breast cancer (TNBC) cells. Before the start of the experiment the cells were treated overnight with 0,5% DMSO (indicated by filled circles), 10 pM Phenformin (indicated by open triangles), or 5 pM KLC-004 (indicated by crosses). The oxygen consumption rate (OCR) in pmol / min / 1000 cells is shown on the y-axis, and its changes are monitored at an injection series. X-axis shows time in minutes. (A) represents the time point shown in x-axis, wherein oligomycin (1,5 pM) is injected in the cell culture. (B) represents the time point shown in x-axis, wherein a protonophore Bam15 (2,5 pM) is injected in the cell culture. (C) representsthe time point shown in x-axis, wherein a mixture of rotenone and antimycin A (0.5 pM) is injected in the cell culture. The data are presented as means ± SD and n=4 replicates / group. These data show that the compound KLC-004 efficiently inhibits mitochondrial respiration, as evidenced by reduced OCR in BT549 cells. Error bars represent mean ±SD.

[0051] Fig. 15 b) Shows a quantitative analysis of the results shown in Fig. 15 a), presenting as bar graphs the basal respiration (prior to injection A) which is indicated in Fig. 15 b) with letter ‘L’, and maximal respiration (Bam15-stimulated OCR prior to injection C), indicated in Fig. 15 b) with letter ‘M’. These bars represent the mean ± SD for each treatment group of n=4 replicates / group and illustrate the extent to which KLC-004 compound reduces both basal mitochondrial oxygen consumption and maximal electron-transport capacity. The p value shown is: <0.0001=****, <0.001=***, wherein the comparison of indicated groups was done by unpaired t-test.

[0052] Fig. 16 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-005 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0053] Fig. 16 b) shows a quantitative analysis of the data presented in Fig. 16 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0054] Fig. 17 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-048 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0055] Fig. 17 b) shows a quantitative analysis of the data presented in Fig. 17 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0056] Fig. 18 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-049 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0057] Fig. 18 b) shows a quantitative analysis of the data presented in Fig. 18 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0058] Fig. 19 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-050(5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0059] Fig. 19 b) shows a quantitative analysis of the data presented in Fig. 19 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0060] Fig. 20 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-051 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0061] Fig. 20 b) shows a quantitative analysis of the data presented in Fig. 20 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0062] Fig. 21 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-052 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0063] Fig. 21 b) shows a quantitative analysis of the data presented in Fig. 21 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0064] Fig. 22 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-053 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0065] Fig. 22 b) shows a quantitative analysis of the data presented in Fig. 22 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0066] Fig. 23 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-054 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0067] Fig. 23 b) shows a quantitative analysis of the data presented in Fig. 23 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0068] Fig. 24 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-055 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).Fig. 24 b) shows a quantitative analysis of the data presented in Fig. 24 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0069] Fig. 25 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-056 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0070] Fig. 25 b) shows a quantitative analysis of the data presented in Fig. 25 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0071] Fig. 26 a) shows the results of an Oxygen Consumption Rate (OCR) measurement performed as described for Fig. 15 a), with the exception that the compound KLC-057 (5 pM) was used instead of KLC-004. The experimental setup, treatment conditions, and sequential mitochondrial inhibitor injections were identical to those described for Fig. 15 a).

[0072] Fig. 26 b) shows a quantitative analysis of the data presented in Fig. 26 a), corresponding to the quantitative analysis format described for Fig. 15 b).

[0073] Fig. 27 Cell death analyses panel including fifteen triple-negative breast cancer (TNBC) cell lines treated in vitro with KLC-004 (10 pM), phenformin (10 pM), or IACS-10759 (10 pM) represented in bar graphs, as also explained in the Example 18; DMSO served as vehicle control. Each bar represents the percentage of cell death measured using the Sytox Green assay for either DMSO (indicated by letter ‘D’), KLC-004 (indicated by letter ‘K), phenformin (indicated by letter ‘P’) or IACS-10759 (indicated by letter T), indicated as a mean Sytox-positive percentage of cells (Sytox Pos %). These bars represent the mean ± SD for each treatment group of n=3 repl icates / g roup. The figure provides a comparison of the magnitude of cell death across the TNBC panel achieved by each treatment condition under the stated concentration.

[0074] Fig. 28 shows in vivo antitumor efficacy of KLC-004 in a Raji lymphoma mouse xenograft model (cell line-derived xenograft, CDX), as described in Example 19. The Fig. 28 shows the measured absolute tumor volume (mm3on y-axis) at different time points (days on x-axis) from Raji lymphoma xenograft (CDX) model mice. Tumor-bearing female NOD-SCID mice were treated intravenously (i.v.) with either 10 mL / kg control vehicle (2-hydroxypropyl-p-cyclodextrin (2HPPCD): saline, 20%:80% w / v; i.v. twice weekly; n = 9), represented by closed black circles, or with 5 mg / kg KLC-004 (i.v. twice per week; n = 10) shown as closed grey triangles. Said treatments were administered over a period of 21 days, twice per week. Mice of both treatment groups received six total doses each. Absolute tumor volumes (in mm3) were measured at time points (in days, d) as indicated on the x-axis. Each data point represents the mean ± SD for either vehicle (n= 9 mice, closed circles) or KLC-004 (n= 10 mice, closed triangles) at a given time point. The p values : <0.01=**, <0.05=*, comparisons between indicated groups were performed using two-way ANOVA with Dunnett’s multiple comparisons test.

[0075] DETAILED DESCRIPTION

[0076] In the following description, like reference signs denote like elements or steps.

[0077] In an embodiment, herein is disclosed a compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof. The compound according

[0078] to formula 1 is:

[0079]

[0080] V™.--'

[0081] As used herein, with the term “compound” is meant the compound of the present disclosure, i.e. the compound according to formula 1, unless otherwise specified. The compound according to formula 1 or a tautomer thereof, and / or a pharmaceutically acceptable salt or solvate of the compound according to formula 1, is herein called merely “the compound” or “the compound according to formula 1”, or the “present compound”. Therefore, any reference to “the compound” or “the compound according to formula 1”, or “the present compound”, is indicated to the compound of the claim 1 or any embodiment thereof.

[0082] As used herein, “pharmaceutically acceptable salt,” represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure or separately by reacting the compound with an acid having a suitable cation. Suitable pharmaceutically acceptable cations include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) ions. In addition, the pharmaceutically acceptable salts of the disclosed compounds that contain a basic center are acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids such as oxalic, maleic,succinic, malonic and citric acid. Nonlimiting examples of salts of compounds of the invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethane- sulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, gluconate, benzene sulphonate, and p-toluenesulphonate salts. In addition, available amino groups present in the compounds of the invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides.

[0083] As used herein, the term 'tautomer' refers to isomers of a molecule that can interconvert, typically by the movement of a hydrogen atom and a double bond. Tautomerism is a chemical phenomenon where a compound exists in multiple interconvertible forms, known as tautomers. These tautomers typically differ by the position of a proton and changes in the bonding structure, often involving the movement of hydrogen atoms and shifts in single and double bonds. This dynamic equilibrium can significantly influence the chemical properties and reactivity of the compounds involved.

[0084] As used herein, the term “resonance structure” refers to alternative Lewis structures of a molecule or ion that depict electron delocalization, as understood in organic and theoretical chemistry. Resonance structure refers to the delocalization of electrons within a molecule where multiple equivalent Lewis structures (resonance forms) can be drawn to represent the bonding. Resonance structures are therefore an alternative representation of a molecule’s binding arrangement, illustrating the delocalization of electrons across the conjugated system, including fractional bonds and fractional charges. These molecular structures differ only in the placement of electrons, not the positions of atoms. These resonance forms represent the same chemical entity and contribute collectively to the resonance hybrid, which reflects the true electronic structure of the molecule.

[0085] As used herein, the 5- and 6-membered aromatic rings, for example as part of the compound according to the formula 1, can be illustrated in various resonance structures. In aromatic compounds such as benzene, as shown in the example (X) below, these different representations of resonance structures equally depict the delocalization of electrons withinthe ring, where the double bonds can be drawn in different positions. Therefore, in the example (X) below, both rings 1. and 2. can be represented by both, the rings 3. and 4.

[0086] (X)

[0087]

[0088] As used herein, with the term “substituent” is meant an atom or a group of atoms that replaces one or more hydrogen atoms on a parent molecule, thereby becoming a part of the resultant molecule, and the substituent being replaceable or exchangeable with another suitable substituent. Substituents can be functional groups, side chains, or other moieties that are attached to the main structure of the molecule. In the present compound of the formula 1, the substituents R1-R6 are examples of substituents.

[0089] As used herein, with the term “oxidative phosphorylation (OXPHOS) of mitochondrial respiration” is meant the metabolic pathway in which cells use enzymes to oxidize nutrients, releasing chemical energy to produce adenosine triphosphate (ATP). OXPHOS occurs in the mitochondria of eukaryotic cells and involves two main components: the electron transport chain and chemiosmosis. During OXPHOS, electrons are transferred from electron donors like NADH and FADH2 to a series of electron acceptors through the electron transport chain. This transfer of electrons generates energy, which is used to pump protons across the inner mitochondrial membrane, creating a proton gradient. The energy stored in this gradient is then used by ATP synthase to convert adenosine diphosphate (ADP) into ATP in a process known as chemiosmosis.

[0090] As used herein, with the term “NADH-ubiquinone oxidoreductase chain 1 (ND1)” is meant a protein that plays a role in the mitochondrial respiratory chain, specifically in Complex I. ND1 protein is encoded by the MT-ND1 gene, and it is one of the core subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, which is the largest of the five complexes in the electron transport chain. Complex I is responsible for the transfer of electrons from NADH to ubiquinone (coenzyme Q10), a process that is essential for the production of ATP through oxidative phosphorylation (OXPHOS). ND1 is integral to the assembly of Complex I, and therefore, indirectly facilitating the transfer of electrons and the pumping of protons across the mitochondrial inner membrane.

[0091] As used herein, with the term “NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7)” is meant a core subunit of Complex I in the mitochondrial respiratory chain.NDLIFS7 protein is encoded by the NDLIFS7 gene and is essential for the assembly and proper functioning of Complex I .

[0092] As used herein, with the term “heavy atom” is meant any atom that is heavier than hydrogen. This means that heavy atoms include all elements other than hydrogen. By this definition, especially in computational chemistry and molecular modelling, is referred to atoms that have a greater mass and more protons and neutrons in their nucleus compared to hydrogen . As used herein, the term “active ingredient” in context of a composition, refers to a component of said composition that provides the intended therapeutic effect or at least part of the intended therapeutic effect or at least one of the therapeutic effects. In most embodiments, an active ingredient is the primary component that delivers the desired biological activity. Pharmaceutical compositions typically include the active ingredient along with other substances known as excipients, which may be inactive ingredients that serve various purposes, such as enhancing the stability, solubility, or bioavailability of the active ingredient. For example, in the context of the present disclosure, the present compound is at least one of the active ingredients in the pharmaceutical composition. In some embodiments, supplementary active ingredients are also part of the pharmaceutical composition.

[0093] As used herein, the terms “effective amount” or “pharmaceutically effective amount” or “therapeutically effective amount” refer to an amount sufficient to effect beneficial or desirable biological and / or clinical results. For example, an “effective amount” of a compound (e.g., an OXPHOS inhibitor) may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit the desired response. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. An effective amount also encompasses an amount sufficient to confer benefit, e.g., clinical benefit.

[0094] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, cyclodextrins, silica-based carriers, liposomes, micelles, nanoparticles, antibody-conjugated drugs coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of such carriers or diluents include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. In some embodiments, the liposomes and non-aqueous vehicles such as fixed oils may also be used. In some embodiments, supplementary active compounds are also incorporated into the compositions. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. The term “pharmaceutically acceptable excipient” as used herein refers to any suitable substance that provides a pharmaceutically acceptable carrier, additive or diluent for administration of a compound(s) of interest to a subject. The term “pharmaceutically acceptable excipient” means also an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use and / or human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors and colors.

[0095] The term “pharmaceutically acceptable adjuvant” as used herein refers to substances that enhance the effect of the active ingredient. Pharmaceutical adjuvants useful in the present disclosure include, but are not limited to, immunostimulants, absorption enhancers and stabilizers.

[0096] As used herein, a “subject” refers to an animal for whom a diagnosis, treatment, or therapy is desired. In some embodiments, the subject is a mammal. “Mammal,” as used herein, refers to an individual belonging to the class Mammalia and includes, but not limited to, humans, domestic and farm animals, zoo animals, sports and pet animals. Non-limiting examples of mammals include mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees and apes, and, in particular, humans. In some embodiments, the mammal is a primate. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. In some embodiments the subject can have or is suspected of having cancer and / or has one or more symptoms of a cancerous disease. In some embodiments, the subject is a culture of cells. As used herein, with the term “GI50” or “Growth Inhibition 50” is referred to a calculated value which represents the concentration of a compound required to inhibit cell growth by 50%. It is a measure of the compound's effectiveness in slowing down or stopping cell proliferation. The GI50 concentration values can be determined as disclosed in Shoemaker et al. 2006, which is hereby incorporated by reference.

[0097] As used herein, with the term “TGI” or “Total Growth Inhibition” is referred to a calculated value which indicates the concentration of a compound at which there is no net increase in cell number. This refers to the value of a compound concentration at which cell growth iscompletely halted. The TGI concentration values can be determined as disclosed in Shoemaker et al. 2006, which is hereby incorporated by reference.

[0098] As used herein, with the term “LC50” or “Lethal Concentration 50” is referred to a calculated value representing the concentration of a compound that is lethal to 50% of the cell population it is applied to. It is a measure of the compound's cytotoxicity. The LC50 concentration values can be determined as disclosed in Shoemaker et al. 2006, which is hereby incorporated by reference.

[0099] As used herein, with the term “Myc”, in context of Myc-protein of Myc -gene, is referred to the human c-myc protein of gene (MYC), which is a proto-oncogene, respectively.

[0100] As used herein, with the term “Myc-high” or “Myc-high cells” or “Mychi” or “Mychi9h” -cells, in context of Myc expression status is meant a cell which is expressing elevated levels of Myc, wherein with an 'elevated level' of Myc expression in a Myc-high cell is meant a condition where the Myc protein is expressed at a significantly higher concentration compared to normal or baseline levels observed in normal or non-induced and / or non-transformed cells. This elevated expression is quantitatively defined as a Myc protein level that is at least 15-fold higher than the average Myc protein level in a corresponding normal / control cell population, or when compared to Myc-expression of a Myc-low cell, as measured by standard protein quantification techniques such as Western blotting, ELISA, or immunohistochemistry. As used herein, “elevated MYC expression” (or “MYC-high”) denotes a level of MYC protein expression that is significantly higher than baseline in a relevant comparator, quantified by standard protein-expression assays and meeting at least one of the following criteria: 1) Fold-change threshold: The MYC protein level is > 1.5-fold higher than (i) the mean MYC level of the corresponding MYC-low or non-induced isogenic control cells, or (ii) the mean MYC level of a matched normal cell population, as determined by Western blot, ELISA, or immunohistochemistry (IHC) with appropriate normalization. 2) Quantile threshold (panel context): Within a study panel of specific cancer type cell lines, the MYC protein level of the test cell line falls into the upper quantile (e.g., upper quartile) of MYC levels observed across the panel, as determined by Western blot / ELISA / IHC using the same antibodies and normalization method. Cell lines categorized as MYC-high in the Examples (e.g., BT549, HCC1937, HCC1395, T47D) are representative of elevated MYC expression.

[0101] Myc is a transcription factor known to regulate various cellular processes, including cell cycle, apoptosis, and metabolism. In the context of cancer, e.g. in breast cancer, elevated Myc expression is often associated with aggressive tumor behavior, poor prognosis, and resistance to therapies. Cancers with high Myc protein expression present distinctmolecular and phenotypic characteristics compared to those with lower Myc protein levels. These Myc-high characteristics can include rapid tumor growth, a higher likelihood of metastasis, and a greater sensitivity to specific therapeutic interventions that target cellular pathways regulated by Myc. Cancers expressing elevated levels of Myc exhibit an increased dependency on oxidative phosphorylation, rendering them more sensitive to Complex I inhibitors. This is because Myc overexpression enhances not only glycolysis (the Warburg effect) but also mitochondrial biogenesis and function, creating a potential synthetic lethal interaction with Complex I inhibition.

[0102] As used herein, with the term “intermediate Myc-level” expressing cell is meant a cell having an intermediate MYC expression, wherein the context of a cancer cell such cell can usually still show oncogenic behavior but to a lesser extent than a MYC-high cancer cell.

[0103] As used herein, with the term “Myc-low” or “Myc-low cells” is meant a cell having low or undetectable Myc expression, wherein the context of a cancer cell, such Myc-low cell is often associated with a less aggressive phenotype of the cell.

[0104] In an embodiment, the compound of the present disclosure is the compound of the formula 1, or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug, an antibody conjugated drug (ACD) or a deuterated analog thereof.

[0105] In an embodiment, is disclosed the compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof,

[0106]

[0107] wherein,

[0108] - (A) is selected from formula 2 or 3:

[0109]

[0110] wherein,• the (A) according to the formula 2 comprises Xi - X3, wherein each of the Xi - X3 is independently selected from (CH), (CF), and nitrogen (N);

[0111] • the (A) according to the formula 3 comprises Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5, is independently selected from (N), (NH), (S), and (O), and wherein at least two of the Z1 - Z5, are independently selected from carbon (C) and (CH); and wherein

[0112] • both in the formula 2 and in the formula 3, R1 is selected from R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CHs)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop- 1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop- 1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2- methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0113] • both in the formula 2 and in the formula 3, R2 is selected from R2 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0114] - R3 is selected from R3 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0115] - R4 is selected from R4 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F) - R5 is selected from R5 substituents hydrogen- (H), methyl- (CH3), ethyl- (CH3CH2), isopropyl- ((CH3)2CH); and

[0116] - R6 is selected from R6 substituents hydrogen- (H) and methyl- (CH3),

[0117] and wherein the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0118] In an embodiment, the compound according to formula 1, is a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, the compoundaccording to formula 1 is configured to inhibit complex I of the mitochondrial respiration chain. In an embodiment, the compounds of formula 1 are herein intended to include said compounds in free form, as well as tautomers, pharmaceutically acceptable salts, solvates (e.g. hydrates), resonance structures, esters, an antibody conjugated drug (ACD) or prodrugs thereof. In an embodiment, the compound being configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration, means the structure of the compound is designed, and thus, configured to perform the indicated function, instead of just being suitable for performing the indicated function. Therefore, in an embodiment, the compound according to formula 1 inhibits oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. In an embodiment, the compound according to formula 1 inhibits oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as measured by its effects on the oxygen consumption rate (OCR) of cells recorded using analytical Agilent Seahorse Xfe96 equipment using Seahorse XF Mito Tox Assay Kit, and by measuring of the OCR changes as described by Pratibha Sharma et al. 2024. In an embodiment, the compound according to formula 1 is configured to inhibit the activity of Complex I. In an embodiment, the compound is configured to inhibit OXPHOS by targeting the mitochondrial respiratory chain, specifically inhibiting the activity of Complex I, thereby disrupting the electron transport chain, leading to a reduction in ATP production (and an increase in reactive oxygen species (ROS)) within a cell.

[0119] In an embodiment, the compound according to the formula 1, can exist in several different tautomers. In an exemplary embodiment, the compound according to the formula 1 can exist in tautomers as represented in Fig. 1. Therefore, in an embodiment, the present compound is a compound according to the formula 1 or any of the tautomes of formulas (I)-(VIII) as presented in the Fig. 1.

[0120] Similarly, the substituent R1 of the compound according to the formula 1 can independently exist in several different tautomers, as represented in Fig. 2. Therefore, the present compound is not restricted to the specific implementation as presented in the formula 1 (as depicted, for example, in the first example aspect), but the present compound covers also all the tautomers thereof, as exemplified in the Figs. 1 and 2.

[0121] In an embodiment, herein is disclosed the compound according to the formula 1, or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is selected from the formula 2 or from the formula 3. In an embodiment, the R4 substituent of the compound can exist either as an R-isomer or an S-isomer. The term “R4 substituent” as used herein encompasses both the R-isomer and the S-isomer forms of the R4 substituent within the compound. In an embodiment, herein is disclosed the compound according to any one ofthe formula 1 or formulas (l)-(VIII) of Fig. 1, or a tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the (A) is selected from the formula 2 or 3 and wherein the compound comprises the substituents R1-R6. In an embodiment, the compound is a pharmaceutically acceptable salt or solvate of the compound according to formula 1.

[0122] The compound according to the formula 1 comprises the part (A), wherein the (A) is selected from the formula 2 or 3 as presented here below:

[0123]

[0124] In a preferred embodiment, both the formula 2 and the formula 3 comprise independently the substituents R1 and R2. In an alternative embodiment, both the formula 2 and the formula 3 comprise independently the substituent R2, and optionally the substituent R1. In an embodiment, both in the formula 2 and in the formula 3 of the compound according to the formula 1, the R1 is selected from the R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy-(CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy-((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy-(CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino-((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F).

[0125] In an embodiment, both in the formula 2 and in the formula 3 of the compound according to the formula 1, the R1 is selected from the R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy-(CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy-((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy-(CF3O), methylamino- (CH3NH), dimethylamino- ((CHs^N), ethylamino- (CH3CH2NH), diethylamino- ((CHsCF^N), isopropylamino- ((CHs^CHNH), isobutylamino-((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CHs^CCH), 3-methylbut-2-en-1-yl- ((CHs^CCHCF^), (2-methylprop-1-en-1-yl)oxy- ((CHs^CCHO), (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS), (2-methylprop-1-en-1-yl)amino- ((CHs^CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F), or the R1 is absent.

[0126] In an embodiment, both in the formula 2 and in the formula 3 of the compound according to the formula 1 , the R1 can exist in several different tautomers. In an exemplary embodiment, the R1 can exist in tautomers as depicted in Fig.2. Therefore, the substituent R1 is not restricted to one specific implementation of the R1 substituents, but the present compound covers also all the tautomers thereof, as exemplified in the Fig. 2.

[0127] In an embodiment, the (A) according to the formula 2 of the compound comprises the Xi -X3, wherein each of the X1-X3 is independently selected from (CH), (CF), or nitrogen (N). In an embodiment, the (A) according to the formula 2 of the compound comprises the Xi - X3, wherein each of the X1-X3 is independently selected from (CH), (CF), and nitrogen (N). In an embodiment, the (A) according to the formula 2 of the compound comprises the Xi - X3, wherein each of the X1-X3 is independently selected from (CH), (CF), or nitrogen (N), and wherein at least one of the Xi - X3 is (CF) or nitrogen (N).

[0128] In an embodiment, the (A) according to the formula 2 of the compound is not a phenyl group. In an embodiment, the compound is the compound of the formula 1, wherein the (A) is according to the formula 2.

[0129] In an embodiment, the (A) is according to the formula 2 of the compound, and at least one of the Xi , X2and X3 is selected from (CH) and (CF), preferably at least two, more preferably three of the Xi, X2and X3 is selected from (CH) and (CF). In an embodiment, wherein the (A) is according to the formula 2 of the compound, at least one of the Xi - X3 comprises carbon, preferably at least two comprise carbon, more preferably all three comprise carbon. In an embodiment, wherein the (A) is according to the formula 2 of the compound, each of the Xi, X2and X3 is independently selected from (CH), (CF) or nitrogen (N), and wherein at least one of the Xi, X2and X3 is (CF) or nitrogen (N), preferably at least one of the Xi, X2and X3 is (CF); and / or at least one of the Xi, X2and X3 is selected from (CH) and (CF), preferably at least two, more preferably three of the Xi, X2and X3 is selected from (CH) and (CF). In an embodiment, wherein the (A) is according to the formula 2 of the compound, atleast one of the Xi, X2 and X3 is (CF), preferably at least two, more preferably three of the Xi, X2 and X3 is (CF). In an embodiment, wherein the (A) is according to the formula 2 of the compound, at least one of the Xi, X2 and X3 is (CF), or at least two, or three of the Xi, X2and X3is (CF).

[0130] In an embodiment, wherein the (A) is according to the formula 2 of the compound, and wherein at least one or two of the Xi, X2 and X3 is selected from (CH) and (CF), the (CH) and / or (CF) can be positioned in any of the Xi, X2 and X3. In an embodiment, wherein the (A) is according to the formula 2 of the compound, one or two of the Xi, X2 and X3 is nitrogen (N), preferably none of the Xi, X2 and X3 is nitrogen (N).

[0131] In an embodiment, wherein the (A) is according to the formula 2 of the compound, one of the Xi, X2 and X3 is (CH) or (CF), and two of the Xi, X2 and X3 is (N). In a more preferred embodiment, wherein the (A) is according to the formula 2 of the compound, two of the Xi, X2 and X3 is (CH) or (CF), and one of the Xi, X2 and X3 is (N). In a most preferred embodiment, wherein the (A) is according to the formula 2 of the compound, all three of the Xi, X2 and X3 are (CH) or (CF), more preferably all three of the Xi, X2 and X3 are (CH). The Xi, X2 and X3 are preferably (CH), thereby reducing the risk of potential off-target interactions.

[0132] In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 has a number of heavy atoms of 1 or more, preferably 2 or more, more preferably 3 or more, most preferably 4 or more, and wherein the R1 has a number of heavy atoms of less than 6, and wherein the heavy atoms include C-, O-, S-, N-, F-, Br-, and Cl- atoms. In a preferred embodiment, wherein the (A) is according to the formula 2 in the compound according to the formula 1 , the R1 has a number of heavy atoms (non-hydrogen) of 1 or more.

[0133] In an embodiment, the compound according to the formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, comprises the (A) selected from the formulas 2 or 3, wherein,

[0134] • the (A) according to the formula 2 comprises Xi - X3, wherein each of the Xi - X3 is independently selected from (CH), (CF), and nitrogen (N);

[0135] • the (A) according to the formula 3 comprises Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5, is independently selected from (N), (NH), (S), and (O), and wherein at least two of the Z1 - Z5, are independently selected from carbon (C) and (CH); and wherein

[0136] • both in the formula 2 and in the formula 3, R1 is selected from R1 substituents hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2),isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1- yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop- 1 -en-1 -yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0137] • both in the formula 2 and in the formula 3, R2 is selected from R2 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0138] - R3 is selected from R3 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0139] - R4 is selected from R4 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F) - R5 is selected from R5 substituents hydrogen- (H), methyl- (CH3), ethyl- (CH3CH2), isopropyl- ((CH3)2CH); and

[0140] - R6 is selected from R6 substituents hydrogen- (H) and methyl- (CH3),

[0141] and wherein the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0142] In an embodiment, wherein the (A) is according to the formula 2 of the compound:

[0143] - the (A) according to the formula 2 comprises Xi - Xs, wherein each of the Xi - X3is independently selected from (CH), (CF), and nitrogen (N);

[0144] - the R1 is selected from R1 substituents hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl-(CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl-((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio-((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F); and

[0145] - the R2 is selected from R2 substituents methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl-(CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl-((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio-((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F). In an embodiment, the (A) is according to the formula 2 of the compound, and the R1 has a number of heavy atoms (non-hydrogen) of 1 to 5, preferably 2 to 5, more preferably 3 to 5, even more preferably 4 to 5, most preferably 5 heavy atoms. In an embodiment, wherein the (A) is according to the formula 2 of the compound, and the R1 has a number of heavy atoms (non-hydrogen) of 1 to 5, the R1 substituents exhibit an improved binding affinity to target protein(s) of the Complex I and thus, inhibition of OXPHOS of mitochondrial respiration inside a cell, when compared to compounds wherein the R1 has fewer or no heavy atoms. This is also observed in the binding affinities of the R1 substituents listed in the Table 1, showing enhanced binding affinity (kcal / mol) to mitochondrial Complex I as the number of heavy atoms in the substituent R1 increases towards 5.

[0146] In an embodiment, the (A) is according to the formula 2 of the compound, and the R1 has a number of heavy atoms (non-hydrogen) of 2 to 5, preferably 3 to 5, more preferably 4 to 5, most preferably 5 heavy atoms. In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 has a total number of C-, O-, S-, N-, F-, Br-, and Cl-atoms of 1 to 5, preferably 2 to 5, more preferably 3 to 5, even more preferably 4 to 5, mostpreferably 5. In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 has a number of C-, O-, S-, N-, F-, Br-, and Cl- atoms of 2 to 5, preferably 3 to 5, more preferably 4 to 5, most preferably 5. In an embodiment, wherein the (A) is according to the formula 2 of the compound, and the R1 has a number of heavy atoms (nonhydrogen) of 2 to 5, the R1 substituents exhibit an improved binding affinity to target protein(s) of the Complex I and thus, inhibition of OXPHOS of mitochondrial respiration inside a cell, when compared to compounds wherein the R1 has fewer heavy atoms. In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl-((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CHs^CHO), isobutoxy-((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy-(CF3O), methylamino- (CH3NH), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino-((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl-((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), ethoxy- (CH3CH2O), propoxy-(CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy-(CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), dimethylamino- ((CH3)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl-((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH).

[0147] In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents isobutyl- ((CH3)2CHCH2), isopentyl-((CH3)2CHCH2CH2), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy-((CH3)2CHCH2O), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), diethylamino-((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH),isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CHs^CCHO), (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS), (2-methylprop-1-en-1-yl)amino- ((CHs^CCHNH).

[0148] In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents isopentyl- ((CH3)2CHCH2CH2), isobutoxy-((CH3)2CHCH2O), trifluoromethoxy- (CF3O), diethylamino- ((CH3CH2)2N), isobutylamino-((CH3)2CHCH2NH), isobutylthio- ((CH3)2CHCH2S), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CHs^CCHO), (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS), (2-methylprop-1-en-1-yl)amino- ((CHs^CCHNH).

[0149] In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from methoxy- (CH3O), dimethylamino- ((CHh^N), and trifluoromethoxy- (CF3O). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is selected from the R1 substituents of the categories 1-6 of the table 1 (Example 2), preferably from the categories 1 -5 of the table 1 , more preferably from the categories 1 -4 of the table 1 , more preferably from the categories 1 -3 of the table 1 , even more preferably from the categories 1 -2 of the table 1 , most preferably from the category 1 of the table 1. In some embodiments, wherein the (A) is according to the formula 2 of the compound, the R1 has a number of heavy atoms (non-hydrogen) of 0 or 1 , in which case the R1 is selected from (H), (CH3), (OH), (NH2), (SH), (Cl), (Br), and (F).

[0150] In an embodiment, the (A) is according to the formula 2 of the compound, and the R2 is hydrogen (H) or methyl- (CH3). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R2 is hydrogen (H). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R2 is methyl- (CH3). However, in some other equally possible embodiments, wherein the (A) is according to the formula 2 of the compound, the R2 is selected from: trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F). In an embodiment, wherein the (A) is according to the formula 2 of the compound and the R2 is hydrogen (H) or methyl- (CH3), the R2 substituents exhibit a good binding affinity to target protein(s) of the Complex I and thus, inhibition of OXPHOS of mitochondrial respiration inside a cell. In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R2 is methyl- (CH3). In an embodiment, wherein the (A) is according to the formula 2 of the compound, wherein each of the X1-X3 is selected from (CH), (CF) and nitrogen (N),the R1 has a number of heavy atoms (non-hydrogen) of 1 to 5, preferably 2 to 5, more preferably 3 to 5, even more preferably 4 to 5, most preferably 5 heavy atoms, and

[0151] the R2 is selected from hydrogen- (H), and methyl- (CH3), preferably R2 is methyl- (CH3).

[0152] In an embodiment, the compound of the present disclosure is the compound of the formula 1 , wherein the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is independently selected from (CH) and (N); the R1 is selected from the R1 substituents listed in the table 1; the R2 is hydrogen- (H); the R3 is chloride- (Cl), and each of the R4 to R6 is hydrogen- (H).

[0153] In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0154] - the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is selected from (CH) and (CF);

[0155] - the R1 has a number of heavy atoms (non-hydrogen) of 2 to 5, and

[0156] - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3).

[0157] In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0158] - the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is independently (CH),

[0159] - the R1 is selected from the R1 substituents methoxy- (CH3O), dimethylamino- ((CHs^N), and trifluoromethoxy- (CF3O), and

[0160] - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3).

[0161] In an embodiment, the compound, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, is the compound of the formula 1, wherein the (A) is according to the formula 3, wherein,

[0162] o the (A) according to the formula 3 comprises Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and wherein at least two of the Z1 - Z5 are independently selected from carbon (C) and (CH); and wherein

[0163] o in the formula 3, R1 is selected from R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy-(CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CHs^CHCFW), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CHh^N), ethylamino- (CH3CH2NH), diethylamino- ((CHsCF^N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop-1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1- en-1-yl)thio- ((CH3)2CCHS), (2-methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0164] o in the formula 3, R2 is selected from R2 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0165] R3 is selected from R3 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0166] R4 is selected from R4 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);

[0167] R5 is selected from R5 substituents hydrogen- (H), methyl- (CH3), ethyl- (CH3CH2), isopropyl- ((CH3)2CH); and

[0168] R6 is selected from R6 substituents hydrogen- (H) and methyl- (CH3),

[0169] and wherein the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0170] In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein the (A) is according to the formula 3. In an embodiment, wherein the (A) is according to the formula 3 of the compound, the (A) comprises the Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O). In an embodiment, the (A) according to the formula 3 of the compound comprises the Z1 - Z5, wherein at least one of the Z1 - Z5, is independently selected from (N), (NH), (S), and (O). In an embodiment, the (A) according to the formula 3 of the compound comprises the Z1 - Z5, wherein at least one of the Z1 - Z5, is selected from carbon (C) or (CH). In a preferred embodiment, the (A) according to the formula 3 of the compoundcomprises the Zi - Z5, wherein at least two of the Z1 - Z5, is independently selected from carbon (C) or (CH).

[0171] In an embodiment, the (A) according to the formula 3 of the compound comprises the Z1 -Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5, is independently selected from (N), (NH), (S), and (O), and wherein at least two of the Z1 - Z5, is independently selected from carbon (C) or (CH). In an embodiment, wherein the (A) is according to the formula 3 of the compound, at least two of the Z1 - Z5 are independently selected from carbon (C) and (CH). In an embodiment, wherein the (A) is according to the formula 3 of the compound, at least two of the Z1 - Z5 are independently selected from carbon (C) and (CH), preferably at least three of the Z1 - Z5 are independently selected from carbon (C) and (CH), more preferably four of the Z1 - Zsare independently selected from carbon (C) and (CH).

[0172] In an embodiment, wherein the (A) is according to the formula 3 of the compound, three or four of the Z1 - Z5 are independently selected from carbon (C), and (CH), preferably four of the Z1 - Z5 are independently selected from carbon (C), and (CH).

[0173] In an embodiment, wherein the (A) is according to the formula 3 of the compound, three of the Z1 - Z5 are independently selected from carbon (C) and (CH). In an embodiment, wherein the (A) is according to the formula 3 of the compound, three or four of the Z1 - Z5 are independently selected from carbon (C) and (CH). In an embodiment, wherein the (A) is according to the formula 3 of the compound, four of the Z1 - Z5 are independently selected from carbon (C) and (CH). In an embodiment, wherein the (A) is according to the formula 3 of the compound, at least one of the Z2, Z4 or Z5 is carbon (C).

[0174] In an embodiment, wherein the (A) is according to the formula 3 of the compound, one or two of the Z1 - Z5 is / are independently selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O), more preferably the Z3 is selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O). In an embodiment, wherein the (A) is according to the formula 3 of the compound, one of the Z1 - Z5 is selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O). In an embodiment, wherein the (A) is according to the formula 3 of the compound, two of the Z1 - Z5 are independently selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O).

[0175] In an embodiment, wherein the (A) is according to the formula 3 of the compound and four of the Z1 - Z5 are independently selected from carbon (C) and (CH), one of the of the Z1 -Z5, preferably the Z3 is selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O). In anembodiment, wherein the (A) is according to the formula 3 of the compound, the Zi is (CH) and the Z3 is sulfur (S). In an embodiment, wherein the (A) is according to the formula 3 of the compound and three of the Z1 - Z5 are independently selected from carbon (C) and (CH), the Z3 and one of the Z1 , Z2, Z4 and Z5 are selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O). In an embodiment, wherein the (A) is according to the formula 3 of the compound and three of the Z1 - Z5 are independently selected from carbon (C) and (CH), the Z1 and the Z3 are selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O). In an embodiment, wherein the (A) is according to the formula 3 of the compound, the Z1 contains nitrogen and the Z3 is sulfur (S).The compound according to the formula 1, wherein the (A) is according to the formula 3 and the Z1 - Z5 are selected this way possess good stability and functionality, e.g. the physicochemical parameters of the compound according to the formula 1.

[0176] In an embodiment, regardless whether the compound according to formula 1 comprises (A) according to the formula 2 or according to the formula 3, the substituents R1 and R2 can also be selected similarly, as disclosed herein. Therefore, the selected R1-R2 substituents contribute to the binding affinity to target protein(s) and to Complex I inhibition of the compound, regardless whether the compound comprises (A) according to the formula 2 or according to the formula 3.

[0177] In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is selected from hydrogen (H) or any of the R1 substituents containing oxygen (O) or sulfur (S). In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is selected from hydrogen (H), hydroxy- (OH), thiol- (SH), methoxy- (CH3O), ethoxy-(CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CHs^CHO), isobutoxy-((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy-(CF3O), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio-((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), (2-methylprop-1-en-1-yl)oxy- ((CH3)2CCHO), and (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS). In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is hydrogen (H).

[0178] In another embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is absent. In an exemplary embodiment, wherein the (A) is according to formula 3 of the compound, the R1 is absent when the Z3 is selected independently from nitrogen (N), (NH), sulfur (S) and oxygen (O), and the Z2 is selected independently from nitrogen (N), sulfur (S), and oxygen (O).

[0179] In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R2 is selected from hydrogen (H) or methyl- (CH3). In an embodiment, wherein the (A) isaccording to the formula 3 of the compound, the R2 is hydrogen (H). In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R2 is methyl- (CH3). In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0180] - the (A) is according to the formula 3 and comprises the Z1 - Z5, wherein four of the Z1 -Z5 are independently selected from carbon (C) and (CH), and one of the Z1 - Z5 is independently selected from nitrogen (N), (-NH), sulfur (S);

[0181] - the R1 is selected from selected from hydrogen (H), hydroxy- (OH), thiol- (SH), methoxy-(CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), (2-methylprop-1-en-1-yl)oxy-((CH3)2CCHO), and (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS); and

[0182] - the R2 is selected from hydrogen (H) or methyl- (CH3).

[0183] In an embodiment, the compound of the present disclosure is the compound of the formula 1 , wherein the (A) is according to the formula 3 of the compound, and the (A) comprises Z1 - Z5, wherein one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and four of the Z1 -Z5, are independently selected from carbon (C) and (CH). In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0184] - the (A) is according to the formula 3 of the compound, and the (A) comprises Z1 - Z5, wherein one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and four of the Z1 - Z5, are independently selected from carbon (C) and (CH);

[0185] - the R1 is selected from the R1 substituents methoxy- (CH3O), and hydrogen (H), and - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3).

[0186] In an embodiment, wherein the (A) is according to the formula 3 of the compound, the selected R1 and R2 substituents exhibit a good binding affinity to target protein(s) of Complex I and thus, inhibition of OXPHOS of mitochondrial respiration inside a cell.

[0187] In an embodiment, wherein the (A) is according to the formula 2 or 3 of the compound, the R1 and the R2 are selected from:

[0188] - the R1 is methoxy- (CH3O), and the R2 is hydrogen (H);

[0189] - the R1 is hydrogen (H), and the R2 is methyl- (CH3);

[0190] - the R1 is methoxy- (CH3O), and the R2 is methyl- (CH3);

[0191] - the R1 is (CF3O), and the R2 is hydrogen (H); and

[0192] - the R1 is dimethylamino- ((CHs^N), and the R2 is hydrogen (H).In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0193] - the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is independently (CH),

[0194] - the R1 is selected from the R1 substituents methoxy- (CH3O), dimethylamino- ((CHs^N), and trifluoromethoxy- (CF3O), and

[0195] - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3);

[0196] or wherein

[0197] -the (A) is according to the formula 3 of the compound, and comprises Z1 - Z5, wherein one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and four of the Z1 - Z5, contain carbon,

[0198] - the R1 is selected from the R1 substituents methoxy- (CH3O), and hydrogen (H), and - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3).

[0199] In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is methoxy- (CH3O), and the R2 is hydrogen (H). In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R1 is hydrogen (H), and the R2 is methyl-(CH3).

[0200] In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is methoxy- (CH3O), and the R2 is methyl- (CH3). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is (CF3O), and the R2 is hydrogen (H). In an embodiment, wherein the (A) is according to the formula 2 of the compound, the R1 is dimethylamino- ((CHs^N), and the R2 is hydrogen (H).

[0201] In an embodiment, wherein the (A) is according to the formula 3 of the compound, the R2 is a fluoride or bromide containing substituent.

[0202] In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0203] - the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is selected from (CH) and (CF);

[0204] - the R1 has a number of heavy atoms of 2 to 5, and

[0205] - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3);

[0206] or

[0207] - the (A) is according to the formula 3 and comprises the Z1 - Z5, wherein four of the Z1 -Z5 contain carbon and one of the Z1 - Z5 is independently selected from nitrogen (N), (-NH) and sulfur (S);- the R1 is selected from selected from hydrogen (H) , hydroxy- (OH), thiol- (SH), methoxy-(CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), (2-methylprop-1-en-1-yl)oxy-((CH3)2CCHO), and (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS); and

[0208] - the R2 is selected from hydrogen (H) or methyl- (CH3).

[0209] In an embodiment, regardless whether the compound according to the formula 1 comprises the (A) according to the formula 2 or 3, the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as shown in the examples. In an embodiment, regardless whether the compound according to formula 1 comprises (A) according to the formula 2 or according to the formula 3, the substituents R3 to R6 can be selected similarly, as disclosed herein. Therefore, the selected R3-R6 substituents contribute to the binding affinity to target protein(s) of Complex I and to inhibition of OXPHOS, regardless whether the compound comprises (A) according to the formula 2 or according to the formula 3. In an embodiment, the substituents R3-R6 described herein are selected so that they optimally contribute to the binding affinity to target protein(s) of Complex I and to inhibition of OXPHOS.

[0210] In an embodiment, the R3 of the compound is chloride- (Cl) or methyl- (CH3), and / or the R4 is hydrogen (H) or methyl- (CH3). In an embodiment, the R3 of the compound is chloride-(Cl) or methyl- (CH3), and / or the R4 is hydrogen (H) or methyl- (CH3), irrespective whether the (A) of the compound is according to the formula 2 or 3. In an embodiment, the R3 of the compound is chloride- (Cl) or methyl- (CH3). In an embodiment, the R4 is hydrogen (H) or methyl- (CH3). In an embodiment, wherein the (A) is according to the formula 2 or 3, the R3 is chloride- (Cl), and the R4 is hydrogen (H). In an embodiment, the R3 of the compound is chloride- (Cl) and the R4 is hydrogen. In an embodiment, the R4 is selected from the R-isomer and S-isomer of the R4 substituent.

[0211] In an embodiment, the R5 and / or the R6 of the compound are / is hydrogen (H). In an embodiment, wherein the (A) is according to formula 2 or 3 of the compound, the R5 and / or the R6 of the compound is / are hydrogen (H). In an embodiment, the R5 of the compound is hydrogen (H). In an embodiment, the R6 of the compound is hydrogen (H).

[0212] In an embodiment, the compound of the present disclosure is the compound of the formula 1, wherein:

[0213] - the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is independently (CH),- the R1 is selected from the R1 substituents methoxy- (CH3O), dimethylamino- ((CHs^N), and trifluoromethoxy- (CF3O), and

[0214] - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3);

[0215] or wherein

[0216] -the (A) is according to the formula 3 of the compound, and comprises Z1 - Z5, wherein one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and four of the Z1 - Z5, contain carbon,

[0217] - the R1 is selected from the R1 substituents methoxy- (CH3O), and hydrogen (H), and - the R2 is selected from the R2 substituents hydrogen- (H), and methyl- (CH3);

[0218] and wherein each of the R4, R5 and R6 are hydrogen (H).

[0219] In an embodiment, the compound according to the formula 1 is any one of the compounds KLC-004, KLC-005, KLC-048, KLC-049, KLC-050, KLC-051, KLC-052 and KLC-053. In an embodiment, the compound is configured to bind to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or to NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, inside a cell. In a preferred embodiment, the compound binds to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, inside a cell. In a most preferred embodiment, the compound binds to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, inside a cell and inhibits oxidative phosphorylation (OXPHOS) of mitochondrial respiration. In an embodiment, the compound according to the formula 1 is configured to bind to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or to NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, inside a cell, thereby inhibiting oxidative phosphorylation (OXPHOS). The present compound being configured to bind to ND1 and / or to NDLIFS7 of the mitochondrial complex I can be assessed by an in silico assessment of protein-ligand interactions in a binding analyses involving the tethered consensus structure of mitochondrial complex I, focusing on the ND1 and / or to NDLIFS7 subunits, and the present compound according to the formula 1, and by using a docking protocol MOE 2022.02 software suite (Chemical Computing Group Inc., Montreal, Canada), as explained in the example 2. In an embodiment, the compound is configured to bind to ND1 inside a cell. In an embodiment, the compound is configured to bind to ND1 and NDLIFS7 inside a cell, but preferably the compound is configured to bind to at least ND1 inside a cell. As used herein, the “configured to” means the compound is configured to perform the indicated function based on in its designed structural configuration, instead of just being suitable for performing the indicatedfunction. Thus, in an embodiment, the compound according to the formula 1 is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration, as it is configured to bind to ND1 and / or NDLIFS7 inside a cell. The compound according to the formula 1 is used for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0220] In an embodiment, at least one of the substituents R1 to R6, preferably at least the R1 and / or the R2, and / or the R3 of the compound is / are configured to bind to ND1, preferably with a calculated binding affinity contribution of the selected substituent R1 to R6, or the R1 , the R2, and / or the R3 substituent in comparison to hydrogen (H) resulting in Gibbs energy of binding (AG) that is less than 0 kcal / mol. In other words, at least one of the substituents R1 to R6 of the compound is / are configured to bind to ND1 in a way that is energetically more favorable than if a hydrogen atom were to bind there. This can be measured at least by comparing the energy changes (AG) of said two binding scenarios with computational modelling. In an embodiment, at least one, preferably at least two, more preferably at least three of the substituents R1 to R3 of the compound is / are configured to bind to ND1 inside a cell. In an embodiment, at least one of the substituents R1 to R6, preferably at least the R1 and / or the R2, and / or the R3 of the compound is / are configured to bind to ND1 , thereby inhibiting oxidative phosphorylation (OXPHOS) inside a cell.

[0221] In one embodiment, the substituent R1 of the compound is configured to bind to ND1 with a calculated binding affinity contribution of the R1, compared to hydrogen (H), resulting in a Gibbs energy of binding (AG) that is less than 0 kcal / mol. In one embodiment, the substituent R2 of the compound is configured to bind to ND1 with a calculated binding affinity contribution of R2, compared to hydrogen (H), resulting in a Gibbs energy of binding (AG) that is less than 0 kcal / mol. In one embodiment, the substituent R3 of the compound is configured to bind to ND1 with a calculated binding affinity contribution of R3, compared to hydrogen (H), resulting in a Gibbs energy of binding (AG) that is less than 0 kcal / mol. In an embodiment, the substituents R1 to R6, preferably at least one of the substituents R4, the R5 and / or the R6 of the compound is / are configured to bind to ND1 and / or NDLIFS7, preferably with a calculated binding affinity contribution of the selected R1 to R6, or the R4, the R5 and / or the R6 substituent in comparison to hydrogen (H) resulting in Gibbs energy of binding (AG) that is less than 0 kcal / mol. In other words, at least one of the substituents R1 to R6 of the compound is / are configured to bind to ND1 and / or NDLIFS7 in a way that is energetically more favorable than if a hydrogen atom were binding there.

[0222] In an embodiment, at least one of the substituents the R1, the R2 and / or the R3 of the compound is / are configured to bind to ND1 , and at least one of the substituents the R4, theR5 and / or the R6 of the compound is / are configured to bind to ND1 and / or NDLIFS7, inside a cell. In an embodiment, at least one of the substituents the R1, the R2 and / or the R3 of the compound is / are configured to bind to ND1, and at least one of the substituents the R4, the R5 and / or the R6 of the compound is / are configured to bind to NDLIFS7, inside a cell. In an embodiment, at least one of the substituents the R1, the R2 and / or the R3 of the compound is / are configured to bind to ND1, and at least one of the R4, the R5 and / or the R6 of the compound is / are configured to bind to ND1, inside a cell. In an embodiment, the compound with the specified binding affinities is advantageous as it enhances the compound's binding its target, and thus, the ability of the compound to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0223] In an embodiment, the compound according to the formula 1 is configured to bind to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or to NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, and it is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration, as evidenced by a reduction in cellular oxygen consumption rate (OCR) observed in vitro and / or in v / vo.ln an embodiment, the compound has a calculated Log Partition Coefficient (cLogP) of 0-4, and / or a Topological Polar Surface Area (TPSA) of 79-140 A2. In an embodiment, the structure and composition of the compound, especially the composition of the substituents R1 to R6 is selected so that the compound has a calculated Log Partition Coefficient (cLogP) of 0-4 and / or a Topological Polar Surface Area (TPSA) of 79-140 A.

[0224] Calculated Log Partition Coefficient (cLogP) is a measure of how hydrophobic (waterrepelling) or hydrophilic (water-attracting) a compound is. It is calculated as the logarithm of the partition coefficient between n-octanol and water. A cLogP value between 0 - 4 indicates that the compound is drug-like and has a balanced hydrophilicity and hydrophobicity, which may enhance its absorption and permeation. The cLogP values are herein calculated using the MOE 2022.02 software suite (Chemical Computing Group Inc., Montreal, Canada). In one embodiment, the compound with the specified cLogP and / or TPSA values is advantageous as it enhances the compound's drug-likeness and administration in biological systems.

[0225] A topological Polar Surface Area (TPSA) is a measure of the surface area of a molecule that is occupied by polar atoms (usually oxygen and nitrogen) and their attached hydrogen atoms. TPSA is used to predict the ability of a compound to permeate biological membranes. The TPSA value between 79-140 A2indicates that the compound has a moderate / high polar surface area, which is important for its solubility and ability to crossbiological barriers. The Topological Polar Surface Area (TPSA) is calculated by MOE 2022.02 software suite (Chemical Computing Group Inc., Montreal, Canada).

[0226] In an embodiment, there is provided a pharmaceutical composition comprising the compound of the first aspect as an active ingredient, and at least one further component selected from a pharmaceutically acceptable carrier, excipient and / or adjuvant. In an embodiment, the pharmaceutical composition comprises the compound as an active ingredient, and at least one pharmaceutically acceptable carrier; and optionally one or more pharmaceutically acceptable excipient(s).

[0227] In an embodiment, the pharmaceutical composition comprises the compound as an active ingredient in a form selected from a salt, solvate, crystal, prodrug, an antibody conjugated drug (ACD) or a combination thereof. Such forms of the active ingredient are beneficial for enhancing the stability, solubility, and / or bioavailability of the active ingredient.

[0228] In an embodiment, the pharmaceutical composition comprises the compound as an active ingredient, and at least one pharmaceutically acceptable carrier selected from: solvents, dispersion media, cyclodextrins, silica-based carriers, liposomes, micelles, nanoparticles, antibody-conjugated drugs coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents. Cyclodextrins are beneficial carriers as these can form inclusion complexes with drugs to improve their solubility and stability. Silica-based carriers are beneficial, as they can be used for controlled drug release. In an embodiment, also hydrogels, micro needles, implants, transdermal patches, inhalers, and nebulizers can be considered as carriers, used for the delivery of the active ingredient of the pharmaceutical composition.

[0229] Including at least one pharmaceutically acceptable carrier to the pharmaceutical composition is beneficial for ensuring the stability, efficacy, and safety of the active ingredient, and the pharmaceutical composition as a whole.

[0230] In an embodiment, the pharmaceutical composition comprises the compound as an active ingredient, and at least one pharmaceutically acceptable excipient selected from: binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors, antioxidants, preservatives, chelating agents, and colors.

[0231] In an embodiment, the pharmaceutical composition comprises the present compound as an active ingredient, and at least one pharmaceutically acceptable adjuvant selected from immunostimulants, adsorption enhancers, buffers, tonicity adjusters, viscosity modifiers, humectants, plasticizers, surfactants, solubilizers, and stabilizers.In an embodiment, the pharmaceutical composition comprises the present compound as an active ingredient, and at least one additional active ingredient selected from an additional OXPHOS inhibitor, such as metformin or phenformin. In an embodiment, the pharmaceutical composition comprises the present compound as an active ingredient, and at least one additional active ingredient selected from Aurora Kinase A inhibitor, CHK1 (Checkpoint Kinase 1) inhibitor, Poly(ADP-Ribose) Polymerase (PARP) inhibitor, CDK1 (Cyclin-Dependent Kinase 1) inhibitor, ATR (Ataxia Telangiectasia and Rad3 Related) inhibitor, PI3K / AKT / mTOR Pathway inhibitor, MCL1 (Myeloid Cell Leukemia-1) inhibitor, Nucleoside analog Gemcitabine, Complex I inhibitor, Complex III inhibitor, AMP-activated protein kinase activator, bromodomain and extra-terminal (BET) protein inhibitor, CBP / p300 inhibitor, FLT3 (fms-related tyrosine kinase) inhibitor, selective estrogen receptor modulator / degrader, selective androgen receptor modulator / degrader, or combinations thereof.

[0232] In some embodiments, a total population of cancer cells, e.g., the total population of cancer cells in a subject, the total population of cancer cells in an organ, the total population of cancer cells in a biological tissue, or the total population of cancer cells in a sample of cancer cells, may be composed of multiple sub-populations of cancer cells with distinct metabolic activity. One sub-population of cancer cells may rely on OXPHOS in order to satisfy their metabolic needs, while a second sub-population of cancer cells may not rely on OXPHOS in order to satisfy their metabolic needs and may instead rely on an alternative metabolic pathway, e.g., glycolysis. Thus, the present pharmaceutical composition comprising more than one active ingredient, in addition to the present compound according to the formula 1 , is advantageous as it can be used in treatment of cancers composed of multiple sub-populations of cancer cells with distinct metabolic activities.

[0233] Non-limiting examples of additional active ingredients / components that can be used in the treatment of disease, such as cancer, and which can be administered with the compound according to the formula 1, and / or the pharmaceutical composition, include but are not limited to: Lapatinib (Tykerb®), Temozolomide (Temodar®), Irinotecan (Camptosar®), Olaparib (Lynparza®), Doxorubicin (Adriamycin®), Temsirolimus (Torisel®), Gemcitabine (Gemzar®), Erlotinib (Tarceva®), Carboplatin (Paraplatin®), Paclitaxel (Taxol®), Bevacizumab (Avastin®), Ipilmumab (Yervoy®), Gefitinib (Iressa®), Apatinib, Vandetanib, (Caprelsa®), Sorafenib (Nexavar®), Dabrafenib (Tafinlar®), Vemurafenib (Zelboraf®), Fulvestrant (Faslodex®), Alpelisib (Piqray®), Palbociclib (Ibrance®), Letrozole (Femara®), Trastuzumab (Herceptin®), Pertuzumab (Perjeta®), Nelfinavir (Viracept®), Bortezomib (Velcade®), Disulfiram (Antabuse®), Ritonavir (Norvir®), Memantine hydrochloride(Namenda®), Mefloquine (Lariam®), Chloroquine, Metronomic Cyclophosphamide, Liposomal Doxorubicin (Caelyx®), Docetaxel (Taxotere®), Rituximab (Rituxan®), Cyclophosphamide (Cytoxan®), Vincristine (Marqibo®), Prednisone (Rayos®), Everolimus (Zortress®), Exemestane (Aromasin®), Temsiroliumus (Torisel®), Sapanisertib, Rapamycin (Rapamune®), Trametinib (Mekinist®), Sintilimab (Tyvyt®), Nivolumab (Opdivo®), Durvalumab (Imfinzi®), Pembrolizumab (Keytruda®), Tamoxifen, Raloxifene (Evista®), Elacestrant (Orserdu®), Metformin, Phenformin, Omomyc, IACS-10759, BAY 87-2243, mubritinib, IM156, Midostaurin (Rydapt®), Gilteritinib (Xospata®), Quizartinib (Vanflyta®), Pelabresib, BMS-986158, ZEN-3694, Inobrodib, GNE-781, Talazoparib (Talzenna®), Abemaciclib (Verzenio®) Ribociclib (Kisqali®), Neratinib (Nerlynx®), Capecitabine (Xeloda®), Ascorbic acid, Anastrozole (Arimidex®), Exemestane (Aromasin®), Darolutamide (Nubeqa®), Rucaparib (Rubraca®), Leuprolide, Arsenic Trioxide (Trisenox®), Bleomycin, Nicotinamide riboside, Nicotinamide mononucleotide, Niacin, Nicotinamide, Canagliflozin (Invokana®), Dapagliflozin (Farxiga®), Empagliflozin (Jardiance®), Ertugliflozin (Steglatro®), Imatinib (Gleevec®), Cisplatin, Enzalutamide (Xtandi®), Lenalidomide (Revlimid®), Ibrutinib (Imbruvica®), Abiraterone acetate (Zytiga®), Idebenone (Raxone), Mitoquinone mesylate, Venetoclax (Venclexta®, Venclyxto®), MIK-665, EPI-589, and Rosiglitazone (Avandia®).

[0234] Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, an antibody conjugated drug (ACD), prodrug, or deuterated analog thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts.

[0235] In an embodiment, the pharmaceutical composition is formulated as an injectable, a tablet, a patch, an extended-release formulation, a capsule, a topical formulation, inhalable formulation, suppository, a solid dosage, or a formulation into sprays or drops. The various formulations ensure that the pharmaceutical composition can be tailored to meet specific therapeutic requirements, enhancing the overall effectiveness of the treatment.

[0236] The pharmaceutical composition is used for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. The compound according to the formula 1 and the pharmaceutical composition are advantageous as they provide a targeted cytotoxicity to specific cell types, such as cancer cells, with fewer off-target effects onnormal, non-cancerous cells. This selective inhibition of OXPHOS reduces the energy supply to cancer cells, inhibiting their growth and proliferation. The compound and / or the pharmaceutical composition can also be used in the treatment of other medical conditions or diseases that benefit from the inhibition of OXPHOS, such as cardiovascular diseases, diabetes (type II), polycystic ovarian syndrome, mitochondrial dysfunction, metabolic disorders, neurodegenerative diseases, progeria and other anti-aging related conditions. Additionally, the compound and / or the pharmaceutical composition can enhance the effectiveness of other treatments, such as radiation and immunotherapy, by sensitizing cancer cells to these therapies.

[0237] In an embodiment, the pharmaceutical composition comprises the compound according to the formula 1 wherein said compound is present in an amount effective to treat or prevent a specific disease or condition, such as cancer.

[0238] In an embodiment, the pharmaceutical composition is part of a kit, comprising the pharmaceutical composition and optionally, one or more additional components aiding the delivery of the pharmaceutical composition.

[0239] In an embodiment, there is provided a use of the compound or the pharmaceutical composition, for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. In an embodiment, there is provided a use of the compound or the pharmaceutical composition, for non-therapeutic inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. In an embodiment, there is provided a use of the compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition comprising said compound, for the inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell. Such use is beneficial, as the inhibition of OXPHOS inside cell results in energy deficit and oxidative stress induce cell death, particularly in cells that rely heavily on mitochondrial respiration, such as cancer cells. In an exemplary embodiment, the compound or the pharmaceutical composition is used in in vitro in cells. In an embodiment, there is provided a non-therapeutic use of the compound according to formula 1, a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition comprising said compound, for the inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration in cells.

[0240] In some embodiments, the compound or the pharmaceutical composition of the present disclosure is used by mixing it under sterile conditions with at least one further component selected from a pharmaceutically acceptable excipient, carrier, and / or adjuvant, and withany preservatives, buffers or propellants that are required, and optionally, delivering said mixed composition to a population of cells.

[0241] In an embodiment, herein is disclosed a process for preparing the pharmaceutical composition, the process comprising the steps of: a) providing the compound according to the formula 1 , a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient; and b) mixing the compound according to the formula 1 , a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, with at least one pharmaceutically acceptable carrier, excipient and / or diluent. In an embodiment, the present compound, or the present pharmaceutical composition is for use as a medicament.

[0242] In an embodiment, the present compound or the present pharmaceutical composition is for use in treatment of cancer. In an embodiment, the present compound or the present pharmaceutical composition, is for use in a treatment of breast cancer and / or lymphoma. In an embodiment, the present compound or the present pharmaceutical composition is for use in treatment of breast cancer and / or lymphoma, wherein the treatment comprises inhibiting mitochondrial oxidative phosphorylation (OXPHOS) in cells.

[0243] In an embodiment, the present compound or the present pharmaceutical composition is for use in treatment of cancer expressing elevated levels of Myc.

[0244] In an embodiment, the present compound or the present pharmaceutical composition is for use in treatment of breast cancer and / or lymphoma expressing elevated levels of Myc. In an embodiment, the present compound or the present pharmaceutical composition, wherein the compound specifically binds to ND1 and / or NDLIFS7 of the mitochondrial complex I, for use in treatment of cancer.

[0245] In an embodiment, there is provided the compound or the pharmaceutical composition for use in inhibiting oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, preferably for use in therapeutics, more preferably for use in treatment of a patient, more preferably for use in treatment of a cancer, even more preferably for treatment of a breast cancer.

[0246] In an embodiment, herein is provided the compound or the pharmaceutical composition for use wherein the compound and / or the pharmaceutical composition is used for treating a disorder, comprising administering to a subject an effective amount of the compound and / or the pharmaceutical composition.In an embodiment, the compound or the pharmaceutical composition is for use in therapeutics, preferably in treatment of a patient, more preferably in treatment of a cancer, even more preferably in treatment of a breast cancer.

[0247] In an embodiment, the compound according to the formula 1 or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition comprising the compound according to the formula 1 , is provided for use in a treatment of cancer by inhibiting oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside cells, preferably the cancer is breast cancer or lymphoma, more preferably the cancer is a breast cancer or lymphoma expressing elevated levels of Myc. In an embodiment, the compound according to the formula 1 , or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition comprising the compound according to the formula 1, is provided for use in the treatment of triple-negative breast cancer (TNBC) or lymphoma exhibiting elevated MYC expression, by inhibiting mitochondrial OXPHOS inside cells.

[0248] In an embodiment, disclosed herein is a use of the compound according to the formula 1 or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for preparation of a medicament for the treatment of a cancer, in combination with any one or more of the embodiments, compounds, formulations, dosing regimens, or administration routes disclosed herein. In such an embodiment, said medicament is administered in a therapeutically effective amount to a subject in need thereof by a parenteral route, including intravenous, intramuscular or subcutaneous injection or infusion, or by oral administration. In an embodiment, the compound and / or the pharmaceutical composition is for use for treating cancer. In an embodiment, the cancer is a solid tumor. In some embodiments, the cancer is a metastasis. Particular types of cancer that may be treated with the compound and / or with the pharmaceutical composition, include breast cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, rectal cancer, uterine cancer, vaginal or vulvar cancer, testicular cancer, kidney cancer, hepatic cancer, bile duct cancer, cholangiocarcinoma, gallbladder cancer, melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, BRAF-mutant metastatic melanoma, prostate cancer, castrateresistant prostate cancer, thyroid cancer, glioblastoma, endometrial cancer, ovarian cancer, cervical cancer, brain cancer, glioblastoma, liver cancer, colorectal cancer, skin cancer, basal cell carcinoma, squamous cell carcinoma, melanoma, gynecologic cancer, head or neck cancer, mesothelioma, myeloma, esophageal cancer, and gastric cancer.

[0249] In an embodiment, the compound or the pharmaceutical composition is advantageous as it can be used in a treatment of various medical conditions by selectively targeting tissuesand cells, e.g. selectively targeting cancerous cells, such as cells expressing elevated levels of Myc. In an embodiment, the compound or the pharmaceutical composition is used in treatment of a cancer expressing elevated levels of Myc, such as breast cancer expressing elevated levels of Myc. Cancers expressing elevated levels of Myc can exhibit an increased dependency on oxidative phosphorylation, rendering them more sensitive to Complex I inhibition. Therefore, the present compound or the pharmaceutical composition can exhibit advantageous anticancer effects when used in inhibiting oxidative phosphorylation of a cancer expressing elevated levels of Myc. Thus, in some embodiments, the present compound is advantageous as it shows improved selective inhibition of OXPHOS inside a cancer cell expressing elevated levels of Myc, when compared to a cancer cell expressing low or basal levels of Myc.

[0250] In an embodiment, the compound or the pharmaceutical composition can be formulated in various dosage forms to accommodate different routes of administration and therapeutic needs. In an embodiment, the compound or the pharmaceutical composition may be provided in a dosage form that is suitable for sublingual, buccal, oral, parenteral (e.g., intravenously, intramuscularly), pulmonary, intranasal, transdermal, vaginal, or rectal administration route. In a preferable embodiment, the administration route of the compound or the pharmaceutical composition is selected from intravenous (IV), intramuscular (IM), subcutaneous (SC), or intraperitoneal (IP) route of administration.

[0251] In an embodiment, the compound or the pharmaceutical composition is in the form of, e.g., injectables, solid dosages such as tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, extended-release formulations, inhalables, ointments, creams, plasters, patches, drenches, osmotic delivery devices, suppositories, enemas, injectables, sprays, vapors, or aerosols, or drops.

[0252] In an embodiment, the compound and / or the pharmaceutical composition, is administered to a subject with or without a second active ingredient or component.

[0253] The administration of the compound and / or the pharmaceutical composition can be done by any suitable means that results in the desired therapeutic treatment, such as treatment of cancer. The compound can be contained in the pharmaceutical composition in any appropriate amount.

[0254] In an embodiment, the use of the compound or the pharmaceutical composition has several benefits. In an exemplary embodiment, the compound shows selective cytotoxicity towards cancer cells over healthy, non-cancerous cells, reducing the risk of adverse effects. In an embodiment, the compound can also enhance the effectiveness of other treatments, suchas chemotherapy, radiation, and immunotherapy, by sensitizing cancer cells to these therapies. When used together with other treatment(s), in a combination therapy, the compound or the pharmaceutical composition can significantly enhance therapeutic efficacy while concurrently reducing adverse effects. This approach may allow for the utilization of lower doses of individual agents, which collectively achieve the desired therapeutic outcome. By leveraging the synergistic effects of multiple agents / treatments, combination therapies can optimize treatment regimens, improving patient outcomes and minimizing the risk of adverse effects.

[0255] In an embodiment, the use of the compound or the pharmaceutical composition comprises administering an effective amount of the compound or the pharmaceutical composition, which effective amount refers to an amount sufficient to effect beneficial or desirable biological and / or clinical effects. In an embodiment, the use of the compound or the pharmaceutical composition is a method of using the compound or the pharmaceutical composition. Thus, in the context of this disclosure a use can refer to a method of using.

[0256] EXAMPLES

[0257] Example 1. Computational platform for the physicochemical characterization of compounds

[0258] For the characterization of the physicochemical parameters of different compounds according to the formula 1 , cLogP and TPSA were calculated.

[0259] cLogP (calculated Log Partition Coefficient) measures the lipophilicity of a compound, reflecting its ability to dissolve in fats, oils, and non-polar solvents. This parameter can be used for example, to estimate how a compound will interact with biological membranes and its overall solubility character. High cLogP values generally indicate enhanced membrane permeability but can also result in poor water solubility and increased potential for toxicity. TPSA (Topological Polar Surface Area) quantifies the polar surface area of a molecule, which includes regions with nitrogen, oxygen, and attached hydrogen atoms. TPSA is used to predict the compound’s ability to permeate cell membranes and its overall solubility. Lower TPSA values are often associated with enhanced cell membrane permeability, while higher values often indicate improved solubility in water.

[0260] The calculation of the logarithm of the octanol / water partition coefficient (cLogP) in the MOE 2022.02 software suite (Chemical Computing Group Inc., Montreal, Canada) involves using an 8-parameter model based on Hueckel Theory. This model incorporates various molecular descriptors to predict the partitioning behaviour of a compound between octanoland water. The accuracy of the model is indicated by a coefficient of determination (r2) value of 0.84 and a root mean square error (RMSE) of 0.59, based on a dataset of 1,836 molecules. The calculated cLogP value corresponds to the protonation state of the structure as depicted in the MOE.

[0261] The calculation of the topological polar surface area (TPSA) in the MOE software is based on the summation of fragment contributions. TPSA is a 2D molecular descriptor that quantifies the polar surface area of a molecule, which is important for predicting drug absorption, distribution, and permeability. The MOE software calculates TPSA by summing predefined fragment contributions based on empirical data.

[0262] The calculated physicochemical parameter cLogP was 0.75 and the calculated TPSA was 102.02 A2for the compound according to the formula 1, KLC-004, wherein the KLC-004 is shown below:

[0263]

[0264] Example 2. Tautomers and protein-ligand interaction assessment

[0265] Tautomers:

[0266] A set of possible tautomers of the compound according to the formula 1 were designed. Similarly, the tautomers of the R1 of the compound according to the formula 1 were presented.

[0267] Some of the exemplary possible tautomers (l)-(VIII) of compound according to the formula 1 (Fig. 1) and some of the exemplary possible tautomers (l)-(l V) of the R1 substituents of the compound according to the formula 1 (Fig. 2) are included herein, to exemplify some of the alternative possible tautomers of the compound 1 and R1 substituents, respectively. The tautomers presented in the Figs 1. and 2 are alternative Lewis structures of a molecule, as understood in organic and theoretical chemistry. These tautomers typically differ by the position of a proton and by changes in the bonding structure.

[0268] Protein-ligand interaction assessment:

[0269] The protein-ligand interaction between the designed compounds according to the formula 1 and its binding partners was assessed. The in silico assessment of protein-ligand interactions and the corresponding binding energy estimates (in kcal / mol) were derived from theoretical binding analyses involving the tethered consensus structure of mitochondrialcomplex I, specifically focusing on the NADH-ubiquinone oxidoreductase chain 1 (ND1) and NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) subunits, and the designated ligand, i.e. the designed compound(s) according to the formula 1.

[0270] Docking protocol used for assessing protein-ligand interactions was the MOE 2022.02 software suite (Chemical Computing Group Inc., Montreal, Canada), which was utilized for the protein modelling and docking experiments. Consensus model of experimentally and computationally determined protein structures were employed in this study: mitochondrial Complex I from Mus musculus (PDB 7B93) and from Bos taurus (bovine) (PDB 5LDW, 5031, 7QSM, 7QSN, 7R45, 7R46, 7R47, 7R48, 7R4C, 7R4D, 7R4F, 7R4G). Additionally, the corresponding Complex I substructures for human, rat, and mouse were downloaded from AlphaFold. The initial structure preparation for protein-ligand complex involves several independent steps: first, hydrogens are added and positioned; tethers are assigned; and finally, energy minimization is performed. During the docking evaluation, selected ligands were positioned within the ubiquinone binding site (Q-site) of the consensus model of Complex I by using the Triangle Matcher algorithm. These conformations were subsequently assessed with the London dG scoring function, utilizing the AmberlO-Extended Huckel Theory force field. The top 30 ranked poses were then subjected to a refinement process involving energy minimization and re-evaluation using the Generalized-Born Volume Integral / Weighted Surface area (GBVI / WSA dG) scoring function.

[0271] This described docking evaluation was also used, when assessing the binding affinity for the different R1 substituents, and the results are shown in Table 1. The computation calculation of the binding affinities to mitochondrial Complex I of the R1 substituents in the table 1 were calculated for the compound wherein the (A) is according to formula 2, and wherein the R2 substituent is (H), and Xi, X2, and X3 represent either (CH) or nitrogen (N), as in the compound according to the formula 1 below:

[0272]

[0273] Table 1. Selected examples of computational calculations of a binding affinity for the R1 substituents, wherein the (A) is according to the formula 2 of the compound. These calculations highlight priority and categorization of the R1 substituents presented based onthe number of heavy atoms (excluding hydrogen, H) in the R1 substituent. These selected exam . ..

[0274] ...ples were prepared for the compound wherein the (A) is according to formula 2, and W <<<<<<<<<<<<<

[0275] wherein the Xi, X2, and X3 represent either carbon (CH) or nitrogen (N), and wherein the lli I

[0276] R2 is hydro 'gk & ..en (H). The table provides the structure, the molecular weight (g / mol), the ^ <<<<<<

[0277] number of heavy atoms, the binding affinity (kcal / mol) and R1 category, for each R1 substituent.

[0278] Heavy

[0279] Molecular Binding

[0280] atoms R1 R1

[0281] R1 Substituent Weight affinity

[0282] (other than Category

[0283] R1 kcal / mol

[0284] H)

[0285] ,.5:^XV

[0286] 70 5 -8.83 1

[0287] ; H

[0288] 71 5 -8.78 1

[0289] 72 5 -8.77 1

[0290] 89 5 -8.76 1

[0291] ■V *

[0292] 71 5 -8.74 1

[0293] / b

[0294] 4

[0295] . \

[0296] /

[0297] 87 5 -8.74 1

[0298] 71 5 -8.71 1

[0299] 'V5' 'O'' 71 5 -8.67 1

[0300] 85 5 -8.09 1

[0301] F-o

[0302] 59 4 -8.64 2

[0303] 75 4 -8.55 2

[0304] 55 4 -8.46 2

[0305]

[0306] 59 4 -8.41 2

[0307] / T 59 4 -8.35 2

[0308] V

[0309] 69 4 -8.07 2

[0310] i J 43 3 -8.33 3

[0311] X 43 3 -8.22 3

[0312] ■xs,A> 47 2 -8.13 4

[0313] 31 2 -7.93 4

[0314] Qr 15 1 -7.98 5

[0315] 33 1 -7.93 5

[0316] 35 1 -7.93 5

[0317] cK f "'T

[0318] 17 1 -7.87 5

[0319] . .. 1 0 -7.70 6

[0320]

[0321] The R1 substituents listed in Table 1 show enhanced binding affinity (kcal / mol) to mitochondrial Complex I as the category number decreases. Generally, lower binding affinity values indicate stronger interactions, meaning the R1 substituent binds more tightly to a target protein. As the number of heavy atoms in the R1 substituent increases, the binding affinity, calculated using computational chemistry and molecular modelling, also improves, showing a Gibbs energy of binding (AG) less than 0 kcal / mol when compared to hydrogen (H). This calculation of binding affinity, AG, is advantageous for estimating the compound's binding affinity to the desired target proteins in vitro and / or in vivo, thereby serving as a valuable criterion for ranking and assessing of drug-target interactions. Therefore, these results indicate the R1 substituents having the lowest binding affinity provide the most potent binding to the target protein (s), and thus, Complex I inhibition. These results indicate that R1 substituents exhibiting lower calculated binding affinity valuesare associated with stronger binding to the ND1 and / or NDLIFS7 subunits of mitochondrial complex I, thereby resulting in enhanced inhibition of oxidative phosphorylation (OXPHOS) inside a cell.

[0322] Example 3. Synthesis of KLC-004 (compound 5(l) in Figure 3a)

[0323] The following explains a step-wise synthesis of one of the compounds according to the formula 1, KLC-004. Herein, a reference is made to synthesis steps A-D and compounds 1- 5(l) in Figure 3 a.

[0324] To a suspension of a compound 1 hydrochloride (1 g 3.69 mmol) in DCM (10 mL) was added TEA (0.75g, 7.38 mmol) and the mixture was cooled to 0 °C. Then a solution of Boc2O (0.8 g, 3.69 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was stirred for 24 h. The resulting mixture was washed with NaHSC (twice) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give compound 2 (0.85 g, 69%).

[0325] B To a vial was added compound 2 (0.2 g 0.6 mmol), 4,4,5,5-tetramethyl-2-(2-methylthiophen-3-yl)-1,3,2-dioxaborolane (0.16 g, 0.72 mmol), and Na2COs (0.16 g, 1.5 mmol). Then dioxane: H2O (9:1, 4 mL) was added to the mixture. The reaction vial was purged with Ar. After that, Pd(dppf)CI2 (0.050 g, 0.06 mmol) was added. The reaction mixture was stirred at 95 °C overnight. The reaction progress was monitored by LCMS. After consumption of the starting material, the resulting mixture was diluted with water and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography to give compound 3 (0.11 g, 52%).

[0326] Compound 3 (0.110 g 0.31 mmol) was dissolved in dioxane (1 mL). Then dioxane / HCI (1 mL) was added. The reaction mixture was stirred at rt overnight and evaporated to dryness to give compound 4 which was used in the next step D without any purification.

[0327] D Crude compound 4 (0.100 g, 0.35 mmol) was mixed with cyanoguanide (0.030 g, 0.35 mmol) and stirred at 170 °C for 1 h. The crude reaction mixture was purified by prepHPLC to give compound 5(l), KLC-004 (0.056 g, 48% for 2 steps).

[0328] Example 4. Synthesis of KLC-005 (compound 7(l) in Figure 3b)

[0329] The following explains a step-wise synthesis of one of the compounds according to the formula 1, KLC-005. Herein, a reference is made to synthesis steps E-G and compounds 2 - 7(l) in Figure 3 b.Step E: To a vial was added compound 2 (0.2 g, 0.6 mmol, same compound 2 as in the Example 3), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)thiazole (0.16 g, 0.72 mmol), and Na2COs (0.16 g, 1.5 mmol). Then dioxane:H2O (9:1, 4 mL) was added to the mixture. The reaction vial was purged with Ar. After that, Pd(dppf)CI2 (0.050 g, 0.06 mmol) was added. The reaction mixture was stirred at 95 °C overnight. The reaction progress was monitored by LCMS. After consumption of the starting material, the resulting mixture was diluted with water and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography to give compound 5 (0.1 g, 47%).

[0330] Step F: Compound 5 (0.100 g, 0.28 mmol) was dissolved in dioxane (1 mL). Then dioxane / HCI (1 mL) was added. The reaction mixture was stirred at rt overnight and evaporated to dryness to give compound 6 which was used in the next step without any purification.

[0331] Step G: Crude compound 6 (0.030 g, 0.1 mmol) was mixed with cyanoguanide (0.008 g, 0.1 mmol) and stirred at 170 °C for 1 h. The crude reaction mixture was purified by prepHPLC to give compound 7(l), KLC-005 (0.009 g, 27% for 2 steps).

[0332] Example 5. Analysis of compounds KLC-004 and KLC-005

[0333] An NMR peak list and LC / MS spectra were prepared for the synthesized compounds KLC-004 and KLC-005.

[0334] The measurements of the nuclear magnetic resonance (NMR) spectra were recorded with BrukerAVANCE DRX500 Mhz and / or BrukerAVANCE III 400 Mhz. Chemical shifts (J) are reported in parts per million (ppm) relative to the NMR solvent signals. When necessary, two-dimensional NMR experiments (COSY, NOESY, gHSQC, gHMBC) were conducted to support structure determination. Multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets), t (triplet), q (quartet), sept (septet). The additional letter “br” indicates a broad signal, such as br s (broad singlet). Multiplets (m) are reported as a centered multiplet (m). Coupling constants J are quoted in Hertz (Hz).

[0335] Table 2. The NMR Peak list for the compounds KLC-004 and KLC-005.

[0336] i | 'H NMR (500 MHz. DMSO -fifes 6747 (m. 1H). 7.34 (d. 1H).

[0337] 1 | KLC-004 § 7.27 (m. 2H). 6.92 (d J = 5 .20 Hz. 8.8D'(brs. 2H);2.81 (t.

[0338] M = 736 Hz, 2H). 2.53 (m. 2H). 2.25 (s, 3H).

[0339] ]:H NMR (500 MHz, Mettiar 59.12 (s„ 1 H), 7.55 (s, 1 H), 2 KLC-005 | 7.41 (m, 1H)t7.38 (m, 1H), 3.64 (t, J = S.22 Hzt2H), 3.04 (t, J

[0340]

[0341] i s - 10.02 Hz, 2H), 2.37 (s, 3 H).The measurements of the LC / MS (Liquid Chromatography-Mass Spectrometry) spectra were executed with Agilent 1100 Series LC / MSD system, equipped with DAD\ELSD Alltech 2000ES and Agilent LC\MSD VL (G1956B), SL (G1956B) mass-spectrometer.

[0342] Samples were subjected to identification and purity analysis using liquid chromatography with diode array detection (DAD) at wavelengths of 215 nm and 254 nm, along with precise recording of retention times for the studied compounds and all detected impurities. Moreover, comprehensive scanning and molecular weight determination was performed using mass spectrometry with electrospray-atmospheric pressure ionization (ES-API), generating total ion chromatograms and individual ES-API detection of all principal signals in both positive and negative ionization modes. The analysis further incorporated signals from Evaporative Light Scattering Detection (ELSD).

[0343] Table 3. The LC / MS spectra measurements mass-to-charge ratios (m / z [M+H]) and Retention Time (Ret time, min) of the compounds KLC-004 and KLC-005.

[0344] I $ 1 I ; i l / \iLrC-nUnU4 / 1 I mfe * 336.0 Ret — Time: 1 .098 min | i I I I m / z [M+HH 3370 Ret Time: 0.960 min I ; | KLC-005 § |

[0345]

[0346] The synthesis of the compounds KLC-004 and KLC-005 were executed with meticulous precision, followed by extensive analytical characterization utilizing NMR and LC / MS. These analytical results unequivocally confirmed that the compound's identity and purity conform to stringent specifications. NMR spectroscopy (1H NMR) provided comprehensive structural elucidation, ensuring the accurate molecular configuration. LC / MS verified the compound's purities >95% and molecular weights, affirming the absence of any major impurities. Collectively, these results substantiate that all the synthesized compounds meet the highest standards of identity and purity, as mandated for its intended application.

[0347] Examples. Synthesis of compounds KLC-048, KLC-049, KLC-050, KLC-051, KLC-052, KLC-053

[0348] The following explains a step-wise synthesis of the compounds according to the formula 1 , KLC-048, KLC-049, KLC-050, KLC-051, KLC-052, KLC-053. Herein, a reference is made to synthesis steps A-S and compounds in Fig. 4 and in Fig. 5.

[0349] Synthesis of KLC-051: Scheme 1, Fig. 4: Step A

[0350] To a mixture of compound 1 (3.4 g, 12.55 mmol, as HCI salt) in DCM (35 mL) was added TEA (3.5 mL, 25.1 mmol) and cooled to 0 °C. Then a solution of Boc2O (2.74 g, 12.55mmol) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at rt overnight. Then the resulting mixture was washed with water (20 mL) and NaHSO4 (10% aq., 2 x 20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain compound 2 (3.8 g, 90%).

[0351] Synthesis of KLC-051: Scheme 1, Fig. 4: Step B:

[0352] To a mixture of compound 2 (0.500 g, 1.5 mmol) and Na2CO3 (0.400 g, 3.75 mmol) in dioxane:H2O (9:1, 5 mL) were added corresponding boronic acid (for Step B, N) or pinacol ester of corresponding boronic acid (for Step H, K, Q) (1.2 eq, 1.8 mmol). The mixture was evacuated and refilled with argon, then Pd(dppf)CI2 (0.061 g) was added. The reaction mixture was stirred for 16 h at 100 °C. Then the volatiles were removed, the residue was partitioned between water and EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by FCC (SiO2, Hex:EA from 100:0 to 50:50) to obtain the desired product: compound 3 (0.230 g, 41%)

[0353] Synthesis of KLC-051: Scheme 1, Fig. 4: Step C:

[0354] To a solution of compound 3 in dioxane (5 mL per 1 g) was added dioxane / HCI (5 mL per 1 g). The reaction mixture was stirred at rt overnight and concentrated in vacuo to obtain pure hydrochloride compound 4, in quantitative yields.

[0355] Synthesis of KLC-051: Scheme 1, Fiq. 4: Step D

[0356] A mixture of compound 4 (0.094 g, 0.3 mmol) and N-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain KLC-051 (0.015 g, 14%).

[0357] Synthesis of KLC-048: Scheme 2, Fig. 4: Step E

[0358] Compound 2 was obtained as in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step A”. To a mixture of compound 2 (0.500 g, 1.5 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole (0.670 g, 1.81 mmol) in dioxane (5 mL) was added Pd(PPh3)4 (0.175 g, 0.15 mmol) under an inert atmosphere. The reaction mixture was stirred for 16 h at 100 °C. The volatiles were removed, the residue was purified by prepHPLC to obtain compound 5 (0.232 g, 46%). Synthesis of KLC-048: Scheme 2, Fig. 4: Step F

[0359] The compound 5 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step C”, to obtain pure hydrochloride compound 6 in quantitative yields.

[0360] Synthesis of KLC-048: Scheme 2, Fiq. 4: Step G:

[0361] A mixture of compound 6 (0.081 g, 0.3 mmol) and / V-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain compound KLC-048 (0.036 g, 38%).

[0362] Synthesis of KLC-049: Scheme 3, Fig. 4: Step H:Compound 2 was obtained as in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step A”. The compound 2 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step B”, to obtain compound 7 (0.300 g, 60%).

[0363] Synthesis of KLC-049: Scheme 3, Fig. 4: Step I:

[0364] The compound 7 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step C”, to obtain pure hydrochloride compound 8 in quantitative yields.

[0365] Synthesis of KLC-049: Scheme 3, Fig. 4: Step J:

[0366] A mixture of compound 8 (0.160 g, 0.59 mmol) and N-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain compound KLC-049 (0.096 g, 51%).

[0367] Synthesis of KLC-050: Scheme 4, Fig. 5: Step K:

[0368] Compound 2 was obtained as in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step A”. The compound 2 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step B”, to obtain compound 9 (0.120 g, 15%).

[0369] Synthesis of KLC-050: Scheme 4, Fig. 5: Step L:

[0370] The compound 9 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step C”, to obtain pure hydrochloride compound 10 in quantitative yields.

[0371] Synthesis of KLC-050: Scheme 4, Fig. 5: Step M:

[0372] A mixture of compound 10 (0.120 g, 0.4 mmol) and / V-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain compound KLC-050 (0.031 g, 22%).

[0373] Synthesis of KLC-052: Scheme 5, Fig. 5: Step N:

[0374] Compound 2 was obtained as in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step A”. The compound 2 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step B”, to obtain compound 11 (0.480 g, 77%).

[0375] Synthesis of KLC-052: Scheme 5, Fig. 5: Step O:

[0376] The compound 11 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step C”, to obtain pure hydrochloride compound 12 in quantitative yields.

[0377] Synthesis of KLC-052: Scheme 5, Fig. 5: Step P:

[0378] A mixture of compound 12 (0.110 g, 0.31 mmol) and / V-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain compound KLC-052 (0.031 g, 25%).

[0379] Synthesis of KLC-053: Scheme 6, Fig. 5: Step Q:

[0380] Compound 2 was obtained as in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step A”. The compound 2 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step B”, to obtain compound 13 (0.490 g, 87%).Synthesis of KLC-053: Scheme 6, Fig. 5: Step R:

[0381] The compound 13 was treated as described in “Synthesis of KLC-051: Scheme 1, Fig. 4: Step C”, to obtain pure hydrochloride compound 14 in quantitative yields.

[0382] Synthesis of KLC-053: Scheme 6, Fig. 5: Step S:

[0383] A mixture of compound 14 (0.156 g, 0.5 mmol) and N-cyanoguanidine (1 eq) was melted at 170 °C for 50 min. The residue was purified by prepHPLC to obtain compound KLC-053 (0.034 g, 20%).

[0384] After the synthesis, the NMR spectra and Liquid Chromatography-Mass Spectrometry were performed with all the synthesized compounds. The measurements of the nuclear magnetic resonance (NMR) spectra and of the LC / MS were performed as described in the example 5.

[0385] The NMR Peak list measured for the compound KLC-048 was:1H NMR (500 MHz, DMSO-d6) 5 8.63 (br s, 1 H), 7.96 (br s, 1 H), 7.50 (m, 1 H), 7.30 (m, 2H), 6.83 (s, 1 H), 6.05 (t, J = 3.27 Hz, 1 H), 6.01 (d, J = 3.71 Hz, 1 H), 3.44 (m, 2H), 3.40 (s, 3H), 2.86 (m, 2H). The LC / MS spectra measurement mass-to-charge ratio (m / z [M+H]) and Retention Time (Ret time, min) of the compound KLC-0048 was: m / z [M+H]+ 319.0 Ret_Time: 0.839 min.

[0386] The NMR Peak list measured for the compound KLC-049 was:1H NMR (500 MHz, DMSO-d6) 5 7.57 (s, 1H), 7.48 (m, 1H), 7.27 (m, 2H), 6.98 (br s, 2H), 6.51 (s, 1H), 3.40 (m, 2H), 2.82 (m, 2H), 2.20 (s, 3H). The LC / MS spectra measurement mass-to-charge ratio (m / z [M+H]) and Retention Time (Ret time, min) of the compound KLC-049 was: m / z [M+H]+ 320.2 Ret_Time: 0.888 min.

[0387] The NMR Peak list measured for the compound KLC-050 was:1H NMR (500 MHz, DMSO-d6) 57.49 (d, J = 7.96 Hz, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 7.08 (d, J = 4.14 Hz, 1H), 6.95 (br s, 1H), 6.36 (d, J = 4.04 Hz, 1H), 3.88 (s, 3H), 3.36 (m, 2H), 2.80 (m, 2H). The LC / MS spectra measurement mass-to-charge ratio (m / z [M+H]) and Retention Time (Ret time, min) of the compound KLC-050 was: m / z [M+H]+ 352.0 Ret_Time: 0.982 min.

[0388] The NMR Peak list measured for the compound KLC-051 was:1H NMR (500 MHz, DMSO-d6) 57.46 (m, 1H), 7.26 (d, J = 6.73 Hz, 1H), 7.19 (m, 1H), 6.97 (m, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.47 Hz, 1H), 3.76 (s, 3H), 3.40 (m, 2H), 2.83 (m, 2H), 2.01 (s, 3H). The LC / MS spectra measurement mass-to-charge ratio (m / z [M+H]) and Retention Time (Ret time, min) of the compound KLC-051 was: m / z [M+H]+ 360.2 Ret_Time: 0.847 min.

[0389] The NMR Peak list measured for the compound KLC-052 was:1H NMR (500 MHz, DMSO-d6) 57.69 (br s, 1 H), 7.54 (m, 1 H), 7.52 (m, 2H), 7.44 (m, 2H), 7.38 (m, 1 H), 7.34 (m, 1 H), 3.42 (m, 2H), 2.84 (m, 2H). The LC / MS spectra measurement mass-to-charge ratio (m / z[M+H]) and Retention Time (Ret time, min) of the compound KLC-052 was: m / z [M+H]+ 400.2 Ret_Time: 1.255 min.

[0390] The NMR Peak list measured for the compound KLC-053 was:1H NMR (500 MHz, DMSO-d6) 57.43 (m, 2H), 7.28 (m, 5H), 7.05 (br s, 2H), 6.83 (br s, 2H), 3.34 (m, 2H), 2.94 (s, 6H), 2.80 (m, 2H). The LC / MS spectra measurement mass-to-charge ratio (m / z [M+H]) and Retention Time (Ret time, min) of the compound KLC-053 was m / z [M+H]+ 359.2 Ret_Time: 1.003 min.

[0391] The synthesis of the compounds KLC-048, KLC-049, KLC-050, KLC-051, KLC-052, KLC-053 were executed with meticulous precision, followed by extensive analytical characterization utilizing NMR and LC / MS. These analytical results unequivocally confirmed that the compound's identity and purity conform to stringent specifications. NMR spectroscopy (1H NMR) provided comprehensive structural elucidation, ensuring the accurate molecular configuration. The LC / MS analysis with diode array detection at wavelengths 215 nm and 254 nm, electrospray-atmospheric pressure ionization (ES-API) total ion chromatogram and individual ES-API detection of all major signals in both positive and negative ionization modes, ELSD signal, verified the compound's purities >95% and molecular weights, affirming the absence of any major impurities. Collectively, these results substantiate that all the synthesized compounds meet the highest standards of identity and purity, as mandated for its intended application.

[0392] Example 7. Complex-1 inhibition Measured by Oxygen Consumption Rate (OCR) The oxygen consumption rate (OCR) was measured to evaluate mitochondrial respiration in BT549 (MYChi) and MDAMB231 (MYC|OW) triple-negative breast cancer (TNBC) cells after overnight treatment with DMSO or KLC-004 at concentrations of 1 pM, 5 pM, and 10 pM. The OCR changes were recorded using analytical Agilent Seahorse Xfe96 equipment in real-time under sequential injection of mitochondrial inhibitors A-C. The assay was performed by following the instructions provided in the used Seahorse XF Mito Tox Assay Kit, and by measuring of the OCR changes as described by Pratibha Sharma et al. 2024. The reagents used in the assay were: A) Oligomycin (2 pM), B) FCCP (1 pM) and C) combined Rotenone and Antimycin A (0.5 pM) (in reference to Figs. 6 and 7). Oligomycin Inhibits ATP synthase (Complex V), reducing ATP-linked respiration. FCCP is a mitochondrial uncoupler that maximizes electron transport and oxygen consumption, indicating maximal respiratory capacity. Rotenone and Antimycin A inhibit Complex I and III, respectively, leading to complete mitochondrial respiration shutdown. These compounds are used in sequence to dissect different components of cellular respiration, providing a more detailed view of mitochondrial function under treatment with DMSO or KLC-004.The measured and analysed data, presented in Fig. 6 and Fig. 7 shows the kinetic graph of DMSO or KLC-004 treated MychiTNBC (BT549) cells expressing high levels of endogenous Myc (Fig. 6) and MyclowTNBC (MDAMB231) cells expressing low levels of endogenous Myc (Fig. 7) as means ± SD. These results demonstrate that KLC-004 impairs the basal respiration of the cancer cells, as well as the maximal respiratory capacity of the mitochondria thus compromising mitochondria's ability to respond to increased energy demand, therefore causing mitochondrial dysfunction. These results demonstrate that KLC-004 is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

[0393] These results further demonstrate that KLC-004 exhibits a stronger inhibitory effect on mitochondrial Complex I activity in MychiTNBC cells compared to MyclowTNBC cells. This indicates that compounds according to formula 1 , such as KLC-004, are more effective as a Complex I inhibitor in cancer cells expressing high levels of Myc, leading to a significant reduction in mitochondrial respiration and energy production. This also indicates that compounds according to formula 1 , such as KLC-004 have a higher efficacy against breast cancer cells expressing high levels of Myc, when compared to breast cancer cells expressing low or normal / base line levels of Myc. Thus the compounds according to formula 1 are configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as shown at least under the Seahorse Mito Stress Test conditions of the Example 7.

[0394] Example 8. Cytotoxicity assay in vitro

[0395] Sulforhodamine B (SRB) cytotoxicity assay, used for cell density determination, was used for evaluating the In Vitro efficacy of KLC-004 compound in breast cancer cell lines. The cell lines used for the experiments were doxycycline-inducible isogenic Hs578T or MDAMB157 triple-negative breast cancer (TNBC) cells, either induced to express high levels of Myc (Mychi) or as non-induced, expressing low (basal) level of Myc (Myc10). Upon doxycycline-induction, the cells express at least 1.5 folds higher level Myc. The SRB assay protocol and the measurement of the cytotoxicity was done as described in Vichai V. et al 2006, which is hereby incorporated by reference.

[0396] The Sulforhodamine B (SRB) cytotoxicity assay is a colorimetric assay, based on the ability of SRB dye to bind to cellular proteins, providing a quantitative measure of cell density and viability following drug treatment.

[0397] Experimental Procedure

[0398] Cells were seeded in 96-well plates and allowed to adhere overnight. After 24 hours, they were exposed to increasing log concentrations of KLC-004 (100 pM, 10 pM, 1 pM, 0.1 pM,and 0.01 pM) for 48-72 hours. Following the KLC-004 exposure, cells were fixed with trichloroacetic acid (TCA), stained with SRB dye, and washed to remove unbound dye. The bound SRB was solubilized in a T ris buffer, and absorbance was measured at 564 nm using a TECAN microplate reader. The percentage of cell growth inhibition / cytotoxicity was calculated relative to control cells not treated with KLC-004. The results of the cytotoxicity assay with Human Hs578T cells are shown in Fig. 8 and the results of the cytotoxicity assay with Human MDA-MB-157 cells are shown in Fig. 9.

[0399] Derivation of Glso, TGI, and LC50

[0400] The cytotoxic effects of KLC-004 were determined by plotting the percentage of cell viability against the log concentration of the compound to generate a dose-response curve. From this curve, key cytotoxicity parameters GI50, TGI and LCS0were derived. GI50(Growth Inhibition 50%) indicates the concentration of KLC-004 that reduces cell growth by 50% relative to the control cells not treated with KLC-004. The GI50concentration was interpolated from the sigmoidal dose-response curve. TGI (Total Growth Inhibition) indicates the concentration at which net cell growth is completely inhibited (0% growth), indicating cytostatic activity. LCS0(Lethal Concentration 50%) indicates the concentration that induces 50% cell death, inferred from the dose-response curve when cell viability drops below baseline levels (negative growth).

[0401] These parameters were determined using nonlinear regression analysis, fitted with a sigmoid or logistic model, to quantify the efficacy and potency of the KLC-004 compound. The lower the GI50value (i.e. the compound according to the formula 1 concentration in pM), more potent the compound is to inhibit the growth of the cells, and more potent the compound is against the tested cancer cells.

[0402] Table 4 shows the results of the Fig. 8, providing the calculated concentrations of KLC-004 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LCso).

[0403] KLC0004 Hs578T-Mycl0[pM] Hs578T-Mychi[pM]

[0404] Glso 4,2 2,6

[0405] TGI 45 12

[0406] LCso >100 >100

[0407]

[0408] Table 5 shows the results of the Fig. 9, providing the calculated concentrations of KLC-004 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50).

[0409] KLC0004 MDAMB157-Myclow[pM] MDAMB157-Mychi[pM]

[0410] GI50 5 3,1

[0411] TGI 32 22

[0412] LC50 >100 >100

[0413]

[0414] These results indicate that compound according to formula 1 KLC-004, demonstrates cytotoxic effects already at low concentrations, such as at sub-micromolar (sub- pM) concentrations, exhibiting GI50 at less than 5pM of KLC-004. These results further indicate, the compound according to formula 1 KLC-004, exhibits growth inhibitory selectivity towards TNBCs expressing high levels of Myc, when compared TNBCs expressing low or normal / base line levels of Myc.

[0415] Example 9. Cytotoxicity assay in vitro, multiple cell lines tested

[0416] The cytotoxicity activity of KLC-004, and its effect on cell growth inhibition (GI50) was further tested in vitro in various breast cancer cell lines expressing different levels of Myc.

[0417] All the cells were seeded in 96-well plates and allowed to adhere overnight. After 24 hours, they were exposed to increasing log concentrations of KLC-004 (100 pM, 10 pM, 1 pM, 0.1 pM, and 0.01 pM) for 48-72 hours. Following the KLC-004 exposure, cells were treated as described in the example 8 and the assessment of GI50 values was done as described in the example 8.

[0418] The table 6 shows the concentrations of KLC-004 required to reach GI50 in various KLC-004-treated cells, including Myc inducible TNBC cell lines (MDAMB157 and Hs578T) either induced to express high levels of Myc or expressing basal levels of Myc; TBNC cell lines endogenously expressing Mychi(BT549, HCC1937, HCC1395) or Myclow(Hs578T, MDAMB157, MDAMB 231); Luminal type (T47D and MCF7) and HER2 (BT474) type breast cancer cell lines, and normal human mammary epithelial cells (HMEC and MCF10A).

[0419] Table 6 shows the calculated concentrations of KLC-004 (in pM) required for 50% growth inhibition (GI50), in different breast cancer cell lines and in normal mammary cells.Dox-MYC inducible cell lines GI50(pM) Dox-MYC inducible cell lines GI50(pM)

[0420] MDAMB157-Myc low 5 MDAMB157-Myc high 3 MDAMB157-Myc low 2.9 MDAMB157-Myc high 4.2 MDAMB157-Myc low 4.2 MDAMB157-Myc high 3.1 Hs578T-Myc low 3.1 Hs578T-Myc high 2.6 Hs578T-Myc low 2.2 Hs578T-Myc high 2 Hs578T-Myc low 4.2 Hs578T-Myc high 2.2 Average GI50 value 3.6 Average GI50 value 2.9 Endogenous MYC low cell GI50(pM) Endogenous MYC high cell GI50(pM) lines lines

[0421] Hs578T 3 BT549 2.2 Hs578T 2.8 BT549 1.3 MDAMB157 5.2 HCC1937 6 Hs578T (TNBC) 4.2 HCC1935 3.1 MDAMB157 (TNBC) 6.8 HCC1935 (TNBC) 6.1

[0422] M DAM B231 (TNBC) 7.1 HCC1937 (TNBC) 5.1 Average GI50 value 4.9 BT549 (TNBC) 4

[0423] Average GI50 value 4.0 Normal mammary cell lines GI50(pM) Luminal and HER2 type cell GI5O (pM) lines

[0424] HMEC 5 BT474 (HER2) 4.3 HMEC 5 T47D (LumA) 1.7 MCF10A 10.2 MCF7 (LumA) 2.8 MCF10A 11 Average GI50 value 2.9 Average GI50 value 7.8

[0425]

[0426] These results in table 6 indicate that the compound according to formula 1 KLC-004 exhibits higher cytotoxicity in cells expressing high or induced levels of Myc, when compared to cells expressing low or normal / base line levels of Myc. These results further indicate that the compounds according to formula 1 KLC-004 exhibits less, even 2-3 fold less, cytotoxiceffects on normal mammary cells, when compared to the tested cancerous mammary cells, the compound showing thus targeted cytotoxicity in cancerous cells.

[0427] Example 10. Cytotoxicity assay in vitro, multiple compounds

[0428] The cytotoxicity activity of multiple compounds according to the formula 1 , and their effect on cell growth inhibition (GI50) was further tested in vitro in breast cancer cell lines expressing different levels of Myc. The experimental procedure and the assessment of GI50 values was done as described above in the Example 8.

[0429] Table 7 shows the concentrations (in pM) of compounds KLC-004, KLC-005, KLC-048, KLC-049, KLC-050, KLC-051, KLC-052 and KLC-053, required to reach GI50 in Myc inducible TNBC cell line Hs578T either induced to express high levels of Myc or not, and in normal human mammary epithelial cells (HMEC and MCF10A).

[0430] Table 7 shows the calculated concentrations (in pM) of multiple compounds according to the formula 1, required for 50% growth inhibition (GI50), in Hs578T breast cancer cell line and in normal mammary cells HMECs and MCF10A. "NA" stands for "Not Available". The breast cancer cell line used was doxycycline-inducible isogenic Hs578T triple-negative breast cancer (TNBC) cell line, either induced to express high levels of Myc (MycHi) or as non-induced, expressing basal level of Myc (Myclow).

[0431] GI5o[pM] MyclowMycHiNormal mammary cells

[0432] Compound Hs578T Hs578T HMEC MCF10A

[0433] KLC-004 3.2 2.3 5 10.6

[0434] KLC-005 45 31 NA NA

[0435] KLC-048 22 19 28 40

[0436] KLC-049 10.5 10 13 18

[0437] KLC-050 3 2.8 6.2 12

[0438] KLC-051 7 4.8 10.2 18

[0439] KLC-052 6.2 6 11 18

[0440] 2.1 2

[0441]

[0442] KLC-053 4.5 12

[0443] The results obtained from the experiment in table 7 indicate that the compounds according to formula 1 have lower GI50 concentrations in cancerous cells, such as 2-3-fold lower GI50 concentrations, when compared to the tested normal mammary cells. In other words, the results of the table 7 indicate that the compounds according to formula 1 tested, are less (2-3-fold) cytotoxic in normal mammary cells compared to cancerous cells. The results obtained from the experiment further indicate that the tested compounds according to formula 1 show increased cytotoxicity in the breast cancer cells expressing elevated levels of Myc when compared to the breast cancer cells expressing basal levels of Myc. Theresults obtained from the experiment further indicate that some of the tested compounds according to formula 1, such as KLC-050 and KLC-053 and KLC-004, have comparable GI50 concentrations and highly increased cytotoxic activity.

[0444] Example 11. Cytotoxicity assay in vitro with KLC-004

[0445] Cytotoxicity of compounds according to the formula 1 was studied in a dose-response assay illustrating the effect of KLC-004 in a panel of 9 breast cancer cell lines and 2 normal mammary epithelial cell lines (HMEC, MCF10A), as shown in Fig. 10. The experimental panel included endogenous Myc high (cells expressing increased levels of MYC) cancer cell lines (T47D, HCC1395, BT549, HCC1937), Myc low cancer cell lines (cells expressing low levels of Myc, Hs578T, MDAMB157, MDAMB231, MCF7), cancer cells expressing intermediate levels of Myc (BT474) and normal transformed mammary epithelial cell lines (HMEC and MCF10A). The experimental procedure and the assessment of GI50 values was done as described above in the Example 8. The results obtained from the proliferation % measurement of the assay of Fig. 10, and shown in the table 8 below, provides the calculated concentrations of KLC-004 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50), for each cell line used in the doseresponse curve (cell proliferation assay), as represented in Fig. 10.

[0446] Table 8 shows the calculated concentrations of KLC-004 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50), for each cell line used in the dose-response curve, as presented in the Fig. 10 and expressed in pM. The Myc-expression status of each cell line is included in the table.

[0447] Cell lines Myc Status GI [RM] LC [pM]

[0448] 50 TGI [pM] 50

[0449] BT549 High 4 10 20

[0450] HCC1937 High 5.1 18 45

[0451] HCC1395 High 6.1 18 72

[0452] T47D High 1.7 12 22

[0453] BT474 Moderate 4.3 12 30

[0454] MCF7 Low 2.8 14 40

[0455] Hs578T Low 4.2 11 22

[0456] MDA-MB-157 Low 6.8 15 28

[0457] MDA-MB-231 Low 7.1 14 24

[0458] HMEC Normal 5 47.5 >100

[0459] MCF10A Normal 10.6 39 >100

[0460]

[0461] These results indicate, the concentration of the compound according to the formula 1 , KLC-004, which is required for total growth inhibition and 50% lethal concentration is significantly lower in all of the tested cancerous cell lines when compared to the normal mammary epithelial cells. These results thus indicate, that normal mammary epithelial cell lines require 2-3 fold higher concentration of KLC-004 to exhibit similar level of cytotoxicity (measured as TGI and LC50) when compared to the tested breast cancer cell lines.

[0462] The results obtained from the experiment in table 8 further indicate that the compound according to the formula 1 effectively inhibits and kills breast cancer cells at lower concentrations while higher concentrations are required to affect healthy cells. This suggests the compound according to the formula 1 has a favorable therapeutic window between a treatment dose vs a toxic dose, and reduced toxicity to normal cells.

[0463] Example 12. Colony formation in vitro

[0464] The colony formation assay was performed to assess the long-term survival potential of breast cancer cell lines following treatment with KLC-004 or control compound DMSO. This assay evaluates the ability of single cancer cell to survive, proliferate, and form colonies over an extended period, the assay thus evaluating the Long-Term Survival of the cells. Breast cancer cell lines used in the experiment were categorized into:

[0465] Myc-high cell (eMYChi) lines: BT549, HCC1937, HCC1395, T47D; and

[0466] Myc-low cell (eMYClow) lines: Hs578T, MDA-MB-157, MDA-MB-231, MCF7.

[0467] The Myc-high cell lines are cells expressing elevated levels of Myc, the Myc protein being expressed at a significantly higher (> 1.5 folds) level compared to the Myc-low cell lines used in this experiment. The cells plated on 6 well plate at 1000 cells / well and were treated with 3 pM KLC-004 or with 0.5 vol-% control compound DMSO. After treatment, cells were allowed to grow for 14 days while changing the media supplemented with either KLC-004 or DMSO in three days intervals and colonies were stained with SRB dye and quantified microscopically and using Imaged automated software.

[0468] The quantified results are shown in the Fig. 11. The colony formation efficiency is plotted on the y-axis (% colony formed), comparing KLC-004 -treated versus control compound (DMSO)-treated control groups. Statistical significance was determined with p-values, wherein the p values shown are: <0.001=***, and ns=not significant, i.e., no significant difference to control compound.

[0469] The results shown in the Fig. 11 demonstrate that compounds according to the formula 1, such as KLC-004 significantly reduce the ability of cancer cells to form colonies, thus reducing their long-term survival. The results demonstrate that KLC-004 reduces morecolony formation in MYC-high breast cancer cell lines (as shown in Fig. 11 a), when compared to the colony formation of MYC-low cells (as shown in Fig. 11 b).

[0470] Example 13. Solubility and stability

[0471] The solubility and stability of KLC-004 in different vehicles was studied.

[0472] This formulation study was conducted with tests including 5 different vehicles for in vivo experiments. The tested compound according to the formula 1 in this experiment was KLC-004.

[0473] The formulations were prepared as follows:

[0474] #1-2: the respective pre-mixed Captisol or2HPpCD aqueous solution was added to the tested compound KLC-004 (1 mg), and the resulting mixture was vortexed for 5 min, then sonicated for 30 min at 45°C.

[0475] #3-4: Kolliphor EL was pre-warmed and Kolliphor HS 15 was melted at 45°C, then added to the tested compound KLC-004 (1 mg), vortexed for 5 min, and sonicated for 6 min at 45°C. After that, water for injections was added and the formulation was vortexed for 5 min, then sonicated for 30 min at 45°C.

[0476] #5: Saline was added to the tested compound KLC-004 (1 mg) and vortexed for 5 min, then sonicated for 30 min at 45°C.

[0477] Upon final mixing, all formulations #1-5 were kept in an ultrasonic bath at 45°C for 10 min without sonication. After initial mixing, vortexing and sonication steps, the pH of each formulation #1-5 was measured and recorded as its initial pH. Adjusting the pH was unnecessary for the dissolution of the compounds. After preparation, the pH of all formulations with dissolved compounds was adjusted to physiological levels (pH~7.0...7.5) and recorded as the final pH. pH adjustment was carried out with sodium hydroxide solutions (0.25M, 0.5M, and 1 M) and hydrochloric acid solutions (0.25M, 0.5M, and 1 M). All formulations #1-5 were kept at room temperature for ~24 hours with periodic observations to assess solution stability.

[0478] Table 9 discloses the results obtained in this assessment, including concentration (C) (mg / ml) of the tested compound KLC-004, and the solubility and stability of the tested doses. The test compound KLC-004 was fully dissolved in all tested vehicles 1-5 at all target concentrations, as shown in the column “Initial pH” of the table 9; “D” indicating “dissolved” i.e. the substance is in a form of a solution. The formulations were stable for at least 24 hours. These results indicate the compound according to the formula 1, such as KLC-004 possesses the solubility and stability required in pharmacological use.

[0479] Table 9 shows the solubility and stability assay results with the tested compound KLC-004. The data measured for each formulation #1-5 includes: the concentration of the testedcompound KLC-004 (C, mg / ml); initial pH and final pH, and the stability of the dissolved compound at 3h and 24h (D, indicating “dissolved” i.e. the dissolved compound KLC-004 is in a form of a fully dissolved solution).

[0480] pH Stability C,

[0481] # Vehicle

[0482] mg / ml Adjusted

[0483] Initial for Final 3 h 24 h dissolution

[0484] Captisol - Water

[0485] 7.29,

[0486] 1 for injections 4.0 4.46, D n / a D D D

[0487] (40%:60%, w / v)

[0488] 2HP0CD - Saline 7.42,

[0489] 2 4.0 3.40, D n / a D D (20%:80%, w / v) D

[0490] Kolliphor EL - 7.43,

[0491] 3 Saline 4.0 3.66, D n / a D D D

[0492] (10%:90%,v / v)

[0493] Kolliphor HS 15 - 7.42,

[0494] 4 Saline (10%:90%, 4.0 4.86, D n / a D D D

[0495] v / v)

[0496] 7.28,

[0497] 5 Saline (100%, v) 4.0 3.73, D n / a D D

[0498]

[0499] D

[0500] Example 14. Pharmacokinetic profile of KLC-004

[0501] The purpose of this study was to determine the pharmacokinetic characteristics of the compound according to the formula 1, in this case the KLC-004, in female CD-1 mice following intraperitoneal (IP), and oral (Per Os; PO) routes of administration. 2HPPCD -Saline (20%:80%, w / v) was used as formulation vehicle for IP and PO dosing. The levels of the test compound in blood plasma samples were measured over time using LC-MS / MS following a single 10 mg / kg dose.

[0502] The initial concentration of KLC-004 in samples which were injected in mice, was determined using high performance liquid chromatography / tandem mass spectrometry (HP LC-MS / MS). Shimadzu HPLC system comprised 2 isocratic pumps LC-20AD, an autosampler SIL-20AC, a sub-controller FCV-14AH and a degasser DGU-14A. Mass spectrometric analysis was performed using an API 3000 (triple-quadrupole) instrument from AB Sciex (Canada) with an electrospray (ESI) interface. The data acquisition and system control were performed using Analyst 1.6.3 software from AB Sciex.

[0503] Preparation of the calibration standards for quantification of KLC-004 in plasma samples:The compound KLC-004 was dissolved in DMSO, and the resulting solution with a concentration of 2 mg / ml was used for calibration standards preparation (stock solution). The stock solution was consecutively diluted with internal standard (imipramine) to get a series of calibration solutions with final concentrations of 10000, 4000, 2000, 1000, 400, 200, 100, 40, 20, 10, 4, 2, 1, and 0.4 ng / ml. The calibration curve was constructed using blank mouse plasma samples. To obtain calibration standards, blank plasma samples (5 pl) were mixed with 100 pl of corresponding calibration solution. After mixing by pipetting and centrifugation for 4 min at 6000 rpm, 1 pl of each supernatant was injected into LC-MS / MS system.

[0504] Female CD-1 mice (10 weeks old, body weight ranged from 25.4 g to 29.6 g and average body weight across all groups 27.4 g, standard deviation (SD) = 1.4 g) were used in this study. The animals were randomly assigned to the treatment groups before the pharmacokinetic study; all animals were fasted for 4 h before dosing. Intraperitoneal (IP) and peroral (PO) routes of administration; seven serial sampling time points for each administration route (15, 30, 60, 120, 240, 480 and 1440 min) were set for this pharmacokinetic study. Each of the time point treatment groups included 3 animals, and a control group of one animal per administration route. Serial blood sampling (20 pl) was performed at each time point from the saphenous vein without anaesthesia. The vessel was punctured with a 26-gauge needle and blood was collected into tubes containing 1 pl of a 20-fold solution of K2EDTA (36 mg / ml) using pipette. Blood samples were placed on wet ice (0 °C) and centrifuged for 10 min at 3000 rpm (+4 °C). All samples were immediately processed, flash-frozen on dry ice, and stored at -70°C until subsequent analysis.

[0505] The measured pharmacokinetic parameters are shown in a Table 10. The measured parameters included Tmax (min); Cmax (ng / ml); AUC-last (ng min / ml); AUC-INF_obs (ng min / ml); T1 / 2 (HL_Lambda_z, min) and Kei(Lambda_z, min-1). Tmax represents the time required for the compound to reach its maximum concentration in the plasma after administration, thereby indicating the rate of absorption. Cmax indicates the peak concentration of the compound in the plasma, reflecting the highest level attained in the bloodstream. AUC-last indicates the area under the plasma concentration-time curve from time zero to the last measurable concentration, representing the total drug exposure over a specific time period. AUC-INF_obs indicates the area under the plasma concentration-time curve from time zero to infinity, providing an estimate of the total compound exposure over time, assuming the compound is completely eliminated. Ti / 2 or elimination half-life, is the time required for the plasma concentration of the compound to decrease by half. The Keirepresents the elimination rate constant, describing the rate at which the drug is removedfrom the test species. The measured concentration of the compound in the plasma over timel Sampe is shown in the Fig. 12.

[0506] Table 10 shows the pharmacokinetic profile of the compound KLC-004, in plasma of CD-1 mice after KLd AiiittmnsraonC-004 administration in both oral (Per Os, PO) and Intraperitoneal (IP) routes at 10 mg / kg dose.

[0507] / k Dose mgg,

[0508] Pharmacokinetic Parameters

[0509] Tmax Cmax AUC-last AUC-INF_obs Tl / 2

[0510] Keimin1min ng / ml ng*min / ml ng*min / ml min

[0511] IP 10 15.0 847 31600 32400 44.1 0.0194 Plasma

[0512] PO 10 30.0 5.33 40.0 ND ND ND

[0513]

[0514] Based on the results obtained, as shown in the Fig. 12 and the table 10, the compound KLC-004 administered via the intraperitoneal (IP) route achieved an acceptable plasma concentration (Cmax847 ng / ml, Ti / 244 min) ata dose of 10 mg / kg in CD-1 mice (n=3). In this experimental set-up, oral (PO) administration of KLC-004 was not satisfactory. KLC004 was not detected in plasma after oral administration, likely due to the tight binding of the hydrophilic cyclodextrin formulation, which inhibited membrane penetration and subsequent plasma exposure. The measured pharmacological parameters indicate the absorption, distribution, metabolism, and elimination of the compound according to the formula 1, such as KLC-004 are acceptable at least through IP-administration route, thus allowing determination of an appropriate dosing regimens and ensuring therapeutic efficacy.

[0515] Example 15. In Vivo Anti-Tumor Efficacy of KLC-004

[0516] The in vivo efficacy of the compound according to the formula 1, KLC-004 was evaluated using two subcutaneous xenograft models: BT549 Cell Line-Derived Xenograft (CDX) Model and Patient-Derived Xenograft (PDX) Model.

[0517] BT549 Cell line Xenograft (CDX) in vivo mouse model was performed with BT549 tumorbearing female NOD-SCID (NOD.Cg-NSG(Prkdcscidll2rgtm1Wjl / SzJ) mice. The mice were divided into three groups 1-3. The group 1), i.e., the vehicle group, received intraperitoneally 10 mL / kg 2HPpCD:Saline (20%:80%, w / v) once daily (OD). The number of animals in group 1) was 8 (n=8). The group 2) received intraperitoneally 10 mg / kg of KLC-004, once daily (n = 7). The group 3) received intraperitoneally 30 mg / kg of KLC-004, once daily (n = 7). Treatment of all the groups 1-3 was administered for 21 days. Tumor length (L) and width(W) was measured using electronic vernier calipers and calculated using elliptical volume formula (L X W2^) and the tumor volumes were recorded twice weekly. Mice were monitored until day 31.

[0518] Tumor volume in vivo data from with BT549 Cell line Xenograft (CDX) model was averaged according to groups and plotted to compare tumor growth inhibition among groups. Statistical analysis was performed using 2-way ANOVA with Dunnett’s multiple comparisons test, assessing the significance of KLC-004 treatment compared to the vehicle group. The results of the measured tumor volumes (mm3) at different time points, and the statistical significance is shown in the Fig. 13 a). The results indicate that KLC-004 exhibits significant anti-tumor efficacy in CDX tumor model.

[0519] Patient-Derived Xenograft (PDX) in vivo mouse model was performed with patient-derived TNBC cells, wherein tumor tissues were implanted in female NOD-SCID (NOD.Cg-NSG(Prkdcscidll2rgtm1Wjl / SzJ) mice. The mice were divided into two groups 1) and 2). The group 1), i.e., a vehicle group received intraperitoneally 10 mL / kg 2HPPCD - Saline (20%:80%, w / v) twice daily (BID). The number of animals in group 1) was 6 (n = 6). The group 2) received intraperitoneally 30 mL / kg KLC-004 twice daily (BID). The number of animals in group 2) was 6 (n = 6).

[0520] Treatment was given for 21 days, and the tumor volume was measured as described for BT549 Xenograft mouse model. The tumor volumes were recorded twice weekly. Tumor volume in vivo data from with Patient-Derived Xenograft (PDX) model, was averaged according to groups and plotted to compare tumor growth inhibition among groups. Statistical analysis was performed as described for BT549 Xenograft mouse model.

[0521] The results of the measured tumor volumes (mm3) at different time points, and the statistical significance is shown in the Fig. 13 b). The results indicate that KLC-004 exhibits significant anti-tumor growth efficacy in PDX tumor model, when compared to the control vehicle injected tumor model. The results also indicate that KLC-004 exhibits significant anti-tumor growth efficacy in PDX tumor model, when compared to the control vehicle injected tumor model.

[0522] Example 16. Complex-1 inhibition Measured by Oxygen Consumption Rate (OCR) -compounds KLC-004, KLC-005, KLC-048, KLC-049, KLC-050, KLC-051, KLC-052,KLC-053, KLC-054, KLC-055, KLC-056 and KLC-057

[0523] Similarly as described in the Example 7, inhibition of mitochondrial Complex I and OXPHOS by the tested compounds according to the formula 1 was evaluated by measuring the oxygen consumption rate (OCR) using an Agilent Seahorse XF96 Analyzer. The assay wasperformed using BT549 triple-negative breast cancer (TNBC) cells, which were pretreated 18 hours with either vehicle control (DMSO), phenformin (10 pM) serving as a known OXPHOS inhibitor control, or one of the compounds KLC-004, KLC-005, or KLC-048 to KLC-057 at a concentration of 5 pM.

[0524] OCR was recorded in real time following sequential injection of three mitochondrial inhibitors, according to the manufacturer’s instructions of the Seahorse XF Mito Tox Assay Kit and the methods described by Pratibha Sharma et al., 2024. The injections were performed at the indicated time points as follows: A) oligomycin (1 ,5 pM), an ATP-synthase (Complex V) inhibitor that suppresses ATP-linked respiration; B) A protonophore Bam15 (2,5 pM), a mitochondrial uncoupler that collapses the proton gradient and induces maximal electron transport activity, thereby enabling assessment of maximal respiratory capacity; and C) a mixture of rotenone and antimycin A (0.5 pM), inhibitors of Complex I and Complex III, respectively, which together fully shut down mitochondrial respiration and reveal non-mitochondrial OCR.

[0525] The measured OCR (pmol / min / 1000 cells) is presented in Figs. 15-26 as kinetic traces (means ± SD, n=4 replicates / group) showing the respiratory profiles of BT549 cells treated with DMSO, phenformin, or each of the tested compounds as indicated in the Figs. 15-26. Following oligomycin injection, all KLC-compounds (compounds according to formula 1) induced a marked reduction in ATP-linked respiration. After Bam15 injection, the maximal respiratory capacity of KLC-com pound-treated cells remained strongly suppressed compared to the DMSO control. Final inhibition with rotenone / antimycin A reduced OCR to non-mitochondrial levels in all samples.

[0526] A quantitative analysis of basal respiration (prior to injection A) and maximal respiration (Bam15-stimulated OCR prior to injection C) is shown in the accompanying bar graphs in b) in each of the Figs. 15-26. The bars represent the mean ± SD for each treatment group with n=4 replicates / group and illustrate the extent to which each tested KLC-compound according to the formula 1 reduces both basal mitochondrial oxygen consumption and maximal electron-transport capacity.

[0527] Together, these results demonstrate that all tested compounds according to formula 1 , from KLC-004 to KLC-057, substantially impair mitochondrial respiration by reducing both basal and maximal OCR in BT549 cells. This indicates that the compounds are configured to efficiently inhibit oxidative phosphorylation (OXPHOS) within the cell, thereby compromising the ability of mitochondria to respond to increased energetic demand. Such inhibition of OXPHOS is consistent with the intended mechanism of action of the compounds of the formula 1 described herein. Together, these results also demonstrate that the compoundsaccording to formula 1, regardless whether the (A) is according to the formula 2 or 3, substantially impair mitochondrial respiration by reducing both basal and maximal OCR. Thus in an embodiment, the compounds according to formula 1 are configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell, as shown in the Seahorse Mito Stress Test conditions of the Examples 7 and 16.

[0528] Example 17. Cytotoxicity assay in vitro with multiple compounds

[0529] Cytotoxicity of compounds according to the formula 1 was studied in a dose-response assay illustrating the effect of the compounds according to the formula 1 , including KLC-004, and compounds KLC-0048 - KLC-057, in MYC-inducible triple-negative breast cancer cell lines HCC38, MDA-MB-157 and MDA-MB-231. The HCC38 cell line is a basal-like triple-negative breast cancer (TNBC) cell line with moderate invasive capacity. The MDA-MB-157 cell line is a basal-like TNBC cell line with pronounced invasive properties. The MDA-MB-231 cell line is a highly invasive TNBC cell line that exhibits a mesenchymal-like phenotype.

[0530] For each cell line, MYC expression was set to ON or OFF by doxycycline inducible system (Expression of MYC is reversible and tunable by adjusting doxycycline concentration or removing it from the medium). Assays were performed for both MYC states for each compound as indicated in Tables 11-13.

[0531] The experimental procedure, data processing, and calculation of GI50, TGI, and LC50 values were carried out as described in Examples 8 and 11. Briefly, cells were exposed to serial dilutions of each compound according to the formula 1 for 72 h. Cell growth / viability was measured as described in the example 8 and the assessment of GI50 values was done as described in the example 8.

[0532] The results shown in the tables 11-13 below, provide the calculated concentrations of the compounds (KLC-004, and KLC-048 to KLC-057) required for 50 % growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50), for each cell line used. Dose-response curves and the underlying cell proliferation data used to derive GI50, TGI, and LCsoare not shown.

[0533] Table 11 shows the calculated concentrations of compounds KLC-004, KLC-048 to KLC-057 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50), for MYC-inducible cell line HCC38. The Myc-expression status (on or off) of the cell line is included in the table.HCC38-MYC ON HCC38-MYC OFF GI50 [uM] TGI [uM] LC50 [uM] GI50 [uM] TGI [uM] LC50 [uM] KLC-004 3 11 54 2.8 9.1 27 KLC-048 8.5 50 >100 7.1 40 >100 KLC-049 4 20 72 3.8 12 42 KLC-050 2.2 10 51 2 7 20 KLC-051 6.8 22 60 4 12 32 KLC-052 1.8 5.5 63 1.4 4 10 KLC-053 4.8 18 58 3.1 12 36 KLC-054 2.1 11 55 2 8 42 KLC-055 4.3 21 63 4 18 50 KLC-056 2.8 12 72 2 7.2 60 KLC-057 2.2 8.5 82 2.1 7 50

[0534]

[0535]

[0536] Table 12 shows the calculated concentrations of compounds KLC-004, KLC-048 to KLC-057 required for 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% lethal concentration (LC50), for MYC-inducible cell line MDA-MB-157. The Myc-expression status (on or off) of the cell line is included in the table.

[0537] MDA-MB-157-MYC ON MDA-MB-157-MYC OFF GI50 (pM) TGI (pM) LC50 (pM) GI50 (pM) TGI (pM) LC50 (pM) KLC-004 3,1 22 >100 5 32 >100 KLC-048 28 >100 >100 30 >100 >100 KLC-049 10,2 40 >100 10.2 33 90 KLC-050 8 30 >100 4.2 25 90 KLC-051 11 40 >100 10 28 90 KLC-052 10 32 >100 10 28 70 KLC-053 3,1 11 >100 2.1 10 100 KLC-054 3 15 >100 3 9,5 70 KLC-055 8,5 33 >100 10 30 95 KLC-056 3,8 24 >100 5 24 >100 KLC-057 3,8 24 >100 4.1 23 >100

[0538]

[0539]

[0540] * ">100 pM" indicates that the corresponding endpoint was not reached up to 100 M.

[0541] Table 13 shows the calculated concentrations of compounds KLC-004, KLC-048 to KLC-057 required for 50% growth inhibition (Glso), total growth inhibition (TGI), and 50% lethal concentration (LCso), for MYC-inducible cell line MDA-MB-231. The Myc-expression status (on or off) of the cell line is included in the table.

[0542] MDA-MB-231-MYC ON MDA-MB-231-MYC OFF Glso [uM] TGI [uM] LC50 [uM] Glso [uM] TGI [uM] LC50 [uM] KLC-004 2 5 10 2.3 9 20 KLC-048 11 23 45 13 40 100 KLC-049 5.5 12 22 7 18 35 KLC-050 1.2 3.5 7.5 2 8 22 KLC-051 2.8 9 15 4 12 30 KLC-052 1.2 2.8 5 1.6 4.5 14 KLC-053 2.8 8 15 5 13 32 KLC-054 1.05 2.1 3.5 1.2 3.2 7.2 KLC-055 2.1 6 12 3 11 28 KLC-056 1.2 3 5.5 2 5.2 12 KLC-057 1.1 2.5 5 2.1 7.2 28

[0543]

[0544] These results indicate that MYC-overexpressing (MYC-ON) cell lines are more sensitive to KLC compounds, suggesting a MYC-dependent vulnerability.

[0545] The results in Tables 11-13 demonstrate that multiple compounds according to Formula 1 reduce cancer cell growth in MYC-inducible TNBC cell lines, as evidenced by the measured Glso and TGI and LC50 values. All tested compounds according to the formula 1 showed higher cytotoxicity in the experimental setup, when compared to control OXPHOS inhibitors phenformin and IACS10759 (data not shown).

[0546] Across the tested cell models, activity was generally weaker in MDA-MB-157 cells for most compounds, whereas MDA-MB-231 exhibited the lowest GI50 and TGI and LC50 values for multiple compounds, with HCC38 showing an intermediate profile. These data indicate that selected compounds of Formula 1 are configured to inhibit growth and / or reduce viability in TNBC models, with compound- and cell line -dependent potency. These results also indicate within the scope of the tested conditions, the compounds according to formula 1 show strong activity when used against highly invasive cancer cell line phenotypes, i.e. cellsthat have undergone or display characteristics of epithelial-to-mesenchymal transition (EMT).

[0547] With respect to MYC status, in MDA-MB-231 the MYC-ON state was associated with lower GI50 / TGI values relative to MYC-OFF for each compound tested, indicating increased sensitivity under MYC induction in this cell line. These results thus indicate within the scope of the tested conditions, the compounds according to formula 1 show strong activity when used against highly invasive cancer cell line phenotypes expressing Myc. These results thus also indicate the compounds according to the formula 1 exhibit growth inhibitory selectivity towards cells expressing high levels of Myc, when compared cells expressing low or normal / base line levels of Myc.

[0548] Example 18. Cell death panel assay in vitro

[0549] The effect of the compounds according to the formula 1 on cell death was evaluated in a panel of fifteen triple-negative breast cancer (TNBC) cell lines treated in vitro with KLC-004 (10 pM), phenformin (10 pM), or IACS-10759 (10 pM); DMSO serving as vehicle control. Cell death was quantified using a Sytox Green dye assay, followed by automated image analysis using the PICO imaging system.

[0550] Under the tested conditions, the results as shown in Fig. 27 indicate, that KLC-004 induces substantial cytotoxicity indicated by an increased percentage of cell death versus vehicle controls in several TNBC cell lines at 10 pM. Moreover, in several cell lines the effect of KLC-004 is stronger than with other OXPHOS / Complex I inhibitors phenformin or IACS-10759 at the indicated concentrations. Therefore, these data show that KLC-004 induces substantial cytotoxicity in several TNBC cell lines at 10 pM.

[0551] Example 19. In Vivo Anti-Tumor Efficacy of KLC-004 in a further CDX mouse model The in vivo efficacy of the compound according to the formula 1, KLC-004 was evaluated using a further xenograft model: Raji lymphoma Xenograft (CDX) Model.

[0552] Raji lymphoma Xenograft (CDX) in vivo mouse model was performed with Raji lymphoma tumor-bearing female NOD-SCID (NOD.Cg-NSG(Prkdcscidll2rgtm1Wjl / SzJ) mice. The mice were randomly assigned to two treatment groups, group 1 and group 2. The group 1), i.e. , the control vehicle group, received intravenously 10 mL / kg 2-HPpCD:Saline (20%:80%, w / v) twice per week. The number of animals in group 1) was 9 (n=9). The group 2) received intravenously 5 mg / kg of KLC-004, twice per week (n = 10). Treatment of both groups 1 and 2 was administered for 3 weeks, i.e. for 21 days, so that each animal from either group received 6 total doses. Tumor length (L) and width (W) was measured using electronicvernier calipers and calculated using elliptical volume formula (L X W2 / 2) and the tumor volumes were recorded twice weekly. Mice were monitored until humane endpoints.

[0553] Tumor volume in vivo data from Raji lymphoma Xenograft (CDX) model was averaged according to groups and plotted to compare tumor growth inhibition among groups. The results of the measured absolute tumor volumes (mm3) at different time points, and the statistical significance are shown in the Fig. 28. Statistical analysis was performed using 2-way ANOVA with Dunnett’s multiple comparisons test, assessing the significance of KLC-004 treatment compared to the vehicle group. The p values shown in Fig. 28 are: <0.01=**, <0.05=*.

[0554] The results presented in Fig. 28 indicate that compounds according to the formula 1, such as KLC-004, exhibit in vivo anti-tumor efficacy in Raji lymphoma CDX tumor model, reducing tumor volume compared to vehicle controls. Taken together, the results presented in the examples 15 and 19 and Figs. 13 and 28 indicate that compounds according to the formula 1 , such as KLC-004, exhibit in vivo anti-tumor efficacy in multiple distinct tumor models as well as administration routes, including at least breast cancer and lymphoma models, as well as i.p. and i.v. routes, resulting in reduced tumor growth or tumor volume compared to vehicle controls.

[0555] Various embodiments have been presented. It should be appreciated that in this document, words comprise, include, and contain are each used as open-ended expressions with no intended exclusivity.

[0556] The foregoing description has provided by way of non-limiting examples of particular implementations and embodiments a full and informative description of the best mode presently contemplated by the inventors for carrying out the invention. It is, however, clear to a person skilled in the art that the invention is not restricted to details of the embodiments presented in the foregoing, but that it can be implemented in other embodiments using equivalent means or in different combinations of embodiments without deviating from the characteristics of the invention.

[0557] Furthermore, some of the features of the afore-disclosed example embodiments may be used to advantage without the corresponding use of other features. As such, the foregoing description shall be considered as merely illustrative of the principles of the present invention, and not in limitation thereof. Hence, the scope of the invention is only restricted by the appended patent claims.REFERENCES

[0558] Shoemaker, R. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6, 813-823 (2006). https: / / doi.org / 10.1038 / nrc1951

[0559] El-khayat S.M., Abouegylah M., Abdallah D., et al. The effect of metformin when combined with neoadjuvant chemotherapy in breast cancer patients. Med. Oncol. 2022;39:1. doi: 10.1007 / sl 0549-022-06821 -y.

[0560] Serageldin MA, Kassem AB, El-Kerm Y, Helmy MW, El-Mas MM, El-Bassiouny NA. The effect of metformin on chemotherapy-induced toxicities in non-diabetic breast cancer patients: a randomised controlled study. Drug Saf. 2023;46(6):587-599. doi: 10.1007 / S40264-023-01305-4. Jun.

[0561] Bakry H M, Mansour N O, EIKhodary T R, et al. Efficacy of metformin in prevention of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled trial. Front. Pharmacol. 2023 doi: 10.3389 / fphar.2023.1181312.

[0562] Vichai, V., Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1, 1112-1116 (2006). https: / / doi.org / 10.1038 / nprot.2006.179

[0563] Pratibha Sharma, Vinay K. Puduvalli, Protocol for real-time assessment of mitochondrial and glycolytic ATP production in patient-derived glioma stem-like cells, STAR Protocols, Volume 5, Issue 3, 2024,103159, ISSN 2666-1667, https: / / doi.Org / 10.1016 / j.xpro.2024.103159.

Claims

CLAIMS1. A compound according to formula 1 , a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof,(A) is selected from formula 2 or 3:wherein,o the (A) according to the formula 2 comprises Xi - X3, wherein each of the Xi - X3 is independently selected from (CH), (CF), and nitrogen (N);o the (A) according to the formula 3 comprises Z1 - Z5, wherein each of the Z1 - Z5 is independently selected from carbon (C), (CH), nitrogen (N), (NH), sulfur (S), and oxygen (O), and wherein at least one of the Z1 - Z5 is independently selected from (N), (NH), (S), and (O), and wherein at least two of the Z1 - Z5 are independently selected from carbon (C) and (CH); and whereino both in the formula 2 and in the formula 3, R1 is selected from R1 substituents hydrogen- (H), hydroxy- (OH), thiol- (SH), methyl- (CH3), ethyl- (CH3CH2), propyl- (CH3CH2CH2), isopropyl- ((CH3)2CH), isobutyl- ((CH3)2CHCH2), isopentyl- ((CH3)2CHCH2CH2), methoxy- (CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CH3)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylamino- (CH3NH), dimethylamino- ((CHs)2N), ethylamino- (CH3CH2NH), diethylamino- ((CH3CH2)2N), isopropylamino- ((CH3)2CHNH), isobutylamino- ((CH3)2CHCH2NH), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio-(CH3CH2S), isopropylthio- ((CH3)2CHS), isobutylthio- ((CH3)2CHCH2S), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), 2-methylprop- 1-en-1-yl- ((CH3)2CCH), 3-methylbut-2-en-1-yl- ((CH3)2CCHCH2), (2-methylprop- 1-en-1-yl)oxy- ((CH3)2CCHO), (2-methylprop-1-en-1-yl)thio- ((CH3)2CCHS), (2- methylprop-1-en-1-yl)amino- ((CH3)2CCHNH), chloride- (Cl), bromide- (Br) and fluoride- (F);o both in the formula 2 and in the formula 3, R2 is selected from R2 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);R3 is selected from R3 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);R4 is selected from R4 substituents hydrogen- (H), methyl- (CH3), trifluoromethyl- (CF3), difluoromethyl- (CHF2), fluoromethyl- (CH2F), chloride- (Cl), bromide- (Br) and fluoride- (F);R5 is selected from R5 substituents hydrogen- (H), methyl- (CH3), ethyl- (CH3CH2), isopropyl- ((CH3)2CH); andR6 is selected from R6 substituents hydrogen- (H) and methyl- (CH3),and wherein the compound is configured to inhibit oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

2. The compound of claim 1 , wherein the (A) is according to the formula 2, and wherein each of the Xi, X2and X3is independently selected from (CH), (CF) or nitrogen (N), and wherein at least one of the Xi, X2and X3is (CF) or nitrogen (N), preferably at least one of the Xi, X2and X3is (CF); and / orat least one of the Xi, X2and X3is selected from (CH) and (CF), preferably at least two, more preferably three of the Xi, X2and X3is selected from (CH) and (CF).

3. The compound of claim 1 or 2, wherein the (A) is according to the formula 2, the R1 has a number of heavy atoms (non-hydrogen) of 1 to 5, preferably 2 to 5, more preferably 3 to 5, even more preferably 4 to 5, most preferably 5 heavy atoms; and / or the R1 has a total number of C-, O-, S-, N-, F-, Br-, and Cl- atoms of 1 to 5, preferably 2 to 5, more preferably 3 to 5, even more preferably 4 to 5, most preferably 5.

4. The compound of any one of claims 1-3, wherein the (A) is according to the formula 2, and wherein the R2 is hydrogen (H) or methyl- (CH3).

5. The compound of claim 1 , wherein the (A) is according to the formula 3, and wherein three or four of the Z1 - Z5 are independently selected from carbon (C) and (CH), preferably four of the Z1 - Z5 are independently selected from carbon (C) and (CH).

6. The compound of claim 1 or 5, wherein the (A) is according to the formula 3, and wherein one or two of the Z1 - Z5 is / are independently selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O), more preferably the Z3 is selected from nitrogen (N), (-NH), sulfur (S), and oxygen (O).

7. The compound of any one of claims 1 or 5-6, wherein the (A) is according to the formula 3, and wherein the R1 is selected from hydrogen (H) or any of the R1 substituents containing oxygen (O) or sulfur (S).

8. The compound of any one of claims 1 or 5-7, wherein the (A) is according to the formula 3, and wherein the R2 is selected from hydrogen (H) or methyl- (CH3).

9. The compound of any preceding claim, wherein:- the (A) is according to the formula 2 and comprises the Xi - X3, wherein each of the X1-X3 is selected from (CH) and (CF);- the R1 has a number of heavy atoms of 2 to 5, and- the R2 is selected from hydrogen- (H), and methyl- (CH3);or- the (A) is according to the formula 3 and comprises the Z1 - Z5, wherein four of the Z1 -Z5 contain carbon and one of the Z1 - Z5 is independently selected from nitrogen (N), (-NH) and sulfur (S);- the R1 is selected from selected from hydrogen (H) , hydroxy- (OH), thiol- (SH), methoxy-(CH3O), ethoxy- (CH3CH2O), propoxy- (CH3CH2CH2O), isopropoxy- ((CH3)2CHO), isobutoxy- ((CHs)2CHCH2O), fluoromethoxy- (CH2FO), difluoromethoxy- (CHF2O), trifluoromethoxy- (CF3O), methylthio- (CH3S), ethylthio- (CH3CH2S), propylthio- (CH3CH2S), isopropylthio- ((CHs^CHS), isobutylthio- ((CH3)2CHCH2S), (2-methylprop-1-en-1-yl)oxy-((CH3)2CCHO), and (2-methylprop-1-en-1-yl)thio- ((CHs^CCHS); and- the R2 is selected from hydrogen (H) or methyl- (CH3).

10. The compound of any preceding claim, wherein the R3 is chloride- (Cl) or methyl- (CH3), and / or the R4 is hydrogen (H) or methyl- (CH3).

11. The compound of any preceding claim, wherein the R5 and / or the R6 are / is hydrogen (H).

12. The compound of any preceding claim, wherein the compound is configured to bind to NADH-ubiquinone oxidoreductase chain 1 (ND1) and / or to NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDLIFS7) of the mitochondrial complex I, inside a cell.

13. A pharmaceutical composition comprising the compound of any one of claims 1-12 as an active ingredient, and at least one further component selected from a pharmaceutically acceptable carrier, excipient and / or adjuvant.

14. A use of the compound of any one of the claims 1-12, or the pharmaceutical composition of claim 13, for inhibition of oxidative phosphorylation (OXPHOS) of mitochondrial respiration inside a cell.

15. The compound of any preceding claim 1-12, or the pharmaceutical composition of claim 13, for use as a medicament.

16. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, for use in treatment of cancer.

17. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, for use in treatment of breast cancer and / or lymphoma.

18. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, for use in treatment of breast cancer and / or lymphoma, wherein the treatment comprises inhibiting mitochondrial oxidative phosphorylation (OXPHOS) in cells.

19. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, for use in treatment of cancer expressing elevated levels of Myc.

20. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, for use in treatment of breast cancer and / or lymphoma expressing elevated levels of Myc.

21. The compound of any preceding claim 1-12 or the pharmaceutical composition of claim 13, wherein the compound specifically binds to ND1 and / or NDLIFS7 of the mitochondrial complex I, for use in treatment of cancer.

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