EP4720678A1 - Survivin as a biomarker for predicting the responsiveness of cancer treatment - Google Patents

Abstract

The present invention relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein, or to a treatment with a compound inhibiting the interaction between MDM2 and p53, the method comprising measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample. The present invention further relates to the use of Survivin in a method for determining the ability of a compound to inhibit KRAS protein or a mutant of a KRAS protein, or of a compound inhibiting the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting KRAS protein or a mutant of a KRAS protein or said compound inhibiting the interaction between MDM2 and p53, to treat cancer.

Description

29 May 2024 Our reference: BD 42671 ---------------------------------------------------------------------------------------------------------------- Boehringer Ingelheim International GmbH ---------------------------------------------------------------------------------------------------------------- Survivin as a biomarker for predicting the Responsiveness of Cancer Treatment ----------------------------------------------------------------------------------------------------------------- Field of the invention The present invention relates to the field of targeted cancer therapy, to biomarkers for assessment of the activity of particular compounds, and to the monitoring of a treatment with said compounds using biomarkers. In particular, the present invention relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS (K-Ras) protein or a mutant of a KRAS (K-Ras) protein, or with a compound inhibiting the interaction between MDM2 and p53, the method comprising measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample. The present invention further relates to the use of Survivin in a method for determining the ability of a compound to inhibit KRAS protein or a mutant of a KRAS protein, or of a pharmaceutical formulation comprising said compound inhibiting KRAS protein or a mutant of a KRAS protein, to treat cancer. The present invention further relates to the use of Survivin in a method for determining the ability of a compound inhibiting the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, to treat cancer. Background Cancer is a leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. Kirsten rat sarcoma viral oncogene homologue (the terms “KRAS“ and “K-Ras“ are used synonymously in this application) plays a central role in signal transduction, and is the most frequently mutated oncogene. Its gain-of- function mutations have been identified in about 30% of all cancer cells. KRAS mutations are closely related to tumor initiation and development, and is associated with a series of highly fatal cancers, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) (Huang et al.2021). KRAS is the most mutated oncogene in human cancer, including pancreatic ductal adenocarcinoma (PDAC), in which 95% of patients have a mutated form of RAS. KRAS mutations induce the constitutive activation of this oncogene and downstream signalling, including ERKs, PI3K which promote tumorigenesis, invasiveness, metastasis, and therapy resistance (Dhirendra et al.2017). The KRAS gene is a member of the rat sarcoma viral oncogene family (RAS), which includes two other isoforms in humans: the Harvey murine sarcoma virus oncogene (HRAS) and the neuroblastoma rat sarcoma viral oncogene homologue (NRAS). RAS genes are evolutionarily conserved with similar structures and are composed of four exons distributed on the full length of approximately 30 kb DNA. The KRAS gene encodes two highly related protein isoforms, KRAS-4B and KRAS-4A, which consist of 188 and 189 amino acids, respectively, due to different clipping of the fourth exon (Huang et al.2021). RAS is a kind of membrane-bound regulatory protein (G protein) binding guanine nucleotide belonging to the family of guanosine triphosphatases (GTPases). RAS functions as a guanosine diphosphate (GDP)/triphosphate (GTP) binary switch, which controls important signal transduction from activated membrane receptors to intracellular molecules. Ras family proteins including KRAS, NRAS and HRAS and any mutants thereof are small GTPases that exist in cells in either GTP-bound or GDP-bound states (McCormick et al.2016; Nimnual et al.2002). The Ras family proteins have a weak intrinsic GTPase activity and slow nucleotide exchange rates (Hunter et al.2015). Binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of Ras family proteins. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote release of GDP from Ras family proteins, enabling GTP binding (Chardin et al.1993). When in the GTP-bound state, Ras family proteins are active and engage effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF/mitogen or extracellular signal-regulated kinases (MEK/ERK) pathway, PI3K/AKT/mammalian target of rapamycin (mTOR) pathway, and RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al.2016; Rodriguez-Viciana et al. 2005). These pathways affect diverse cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth (Young et al. 2009; Rodriguez-Viciana et al.2005). KRAS proteins function as a finely regulated molecular switch that controls multiple signalling cascades by cycling between activated and inactivated conformations. KRAS proteins can be activated by growth factors, chemokines, Ca2+ or receptor tyrosine kinase (RTK). Activated KRAS protein can activate multiple signalling pathways, including the RAF/MEK/ERK pathway, which is the canonical downstream target of KRAS signalling. Activated KRAS-GTP can recruit rapidly accelerating fibrosarcoma (RAF), a serine/ threonine-specific protein kinase, from the cytoplasm to the plasma membrane, induce conformational changes in RAF and promote the activation of RAF by homologous or heterologous dimerization. The C-terminal catalytic domain of RAF binds to mitogen-activated protein kinase (MEK1/2) and activates it by phosphorylation. MEK1/2 phosphorylates and activates extracellular regulated protein kinases (ERK1/2), and activated ERK phosphorylates ribosomal S6 kinase (RSK), serum response factor (SRF), E26 transformation-specific transcription factors (ETS) and ETS like-1 protein to regulate the transcription and translation of corresponding target genes, thus participating in the regulation of cell proliferation, differentiation, migration and other life activities. KRAS was also found to be involved in the phosphoinositide 3-kinase (PI3K)- protein kinase B (AKT)- mammalian target of rapamycin (mTOR) pathway, which is considered to play an important role in cell life activities such as cell proliferation, differentiation, apoptosis and glucose transport and has a great influence on the generation of tumour resistance. Activated KRAS can activate PI3K by binding to its p110 subunit. Activated PI3K-catalysed phosphatidylinositol 4,5-bisphosphate (PIP2) is converted to phosphatidylinositol 3,4,5- trisphosphate (PIP3). PIP3 promotes phosphoinositide-dependent kinase 1 (PDK1) to phosphorylate AKT at Thr308. mTOR complex 2 further phosphorylates the serine phosphorylation site of AKT (Ser473), resulting in full AKT activation. Activated AKT enters the nucleus, activates or inhibits many downstream pathways, and regulates cell proliferation, apoptosis and metabolic processes. On the one hand, AKT can directly activate mTOR target proteins, which play an important role in cell proliferation, survival, metabolism, protein synthesis, and transcription. On the other hand, AKT phosphorylates and activates Bcl-XL/Bcl- 2-associated death promoters (BADs), facilitating the binding of BAD to the companion protein 14-3-3 instead of Bcl-2/Bcl-XL, thus inhibiting apoptosis. Furthermore, RAL guanine nucleotide dissociation stimulator (RalGDS) is a downstream signalling protein of KRAS that functions as a GTP/GDP exchange factor to promote the GDP/GTP conversion of RAS-like protein (RAL). Downstream effector factors of RAL proteins include Rac/cell division cycle 42 (Cdc42) associated with cell migration, TANK binding kinase 1 (TBK1) associated with viral immunity, and phospholipase D (PLD) associated with endocytosis. KRAS also regulates TIAM1 and RAC1-specific guanine nucleotide exchange factors, to activate RAC1 signalling pathways that affect cell shape, migration, adhesion, actin cytoskeleton formation, endocytosis, and membrane trafficking. In addition, KRAS can also regulate phosphatidylinositol signal pathway by activating PLCε. In short, KRAS-mediated signal networks are complex and related to a variety of life activities (Huang et al.2021). KRAS via MAP kinase (MAPK) signalling mediates immune escape in the tumour macroenvironment by upregulating PD-L1expression, downregulating MHC1expression of tumour cells, and enhancing the secretion of a variety of cytokines and chemokines to recruit immunosuppressive immune cells. Cancer-associated mutations in Ras family proteins suppress their intrinsic and GAP-induced GTPase activity leading to an increased population of GTP-bound/active mutant Ras family proteins (McCormick et al.2015; Hunter et al.2015). This in turn leads to persistent activation of effector pathways (e.g., RAF/MEK/ERK, PI3K/AKT/mTOR, RalGDS pathways) downstream of mutant Ras family proteins. KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in a variety of human cancers including lung cancer, colorectal cancer and pancreatic cancer (Cox et al.2014). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) are also found in a variety of human cancer types however typically at a lower frequency compared to KRAS mutations (Cox et al.2014). Alterations (e.g., mutation, over-expression, gene amplification) in Ras family proteins/Ras genes have also been described as a resistance mechanism against cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al.2014) and the EGFR tyrosine kinase inhibitor osimertinib/AZD9291 (Ortiz-Cuaran et al.2016; Eberlein et al.2015). Glycine to cysteine mutations at residue 12 of Ras family proteins (the G12C mutation, e.g. KRAS G12C, NRAS G12C and HRAS G12C) is generated from a G.C to T.A base transversion at codon 12, a mutation commonly found in RAS genes that accounts for 14 % of all KRAS, 2 % of all NRAS and 2 % of all HRAS mutations across cancer types. The G12C mutation is particularly enriched in KRAS mutant non-small cell lung cancer with approximately half carrying this mutation, which has been associated with the DNA adducts formed by tobacco smoke. The G12C mutation is not exclusively associated with lung cancer and is found in other RAS mutant cancer types including, e.g., 3-5 % of all KRAS mutant colorectal cancer. Inhibitors of such G12C mutant Ras family proteins which are capable to covalently bind to these proteins, e.g., covalent binders to KRAS G12C, NRAS G12C and HRAS G12C, are expected to inhibit signaling in cells downstream of Ras family proteins (e.g., ERK phosphorylation). In cancer cells associated with dependence on mutant Ras family proteins (e.g., KRAS mutant cancer cell lines), such binders/inhibitors are expected to deliver anti- cancer efficacy (e.g., inhibition of proliferation, survival, metastasis etc.). Several selective drugs against KRAS G12C mutant proteins have moved into clinical development; sotorasib has recently been approved for the treatment of KRAS G12C driven lung cancers (corresponding patent applications WO 2018/217651, WO 2017/201161, WO 2019/099524, WO 2020/102730). Prominent amplification of the wildtype (WT) KRAS proto-oncogene has been observed in a subset of tumor indications such as gastric cancer, gastroesophageal junction cancer and oesophageal cancer, where it acts as a driver of alteration and renders tumor models bearing this genotype addicted to KRAS in vitro and in vivo (Wong et al. 2018). In contrast, non- amplified KRAS WT cell lines are KRAS independent, unless they carry secondary alterations in genes indirectly causing activation of KRAS (Meyers et al. 2017). Based on these observations, agents with a KRAS WT targeting activity offer a further approach for the treatment of KRAS-dependent cancers. Proteolysis targeting chimeras (PROTACs) bind to proteins causing their degradation by inducing their ubiquitination. PROTACs are tripartite or heterobifunctional molecules consisting of a part binding to the protein that is to be degraded, a second part that binds to and can artificially recruit an E3 ubiquitin ligase, and a linker that connects the two parts. Whenever a trimeric complex consisting of the target protein, the PROTAC, and the ligase is formed, the close proximity of the ligase to the target results in target protein ubiquitination. Ubiquitination acts as a posttranslational modification of proteins causing, among others, their recruitment to the proteasome resulting in proteolytic degradation. The multi-ubiquitin chain on the target protein is then recognized by the proteasome and the target protein is degraded. In contrast to classical small molecule drugs, PROTAC-driven degradation functions in a sub- stoichiometric nature, thus requiring lower systemic exposures to achieve efficacy. PROTACs have been shown to display higher degrees of selectivity for protein degradation than the target ligand itself due to complementarity differences in the protein-protein-interaction interfaces of the formed ternary complexes. In addition, PROTACs promise to expand the druggable proteome as degradation is not limited to the protein domain functionally responsible for the disease. In the case of challenging multidomain proteins, traditionally viewed as undruggable targets, the most ligandable domain can be targeted for degradation independent of its functionality or vulnerability to small molecule blockade. Irreversible in nature, induced degradation of KRAS by recruitment of an E3 ubiquitin ligase is expected to induce comparable cellular effects as irreversible inhibition. Moreover, since mutant KRAS still is expected to be subject to GEF / GAP induced cycling between the GTP- bound active and GDP-bound inactive states, induced degradation not only of wt-amplified but also of mutant KRAS by PROTACs engaging the GDP-bound state may lead to gradual degradation of a large fraction of the entire cellular KRAS pool. Hence, degradation of oncogenic KRAS may inhibit downstream signaling in tumors delivering anticancer efficacy as described for KRAS inhibition. Upon irreversible target degradation recovery of downstream signaling activity not only depends on elimination of the drug from the treated subject (e.g., by clearance) but is further limited by de novo resynthesis of the target protein by the ribosome. Irreversible inhibition is so far restricted to the KRAS G12C protein, which only constitutes a fraction of the whole complement of KRAS mutant tumors. In contrast, induced degradation of KRAS has the potential to enable irreversible inhibition of KRAS signaling for most remaining KRAS mutations/alterations (including amplifications) driving tumor growth provided they can be bound by a heterobifunctional degrader molecule. Degraders of wild-type (e.g., amplified or overexpressed) or mutated KRAS (e.g., G12C, G12D, G12V, G13D) have been used to deliver anti-cancer efficacy. Although many approaches are pursued in the art to treat patients with KRAS-targeting compounds, there are still a lot of aspects to be investigated, such as providing means to measure the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein. The family of ERBB transmembrane receptor tyrosine kinases (RTKs) consists of the four members EGFR (ERBBI), HER2 (Neu, ERBB2), HER3 (ERBB3) and HER4 (ERBB4). HER2, for which no ligand has been identified, is the preferred dimerization partner for the other ERBB members. Once an active ligand-receptor complex has been formed, the intracellular tyrosine kinase domains of EGFR, HER2, HER3 or HER4 are activated by auto- or transphosphorylation and subsequently elicit a signal transduction cascade most notably engaging the mitogen- activated protein (MAP) kinase and/or the phosphoinositide 3-kinase (PI3K) pathways. Aberrant HER2 signaling is observed in a wide variety of human malignancies. Oncogenic mutations are described for the extracellular, (juxta-) membrane and intracellular regions of the protein. Collectively these mutations render HER2 constitutively active, fueling cancer initiation, tumor maintenance and growth. Similarly, HER2 overexpression increases HER2 signaling and underlies neoplastic transformation and tumor maintenance in a variety of indications including breast, gastric or lung cancer. Consequently, interference with HER2 oncogenic signaling results in inhibition of tumor growth. Targeted therapies include HER2 directed antibodies (including trastuzumab and pertuzumab), HER2 directed antibody-drug conjugates (trastuzumab-DMI (T-DMl, adotrastuzumab emtansine)) and small molecules inhibiting the HER2 kinase domain. Altogether, tumors driven by HER2 oncogenic mutations or HER2 wild type overexpression (for example due to gene amplification) might benefit from a HER2 specific tyrosine kinase inhibitor (TKI). Collectively, HER2 alterations affect up to 6-7% of all human cancers (WO2021213800). Inactivation of p53 is a central mechanism by which tumours escape the body’s control mechanisms and promote tumour growth and proliferation. In many cancer types, the TP53 gene is often mutated or deleted, which inactivates the tumour suppression activity of the p53 protein. However, loss of p53 tumour-suppressor activity can also occur through amplification of MDM2. As MDM2 is a negative regulator of p53, this promotes p53 degradation and inhibits p53 tumour suppressor activity (Zhao et al.2014). Overall, approximately 5–7% of tumours display MDM2 amplifications. However, such amplifications are more common in some tumour types than others, with an incidence of up to 90% in some types of advanced soft tissue sarcoma (STS). Blocking the MDM2–p53 interaction to reactivate wild-type p53 function is therefore a promising cancer therapeutic strategy. Initial compounds designed to target the MDM2–p53 interaction have been developed. Compounds of that kind can have a dual mechanism of action: direct targeting of tumour cells and exertion of immune-cell modulatory effects; they bind directly to MDM2 and block its interaction with p53, leading to stabilization of p53, TP53 target gene induction, cell-cycle arrest and apoptosis in tumour cells with wild-type TP53 status. Activation of p53 also promotes an anti-tumour immune response by increased CD8+ T-cell infiltration in the tumour and induces anti-tumour immune memory. The Mouse Double Minute 2 (MDM2) protein (or its human homolog also known as HDM2) acts to down-regulate p53 activity in an auto-regulatory manner, and under normal cellular conditions (absence of stress), the MDM2 protein serves to maintain p53 activity at low levels. MDM2 directly inhibits the transactivation function of p53, exports p53 out of the nucleus, and promotes proteasome-mediated degradation of p53. The tumor suppressor protein p53 is a sequence specific transcription factor and plays a central role in the regulation of several cellular processes, including cell cycle and growth arrest, apoptosis, DNA repair, senescence, angiogenesis, and innate immunity. Deregulation of the MDM2/p53 balance by overexpression of MDM2 or by p53 mutation or loss leads to malignant transformation of normal cells. Presently p53 is known to play a key role in practically all types of human cancers, and the mutation or loss of the p53 gene can be identified in more than 50 % of all human cancers worldwide. In tumor harboring wildtype p53, MDM2 is the primary cellular inhibitor of p53 activity, and overexpression of MDM2 was found in many human tumors. Since MDM2 inhibits p53 through a direct protein-protein interaction, blocking this interaction using small molecules has recently been pursued. The compound relating to the present invention is characterised by a powerful inhibitory effect on the interaction between MDM2 and p53 and in turn a high in vitro efficacy against tumour cells, e.g. osteosarcoma, ALL etc., which is mediated through the inhibition of the interaction between MDM2 and p53 and is the prerequisite for a corresponding efficacy in in vivo models and future patients (WO 2017/060431). Summary of the invention According to a first aspect, the present invention relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample. Furthermore, the present invention relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting the interaction between MDM2 and p53, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample. According to a second aspect, the present invention relates to a compound inhibiting KRAS protein or a mutant of a K-Ras protein for use in treating a cancer patient, i) wherein the KRAS inhibitor is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP-KRAS inhibitors or degraders, and HER2 inhibitors or degraders; and ii) wherein the patient has been determined to be responsive to the treatment with said compound according to the method described above. Furthermore, the present invention relates to a compound inhibiting the interaction between MDM2 and p53 for use in treating a cancer patient, wherein the patient has been determined to be responsive to the treatment with said compound according to the method described above. According to a third aspect, the present invention relates to a method of treating cancer in a patient with a compound inhibiting KRAS protein or a mutant of a KRAS protein, wherein the patient has been determined to be responsive to the treatment with said compound according to any of the methods described above. Furthermore, the present invention relates to a method of treating cancer in a patient with a compound inhibiting the interaction between MDM2 and p53, wherein the patient has been determined to be responsive to the treatment with said compound according to any of the methods described above. According to a fourth aspect, the present invention relates to the use of Survivin in a method for determining the ability of a compound to inhibit KRAS protein or a mutant of a KRAS protein, or of a pharmaceutical formulation comprising said compound inhibiting KRAS protein or a mutant of a KRAS protein, to treat cancer. Furthermore, the present invention relates to the use of Survivin in a method for determining the ability of a compound to inhibit the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, to treat cancer. According to a fifth aspect, the present invention relates to a kit of parts, comprising the means for determining the level of Survivin in samples provided from a patient suffering from cancer, and instructions for how to perform any of said methods as described above. The inventors have unexpectedly found that the inhibitor of apoptosis (IAP) protein Survivin may serve as a biomarker for selecting cancer patients who can be more advantageously treated by a KRAS inhibitor, and that this biomarker can be easily assessed and monitored by quantitative determination in blood, blood plasma or blood serum samples provided from the patients. By use of such a molecular biomarker, non-effective treatment of cancer patients not responding to a KRAS inhibitor could be avoided, and thus said patients could be changed to a more effective drug category more rapidly, increasing treatment effectiveness and prolonging survival time. The determination of Survivin levels as a biomarker in a sample easily to be provided further reduces overall treatment costs and labour time of clinical personnel. In addition, taking frequent tumor samples for monitoring treatment success and assessing cancer progression can be avoided that way. These objects are met with the subject matter, methods and means according to the independent claims of the present invention. The dependent claims are related to preferred embodiments. Additional details, features, characteristics and advantages of the object of the invention are disclosed in the dependent claims, and the following description of the respective figures and examples, which, in an exemplary fashion, show preferred embodiments of the present invention. However, these examples and drawings should by no means be understood as to limit the scope of the invention. Description of the Figures Fig.1. Survivin levels in untreated patients; (A) Survivin is detected in exosomes released by HPAC cells, but not in exosomes from healthy volunteers; (B) Comparison of plasma Survivin in healthy controls vs cancer patients (Colorectal Cancer, CRC; Pancreatic Ductal Adenocarcinoma, PDAC; and Non-small cell lung cancer, NSCLC); (C) Survivin plasma levels in CRC patients (placebo group) at different time points. Fig.2. Survivin/BIRC5 is a biomarker for sensitivity to KRAS inhibition. Biomarker study in vivo (HCC461) showing dose-dependent Survivin downregulation after 3 days of daily treatment with a KRASG12D inhibitor. Fig. 3. ELISA assay in (A) GP2D cells and (B) HPAC cells treated for 2 hours (top) and 24 hours (bottom) with a KRASG12D inhibitor, showing Survivin downregulation 24 hours post- treatment with a KRASG12D inhibitor in GP2D (left) and HPAC (right) cells. Fig. 4. Survivin is downregulated in NCI-H358 cells treated with different KRASG12C inihibitors. ELISA assay showing Survivin levels in NCI-H358 cells after treatment with 100 nM of compounds G12C-cpd#1 to G12C-cpd#11 for 72 hours. Fig. 5. Survivin is downregulated in the media of NCI-H358 cells treated with different KRASG12C inihibitors. ELISA assay showing Survivin levels in the media of H358 after treatment with 100 nM of compounds G12C-cpd#1 to G12C-cpd#11 for 72 hours. Fig. 6. Survivin is downregulated in the exosomes of NCI-H358 cells treated with different KRASG12C inihibitors. ELISA assay showing Survivin levels in the exosomes of H358 cells after treatment with 100 nM of compounds G12C-cpd#1 to G12C-cpd#11 for 72 hours. Fig. 7. Survivin is downregulated in SW1990 cells treated with different KRASG12D inihibitors and KRAS protac. ELISA assay showing Survivin levels in cell lysates of SW1990 cells after treatment with 300 nM of compounds G12D-cpd#1 to G12D-cpd#9 for 72 hours. Fig. 8. Survivin is downregulated in the media of SW1990 cells treated with different KRASG12D inihibitors and KRAS Protac. ELISA assay showing Survivin levels in the supernatants of SW1990 cells after treatment with 300 nM of compounds G12D-cpd#1 to G12D-cpd#9 for 72 hours. Fig. 9. Survivin is downregulated in the exosomes of SW1990 cells treated with different KRASG12D inihibitors and KRAS Protac. ELISA assay showing Survivin levels in the exosomes of SW1990 cells after treatment with 300 nM of compounds G12D-cpd#1 to G12D- cpd#9 for 72 hours. Fig. 10. ELISA assay showing Survivin levels in PC9 cells after treatment with 50 nM of HER2-cpd#1. Fig.11. Dose-dependent regulation of Survivin upon treatment with two different GDP-KRAS inhibitors (Cpd#a, Cpd#b) in vivo. Fig.12. Dose-dependent regulation of Survivin in tumors and plasma in a SW1990 CDX model after treatment with a KRASG12D inhibitor. Fig.13. Survivin modulation in SNU1196 cells (KRASWT amp) treated for 72 hours with 11 GDP-KRAS inhibitors (see Table 1 for compound numbering) or DMSO. (A) cell lysates; (B) exosomes. Fig.14. Dose-dependent modulation of Survivin in H358 tumors (A) and the respective mouse plasma (B), as well as modulation of Survivin in MKN1 tumors (C) and the respective mouse plasma (D). Fig.15. Downregulation of Survivin and correlation between plasma Survivin levels and tumor volume (TV) in various end of efficacy studies in CDX models. (A, B) = KRAS-WTamp, CDX model treated with an exemplary GDP-KRAS inhibitor; (C - E) = KRAS-G12V CDX model treated with an exemplary GDP-KRAS inhibitor and (F - H) = KRAS-G12D CDX model treated with the KRAS-G12D inhibitor shown as G12D-cpd#2 in Table 1 in the concentrations shown in the Figure. Fig. 16. Downregulation of Survivin levels in tumors (A) and plasma (B) in a HER2 mutant PC9_YMVA-5 NSCLC CDX model after treatment with the HER2 inhibitor HER2-cpd#1; as well as correlation between plasma Survivin levels and tumor volume in end of efficacy studies in CDX models (C) = NCI-N87, (D) = SK-GT-2, (E) = NCI-H2170) with the HER2 inhibitor HER2-cpd#1. Fig. 17. Downregulation of Survivin levels (RNA) by the MDM2 inhibitor MDM2i-cpd#1 in vivo in TP53 WT PDX models. (A) = CRC PDX model (Co10748); (B) = Malignant Peripheral nerve sheath tumors PDX. Detailed Description of the Invention Before the invention is described in detail, it is to be understood that this invention is not limited to the particular compounds or methods described as such compounds or methods may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an", and "the" include singular and/or plural referents unless the context clearly dictates otherwise. It is moreover to be understood that, in case parameter ranges are given which are delimited by numeric values, the ranges are deemed to include these limitation values. It is also to be understood that value ranges delimited by numerical values are to be understood to include said delimiting values. It is further to be understood that embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another. Features discussed with one embodiment are meant to be disclosed also in connection with other embodiments shown herein. If, in one case, a specific feature is not disclosed with one embodiment, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment, but that just for purposes of clarity and to keep the specification in a manageable volume this has not been done. Furthermore, the content of the prior art documents referred to herein is incorporated by reference. This refers, particularly, for prior art documents that disclose standard or routine methods. In that case, the incorporation by reference has mainly the purpose to provide sufficient enabling disclosure and avoid lengthy repetitions. According to a first aspect, the present invention relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample. More than one sample, and more than a first sample and a second sample, can be obtained during the period of treatment to continue to monitor responsiveness of the patient or after the end of treatment to monitor for a potential relapse. Said method of determining the responsiveness of a cancer patient preferably is performed in vitro (ex vivo). The present invention also relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting HER2 protein or a mutant of a HER2 protein, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample, preferably wherein the HER2 inhibitor is HER2-cpd#1. As described above, more than one sample, and more than a first sample and a second sample, can be obtained during the period of treatment to continue to monitor responsiveness of the patient or after the end of treatment to monitor for a potential relapse. Moreover, said method of determining the responsiveness of a cancer patient preferably is performed in vitro (ex vivo). The present invention further relates to a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting the interaction between MDM2 and p53 (also referred to herein as MDM2 inhibitor or MDM2i), the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample, preferably wherein the compound inhibiting the interaction between MDM2 and p53 is MDM2i-cpd#1. As described above, more than one sample, and more than a first sample and a second sample, can be obtained during the period of treatment to continue to monitor responsiveness of the patient or after the end of treatment to monitor for a potential relapse. Moreover, said method of determining the responsiveness of a cancer patient preferably is performed in vitro (ex vivo). As used herein, the term “inhibit“ or “inhibiting“ refers to the reduction or prevention of the activity and/or function, entirely or in part, of said KRAS protein or of a mutant of said KRAS protein, or of said HER2 protein or of a mutant of said HER2 protein, respectively, by said compound. The term “inhibit“ or “inhibiting“ also refers to the binding of said compound to the KRAS protein or to a mutant of said KRAS protein, or to the HER2 protein or to a mutant of said HER2 protein, respectively, wherein said binding may be direct or indirect, competitive or allosteric. The terms “inhibit“ or “inhibiting“ also refers to the degradation of said KRAS protein or of a mutant of said KRAS protein, or of said HER2 protein or of a mutant of said HER2 protein, respectively, and to the marking for degradation of said KRAS protein or of a mutant of said KRAS protein, or of said HER2 protein or of a mutant of said HER2 protein, respectively; and to any other kind of neutralization of the activity and/or function, entirely or in part, of said KRAS protein or of a mutant of said KRAS protein, or of said HER2 protein or of a mutant of said HER2 protein, respectively. The same considerations apply with regard to the term “inhibit” or “inhibiting” when used in the context of a compound inhibiting the interaction between MDM2 and p53 as described further below. As used herein, the term “level“ or “measuring the level“ of Survivin refers to the level or amount or measure of any of RNA, mRNA, or protein of Survivin. The terms further refer to measuring the level or amount of Survivin in samples, wherein the RNA, mRNA, or protein of Survivin may be within cells, in or on the cell membrane, outside of cells, in fluidic medium, in exosomes, and/or may be in (a) blood, blood plasma, or blood serum sample(s). As used herein, the term “decreased“ refers to a decrease or reduction of the level of the biomarker Survivin in the second (or nth +1) sample by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, or 100%, as compared to the level in the first (or nth) sample. As used herein, the term “Survivin“ relates to a protein with an amino acid sequence according to the UniProtKB/TrEMBL entry O15392, as well as to any variants, isoforms, splice variants, active mutants or secondary data base entries of said protein. Survivin, encoded by the BIRC5 (Baculoviral IAP Repeat-Containing 5, also called API4) gene, is the smallest member of the “Inhibitor of Apoptosis” (IAP) family of proteins, and is an inhibitor of apoptosis and a regulator of the cell cycle. These functional attributes make Survivin a unique protein exhibiting divergent functions including regulation of cell death and cell proliferation. Survivin is a small protein of 142 amino acids with multifunctional domains. Its N-terminal two-thirds comprise a globular Baculovirus Inhibitor of apoptosis Repeat (BIR) domain (aa 20– 90), the integrity of which depends on a Zinc finger that is created by C57, C60, C84 and H77; the C-terminal third is an extended α-helix (98–142). IAP family members usually contain multiple Baculovirus IAP Repeat (BIR) domains, but the BIRC5-gene encoded Survivin protein contains only a single BIR domain. Gene expression is high during fetal development and in most tumors, but low in adult tissues. Apart from activated T lymphocytes, erythroblasts and self-renewing stem cells, Survivin is absent from adult cells (Wheatley and Altieri, 2019). Survivin (BIRC5) has been shown to be involved in apoptosis inhibition and cell proliferation (LaCasse et al. 1998). Survivin is upregulated in many cancer types with low expression in normal tissues (Kawasaki et al. 1998). Several publications have shown Survivin to be correlated with poor prognosis (Takai et al.2002) and resistance to chemotherapy (Zafaroni et al.2002). Apoptosis is the primary form of programmed cell death and depends on cysteine proteinases, called caspases, to disassemble the cell in a controlled manner. Survivin protects cells against apoptotic and autophagic death; the localisation of Survivin within the cytoplasm is crucial to its anti-apoptotic activity. Survivin expression has been found to reduce caspase activity, however, Survivin does not bind to caspases at physiological concentrations, but cooperates with XIAP and hepatitis B virus X-interacting protein (HBXIP, also known as LAMTOR5) in a complex with XIAP-associated factor 1 (XAF1) to affect the interaction of XIAP with caspases or to augment the effect of other IAP family members. In addition to its intracellular localization, Survivin has also been found on the surface of exosomes which are constitutively secreted from cancer cells. Such release of Survivin from tumor cells has been found to support neighbouring tumor cells in evading apoptosis (Khan et al.2011). Due to its anti-apoptotic effect, Survivin has been considered as a target for cancer therapy (Altieri 2003; Li et al. 2019; Wheatley and Altieri, 2019). Mutant KRAS and Survivin both were shown to contribute to oncogenesis (Tecleab and Sebti, 2013). The combined application of a KRAS inhibitor and a beta-catenin inhibitor was shown to act synergistically in growth arrest of cancer cells, cell death and downregulation of Survivin; however, this effect was only observed with combined application, but no effect was achieved with single treatment with either inhibitor (Mologni et al.2012). The inventors have surprisingly found that the inhibitor of apoptosis (IAP) protein Survivin could be used in a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein, or inhibiting HER2 protein or a mutant of a HER2 protein, and hence serve as a biomarker for selecting cancer patients, preferably patients having a KRAS-dependent cancer, who can be more advantageously treated by a KRAS or HER2 inhibitor. Similarly, the inventors found that Survivin can also be used in a method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting the interaction between MDM2 and p53, as described further below. They further found that this biomarker can be easily assessed and monitored by quantitative determination in blood, blood plasma or blood serum samples. This finding was also unexpected insofar as it has been reported that K-RAS-dependent human carcinoma cells strongly increase the production of exosomes enriched in Survivin, thus enhancing the protection of themselves and of other carcinoma cells, but also of non-cancerous fibroblasts, from apoptotic cell death (Chang et al. 2021). Moreover, Chang et al. (2021) observed that the upregulation of Survivin was a means of tumour cells to make them resistant to the treatment with anti-tumour drugs. Surprisingly, in spite of said anti-apoptotic and protecting effect of Survivin, therapeutic intervention with K-RAS-inhibitors was found to be effective by the present inventors, who also showed that said therapeutic efficacy can be monitored non-invasively from samples obtained from treated mice. Hence these experiments in mice provide evidence that assessment of Survivin levels is equally suitable for determining the responsiveness of cancer patients to a treatment with a KRAS inhibitor or degrader, or to a treatment with a compound inhibiting the interaction between MDM2 and p53. In preferred embodiment(s) of the present invention, said first and/or said second sample(s) is/are (a) blood, blood plasma, or blood serum sample(s). Preferably, all samples are blood, blood plasma, or serum samples. In preferred embodiment(s) of the present invention, the step of measuring the level of Survivin in a sample comprises the isolation of exosomes from said sample and measuring the level of Survivin comprised in said exosomes. Means and methods for isolating exosomes and measuring the level of Survivin comprised in said exosomes are known in the art and have been described in the experimental part herein. In preferred embodiment(s) of the present invention, the level of Survivin is measured using a Survivin-specific assay selected from the group consisting of Western Blot, ELISA, RIA, the MSD® S-PLEX technology and FACS. Preferably, the level of Survivin is measured using an ELISA or the MSD® S-PLEX technology. In preferred embodiment(s) of the present invention, the cancer is a KRAS-dependent cancer, preferably a KRAS dependent cancer selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). In preferred embodiment(s) of the present invention, the cancer to be treated with a compound inhibiting KRAS protein or a mutant of a KRAS protein selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, and GDP-KRAS inhibitors or degraders, is selected from: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, glioma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder and other urothelial cancers; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma, hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma, multiple myeloma (MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, soft tissue sarcoma, liposarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); myelodysplastic syndromes (MDS); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer (e.g. castration-resistant prostate cancer); throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma, vaginal cancer or vaginal carcinoma, mesothelioma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra, cervical cancer, adenoid cystic carcinoma (AdCC), adrenocortical carcinoma and cancer of the vulva. In another preferred embodiment, the cancer to be treated with a compound inhibiting or degrading HER2 is selected from the group consisiting of cancers/tumors/carcinomas of the head and neck: e.g. tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (inc1uding lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (inc1uding base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (inc1uding supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (inc1uding minor salivary glands); cancers/tumors/carcinomas of the lung: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer); neoplasms of the mediastinum: e.g. neurogemc tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuro- blastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (inc1uding thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendotheli- oma, hemangiopericytoma, Iymphangi oma, Iymphangi opericytoma, lymphangiomyoma); cancers/tumors/carcinomas of the gastrointestinal (GI) tract: e.g. tumors/carcinomas/cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), hypemephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis); cancers/tumors/carcinomas ofthe testis: e.g. seminomas, non-seminomas; gynecologic cancers/tumors/carcinomas: e.g. tumors/carcinomas/cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); cancers/ tumors/carcinomas of the breast: e.g. mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), HER2 positive breast cancer, triple negative breast cancer, Paget s disease of the breast; cancers/tumors/carcinomas of the endocrine system: e.g. tumors/carcinomas/cancers of the endocrine glands, thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (inc1uding prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; nonfluorineunctional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagon- oma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; sarcomas of the soft tissues: e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposis sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing´s sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of the bone: e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget´s sarcoma), Ewing´s tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; mesothelioma: e.g. pleural mesothelioma, peritoneal mesotheli- oma; cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; neoplasms of the central nervous system and brain: e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma,gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medullo- blastomas, merungiomas, schwannomas, hemangioblastomas, hemangiomas, hemangioperi- cytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axis tumors; lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL) (inc1uding small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt s lymphoma (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphorna (ATLL), cutaneous T-cell- lymphoma (CTCL), peripheral T-celllymphoma (PTCL)), lymphoblastic T-celllymphoma (T- LBL), adult T-celllymphoma, lymphoblastic B-celllymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL) B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin´s disease (HD) (including nodular lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte- depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous/myeloid leukemia (AML), acute lymphatic/lympho- blastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic/lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous/ myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML); cancers of unknown primary site (CUP). In another preferred embodiment, the cancer to be treated with a compound inhibiting the interaction between MDM2 and p53 is selected from: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, glioma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder and other urothelial cancers; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non- small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma, hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non- seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma, multiple myeloma (MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, soft tissue sarcoma, liposarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); myelodysplastic syndromes (MDS); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer (e.g. castration-resistant prostate cancer); throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma, vaginal cancer or vaginal carcinoma, mesothelioma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra, cervical cancer, adenoid cystic carcinoma (AdCC), adrenocortical carcinoma and cancer of the vulva. More preferably, the cancer has functional p53 and/or p53 wild-type status. Functional p53 means that p53 is able to bind to DNA and activate transcription of target genes. In preferred embodiment(s) of the present invention, the compound inhibiting KRAS protein or a mutant of a KRAS protein is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP-KRAS inhibitors or degraders, and HER2 inhibitors or degraders. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. The person skilled in the art will understand that depending on the type of compound, the KRAS-dependent cancer will vary. In preferred embodiment(s) of the present invention, the KRAS(G12C) inhibitor or degrader is selected from the group consisting of: sotorasib (AMG510), adagrasib (MRTX849), G12C- cpd#1, G12C-cpd#2, G12C-cpd#3, G12C-cpd#4, G12C-cpd#5, G12C-cpd#6, G12C-cpd#7, G12C-cpd#8, G12C-cpd#9, G12C-cpd#10, and G12C-cpd#11. In preferred embodiment(s) of the present invention, the KRAS(G12D) inhibitor or degrader is selected from the group consisting of MRTX1133, G12D-cpd#2, G12D-cpd#3, G12D-cpd#4, G12D-cpd#5, G12D-cpd#6, G12D-cpd#7, G12D-cpd#8, and G12D-cpd#9. In preferred embodiment(s) of the present invention, the GDP-KRAS inhibitor or degrader is selected from the group consisting of GDP-cpd#1, GDP-cpd#2, GDP-cpd#3, GDP-cpd#4, GDP-cpd#5, GDP-cpd#6, GDP-cpd#7, GDP-cpd#8, GDP-cpd#9, GDP-cpd#10, GDP-cpd#11, GDP-cpd#12, GDP-cpd#13, GDP-cpd#14. In preferred embodiment(s) of the present invention, the HER2 inhibitor or degrader is a compound according to formula (F) (see below), more preferably the HER2 inhibitor or degrader is the compound HER2-cpd#1. In preferred embodiment(s) of the present invention, the compound inhibiting the interaction between MDM2 and p53 is MDM2i-cpd#1. Preferably, the compound is a compound selected from the compounds shown in Table 1. Table 1 Compound Compound Structure Type No./Example G12C G12C- Ic-4 cpd#1 (compound of formula A) for synthesis see WO2021245051 (Ic-4), for results see Fig.4 - 6 G12C- Id-2 cpd#2 (compound of formula A) for synthesis see WO2021245051 (Id-2), for results see Fig.4 - 6 G12C- Ia-1 cpd#3 (compound of formula B) for synthesis see Example 3 as well as WO2023099612 (Ia-1) for results see Fig.4 - 6 G12C- Ia-4 cpd#4 (compound of formula B) for synthesis see Example 3 as well as WO2023099612 (Ia-4) for results see Fig.4 - 6 G12C- Ib-3 cpd#5 (compound of formula B) for synthesis see Example 3 as well as WO2023099612 (Ib-3) for results see Fig.4 - 6 G12C- Ib-5 cpd#6 (compound of formula B) for synthesis see Example 3 as well as WO2023099612 (Ib-5) for results see Fig.4 - 6 G12C- Ib-6 cpd#7 (compound of formula B) for synthesis see Example 3 as well as WO2023099612 (Ib-6) for results see see Fig.4 - 6 G12C- Ib-1 cpd#8 (compound of formula A) for synthesis see WO2021245051 (Ib-1) for results see Fig.4 - 6 G12C- Ib-4 cpd#9 (compound of formula A) for synthesis see WO2021245051 (Ib-4) for results see Fig.4 - 6 G12C- Id-1 cpd#10 (compound of formula A) for synthesis see WO2021245051 (Id-1) for results see Fig.4 - 6 G12C- Ia-2 cpd#11 (compound of formula A) for synthesis see Example 3 as well as WO2023099612 (Ia-2) for results see Fig.4 - 6 G12D and KRAS Protac G12D- MRTX1133 see Wang et al.2022 cpd#1 G12D- I-049 cpd#2 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (I-049) for results see Fig.7 - 9 G12D- I-45 cpd#3 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (I-45) for results see Fig.7 - 9 G12D- II-149 cpd#4 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-149) for results see Fig.7 - 9 GDP- I-27 Protac- (compound of cpd#5 formula D) for synthesis see Example 5 as well as WO2023099620 (I-27) for results see Fig.7 - 9 G12D- II-9 cpd#6 (compound of formula E) for synthesis see Example 6 as well as WO2023099608 (II-9) for results see Fig.7 - 9 G12D- II-184 cpd#7 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-184) for results see Fig.7 - 9 G12D- II-187 cpd#8 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-187) for results see see Fig.7 - 9 G12D- II-165 cpd#9 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-165) for results see Fig.7 - 9 GDP-K-Ras GDP-cpd#1 I-34 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (I-34) for results see Fig.13 GDP-cpd#2 I-58 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (I-58) for results see Fig.13 GDP-cpd#3 II-20 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-20) for results see Fig.13 GDP-cpd#4 II-21 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-21) for results see Fig.13 GDP-cpd#5 II-86 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-86) GDP-cpd#6 II-110 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-110) GDP-cpd#7 II-111 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-111) GDP-cpd#8 II-182 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-182) for results see Fig.13 GDP-cpd#9 II-189 O (compound of HO formula C) N for synthesis see N N Example 4 as O N well as N WO2023099624 N (II-189) N O for results see H2N Fig.13 S GDP- II-191 cpd#10 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-191) for results see Fig.13 GDP- II-192 cpd#11 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-192) for results see Fig.13 GDP- II-194 cpd#12 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-194) for results see Fig.13 GDP- II-201 cpd#13 (compound of formula C) for synthesis see Example 4 as well as WO2023099624 (II-201) for results see Fig.13 GDP- II-94 O cpd#14 (compound of formula C) N O for synthesis see N N WO2023099624 (II-94) N N for results see O Fig.13 H2N S Her-2 Her2-cpd#1 I-01 (compound of formula F) for synthesis see WO2021213800 (I-01) for results see Fig.10 MDM2i MDM2i- Ia-34 O OH cpd#1 for synthesis see WO2017060431 (Ia-34) Cl N F N for results see Fig.17 N O Cl N H Chiral Anti-cancer drugs are sometimes judged for their effect on a “biomarker” or surrogate marker that may predict clinical benefit to the patient, such as regression of tumors. When monitoring a patient’s response to an anti-cancer drug, a “biomarker” can be the basis for clear demonstration that the administered compound and a chosen dose and treatment schedule are capable and the levels reached are sufficient for an efficient inhibition of the targeted cancer. In the evaluation of molecularly targeted therapies, traditional clinical endpoints have proven difficult to apply; standard clinical trial endpoints that are used for cytotoxic compounds have been found to be insufficient for the evaluation of molecularly targeted anti-cancer agents. For their development, it is important to have endpoint assessments available for the efficacy of a compound in modulating the activity of its molecular target, and the relationship between target modulation and clinical response. Thus the availability of biomarkers indirectly indicating the effect of treatment on the disease state is one of the key prerequisites for the development of minimally or non-invasive techniques for assessment of an inhibitor´s efficacy and, consequently, both for the clinical evaluation of the drug and in the long run for monitoring the efficacy of an approved drug in therapy. A “biomarker” can be defined as a measurable feature or characteristic which is an indicator of normal physiological processes, pathogenic processes, or an indicator of a response to an exposure or therapeutic intervention. Molecular, histologic, radiographic, or physiologic biomarkers represent different types of biomarkers (Aboy et al. 2019) by the nature of said measurable feature. FDA and NIH categorizes biomarkers further into prognostic, predictive, responsive, monitoring, safety, diagnostic and susceptibility/risk biomarkers (BEST Resource). According to said categorization, a pharmacodynamic/response biomarker is a biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent (BEST Resource). A pharmacodynamic/response biomarker is a biomarker whose level changes in response to an exposure to a medical product or an environmental agent. A change in a pharmaco- dynamic/response biomarker, such as a circulating small molecule or protein, or a physiologic measure, provides early evidence that a treatment might have an effect on a clinical endpoint of interest or can be used to assess a pharmacologic endpoint related to safety concerns. It can also provide useful information for patient management, e.g., whether to continue treatment or to adjust dose, or for medical product development, e.g., did the drug have the pharmacodynamic effect thought to be related to clinical effect. Because of the serial nature of their assessment, pharmacodynamic/response biomarkers may also fall under the category of monitoring biomarkers. Pharmacodynamic/response biomarkers are very important in the setting of early drug development trials, and can be used to measure the level of response to the intervention, and to guide clinical dose-response studies. The main utility of pharmaco- dynamic/response biomarkers in clinical practice is to guide dosing or continued use of a drug or other intervention. Such biomarkers may be used to gauge the level of response so that individual drug doses can be altered, or to identify whether therapies need to be added, subtracted or replaced. In these cases, pharmacodynamic/response biomarkers can provide evidence of target engagement. In addition, these biomarkers can be used in pharmacologic dose-ranging studies to determine which doses should be considered in trials that evaluate a clinical outcome (BEST Resource). As shown in the experimental examples of the present application, the inventors have found that Survivin is a suitable and reliable biomarker, preferably pharmacodynamic/response biomarker, for assessment of the inhibitory activity of KRAS inhibitors or degraders in KRAS- dependent cancer cells and cancer types. The same applies to HER2 inhibitors or degraders in HER2- and/or KRAS dependent cancer cells and cancer types; the inventors have found that Survivin is a suitable and reliable biomarker, for assessment of the inhibitory activity of HER2 inhibitors. Similarly, as shown in Example 9.5 and Figure 17, Survivin is also downregulated upon successful treatment with the MDM2i-cpd#1 and, accordingly, Survivin can conveniently be employed as a circulation biomarker in patient blood samples for monitoring treatment efficiency during tumor treatment, thereby reducing the burden on patients associated with invasive tumor biopsies or cumbersome imaging approaches. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. Accordingly, the term “compound inhibiting KRAS protein or a mutant of a KRAS protein”, as used herein, encompasses compounds that inhibit or degrade the HER2 protein, or a mutant of said HER2 protein. The present invention further relates to a method for selecting a patient suffering from cancer for a treatment with a KRAS inhibitor or degrader, said method comprising at least the steps of - determining the level of Survivin in a sample from the patient prior to administering to the patient a KRAS inhibitor or degrader, and - determining a decreased level of Survivin in at least one second sample from the patient. Similarly, the present invention further relates to a method for selecting a patient suffering from cancer for a treatment with a compound inhibiting the interaction between MDM2 and p53, said method comprising at least the steps of - determining the level of Survivin in a sample from the patient prior to administering to the patient said compound, and - determining a decreased level of Survivin in at least one second sample from the patient. The present invention further relates to the methods for selecting a patient as described above, wherein a decreased level of Survivin is determined in several samples, preferably in all samples, obtained from the patient after administering to the patient a KRAS inhibitor or degrader, or after administering the compound inhibiting the interaction between MDM2 and p53, respectively. The present invention further relates to the method for selecting a patient as described above, further comprising the step of selecting said patient for continuing the treatment with a KRAS inhibitor or degrader, or with a compound inhibiting the interaction between MDM2 and p53, respectively. The present invention further relates to a method for selecting a cancer patient for being treated with a compound that acts as KRAS inhibitor or degrader by determining ex vivo the level of Survivin in at least a first sample and at least a second sample from said cancer patient, wherein said at least first sample is collected prior to treating said cancer patient with the compound that acts as KRAS inhibitor or degrader and said at least second sample is collected after treating said cancer patient with the compound that acts as KRAS inhibitor or degrader, wherein the level of Survivin in the second or one or more further sample collected from said cancer patient after treating said cancer patient with the compound that acts as KRAS inhibitor or degrader has been determined as being decreased, compared to the first sample, or compared to the immediately penultimate sample of the one or more further sample, respectively. The present invention further relates to a method for selecting a cancer patient for being treated with a compound inhibiting the interaction between MDM2 and p53 by determining ex vivo the level of Survivin in at least a first sample and at least a second sample from said cancer patient, wherein said at least first sample is collected prior to treating said cancer patient with the compound inhibiting the interaction between MDM2 and p53 and said at least second sample is collected after treating said cancer patient with the compound inhibiting the interaction between MDM2 and p53, wherein the level of Survivin in the second or one or more further sample collected from said cancer patient after treating said cancer patient with the compound inhibiting the interaction between MDM2 and p53 has been determined as being decreased, compared to the first sample, or compared to the immediately penultimate sample of the one or more further sample, respectively. The present invention further relates to a method for predicting the responsiveness of a cancer patient to a KRAS inhibitor or degrader, said method comprising at least the steps of - providing a first sample from the patient, - determining the level of Survivin in said first sample from the patient prior to - administering to the patient a KRAS inhibitor or degrader, and - identifying the patient as responsive to treatment with said KRAS inhibitor or degrader, when the level of Survivin in a second or one or more further sample, provided from the patient after administering said KRAS inhibitor or degrader, has been determined as being decreased, compared to the first sample, or compared to the immediately penultimate sample of the one or more further sample, respectively. The present invention further relates to a method for predicting the responsiveness of a cancer patient to a compound inhibiting the interaction between MDM2 and p53, said method comprising at least the steps of - providing a first sample from the patient, - determining the level of Survivin in said first sample from the patient prior to - administering to the patient a compound inhibiting the interaction between MDM2 and p53, and - identifying the patient as responsive to treatment with said compound inhibiting the interaction between MDM2 and p53, when the level of Survivin in a second or one or more further sample, provided from the patient after administering said compound inhibiting the interaction between MDM2 and p53, has been determined as being decreased, compared to the first sample, or compared to the immediately penultimate sample of the one or more further sample, respectively. The present invention further relates to a method of determining whether a compound inhibiting KRAS protein or a mutant of a KRAS protein is efficacious in the treatment of a cancer, and/or in monitoring a cancer patient´s response to said treatment, said method comprising at least the steps of - providing a first sample from the patient, - measuring the level of Survivin in said first sample from the patient, - administering said compound inhibiting KRAS protein or a mutant of a KRAS protein to the patient, - providing a second sample from the patient, - measuring the level of Survivin in said second sample, - comparing the levels of Survivin measured in the first and second sample, and - optionally repeating the fourth to sixth step, wherein a decreased level of Survivin in the second sample indicates an effective response. The present invention further relates to a method of determining whether a compound inhibiting the interaction between MDM2 and p53 is efficacious in the treatment of a cancer, and/or in monitoring a cancer patient´s response to said treatment, said method comprising at least the steps of - providing a first sample from the patient, - measuring the level of Survivin in said first sample from the patient, - administering said compound inhibiting the interaction between MDM2 and p53 to the patient, - providing a second sample from the patient, - measuring the level of Survivin in said second sample, - comparing the levels of Survivin measured in the first and second sample, and - optionally repeating the fourth to sixth step, wherein a decreased level of Survivin in the second sample indicates an effective response. In a preferred embodiment of any of the methods as described above, said sample(s) is/are blood, blood plasma, or serum sample(s). In a preferred embodiment of any of the methods as described above, the compound inhibiting KRAS protein or a mutant of a KRAS protein is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP- KRAS inhibitors or degraders, and HER2 inhibitors or degraders. In further preferred embodiments of any of the methods as described above, the KRAS(G12C) inhibitor or degrader is selected from the group consisting of: sotorasib (AMG510), adagrasip (MRTX849), G12C-cpd#1, G12C-cpd#2, G12C-cpd#3, G12C-cpd#4, G12C-cpd#5, G12C- cpd#6, G12C-cpd#7, G12C-cpd#8, G12C-cpd#9, G12C-cpd#10, and G12C-cpd#11. In further preferred embodiments of any of the methods as described above, the KRAS(G12D) inhibitor or degrader is selected from the group consisting of MRTX1133, G12D-cpd#2, G12D- cpd#3, G12D-cpd#4, G12D-cpd#5, G12D-cpd#6, G12D-cpd#7, G12D-cpd#8, and G12D- cpd#9. In further preferred embodiments of any of the methods as described above, the GDP-KRAS inhibitor or degrader is selected from the group consisting of GDP-cpd#1, GDP-cpd#2, GDP- cpd#3, GDP-cpd#4, GDP-cpd#5, GDP-cpd#6, GDP-cpd#7, GDP-cpd#8, GDP-cpd#9, GDP- cpd#10, GDP-cpd#11, GDP-cpd#12, GDP-cpd#13, and GDP-cpd#14. In further preferred embodiments of any of the methods as described above, the HER2 inhibitor or degrader is a compound according to formula (F) (see below), more preferably the HER2 inhibitor or degrader is the compound HER2-cpd#1. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. In a preferred embodiment of any of the methods as described above, the compound inhibiting the interaction between MDM2 and p53 is the compound MDM2i-cpd#1. In further preferred embodiments of any of the methods as described above, said Survivin is comprised in exosomes. In further preferred embodiments of any of the methods as described above, said cancer is a KRAS-dependent cancer, preferably a KRAS dependent cancer selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). In another preferred embodiment of any of the methods described above, the cancer to be treated with a compound inhibiting the interaction between MDM2 and p53 is selected from any of the cancers defined herein above as preferred cancer types for the treatment with such an MDM2 inhibitor. In further preferred embodiments of any of the methods as described above, determining the level of Survivin comprises a Survivin-specific assay, preferably selected from the group consisting of Western Blot, ELISA, RIA, the MSD® S-PLEX technology and FACS, more preferably wherein said assay is an ELISA or the MSD® S-PLEX technology. According to a second aspect, the present invention relates to a compound inhibiting KRAS protein or a mutant of a KRAS protein for use in treating a cancer patient, i) wherein the KRAS inhibitor or degrader is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP-KRAS inhibitors or degraders, and HER2 inhibitors and degraders; and ii) wherein the patient has been determined to be responsive to the treatment with said compound according to any of the methods described above. In accordance with this second aspect of the invention, the invention also relates to a compound inhibiting the interaction between MDM2 and p53 for use in treating a cancer patient, i) wherein the compound inhibiting the interaction between MDM2 and p53 is the MDM2i-cpd#1; and ii) wherein the patient has been determined to be responsive to the treatment with said compound according to the method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting the interaction between MDM2 and p53 of the invention. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. The present invention further relates to a KRAS inhibitor or degrader for use in a method for treating a KRAS dependent cancer in a patient exhibiting the molecular biomarker Survivin. The present invention further relates to a compound inhibiting the interaction between MDM2 and p53 for use in a method for treating cancer in a patient exhibiting the molecular biomarker Survivin. The present invention further relates to a KRAS inhibitor or degrader for use in a method for treating a KRAS dependent cancer in a patient, wherein said patient has been determined to exhibit the molecular biomarker Survivin. The present invention further relates to a compound inhibiting the interaction between MDM2 and p53 for use in a method for treating cancer in a patient, wherein said patient has been determined to exhibit the molecular biomarker Survivin. The present invention further relates to a KRAS inhibitor or degrader for use in a method for treating a K-ras dependent cancer in a patient, comprising determining that said patient exhibits the molecular biomarker Survivin. The present invention further relates to a compound inhibiting the interaction between MDM2 and p53 for use in a method for treating cancer in a patient, comprising determining that said patient exhibits the molecular biomarker Survivin. The present invention further relates to a KRAS inhibitor or degrader for use in a method for treating a KRAS dependent cancer in a patient, comprising - having measured the level of Survivin in a first sample obtained from said patient, - having compared the level of Survivin in at least a second sample obtained from said patient during treatment to the level of Survivin in the first sample, and - having determined that the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample, or that the level of Survivin in any further sample obtained from said patient during treatment after the second sample is decreased as compared to the level of Survivin in the penultimate sample obtained from said patient during treatment. The present invention further relates to a compound inhibiting the interaction between MDM2 and p53 for use in a method for treating cancer in a patient, comprising - having measured the level of Survivin in a first sample obtained from said patient, - having compared the level of Survivin in at least a second sample obtained from said patient during treatment to the level of Survivin in the first sample, and - having determined that the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample, or that the level of Survivin in any further sample obtained from said patient during treatment after the second sample is decreased as compared to the level of Survivin in the penultimate sample obtained from said patient during treatment. The present invention further relates to said KRAS inhibitor or degrader for use as described above, wherein the compound is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP- KRAS inhibitors or degraders, and HER2 inhibitors and degraders. The present invention further relates to said KRAS inhibitor or degrader for use as described above, wherein the compound is MDM2i-cpd#1. The present invention further relates to said KRAS inhibitor or degrader, or said compound inhibiting the interaction between MDM2 and p53, for use as described above, wherein Survivin is comprised in exosomes. The present invention further relates to said KRAS inhibitor or degrader, or said compound inhibiting the interaction between MDM2 and p53, for use as described above, wherein said sample(s) is/are blood, blood plasma, or serum sample(s). The present invention further relates to said K-Ras inhibitor or degrader for use as described above, wherein the KRAS dependent cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). The present invention further relates to said compound inhibiting the interaction between MDM2 and p53 for use as described above, wherein the cancer is selected from any of the cancers defined herein above as preferred cancer types for the treatment with such an MDM2 inhibitor. The present invention further relates to said K-Ras inhibitor or degrader, or said compound inhibiting the interaction between MDM2 and p53, for use as described above, wherein determining the level of Survivin comprises a Survivin-specific assay, preferably selected from the group consisting of Western Blot, ELISA, RIA, the MSD® S-PLEX technology and FACS. In its broadest sense, a “biomarker” can be defined as a measurable feature which is an indicator of normal physiological processes, pathogenic processes, or an indicator of a response to an exposure or (therapeutic) intervention. Molecular, histologic, radiographic, or physiologic biomarkers represent different types of biomarkers and have been used in medicine: blood pressure or glucose levels are straightforward examples of a physiologic and a molecular biomarker, respectively. Various approaches are being used to further classify biomarkers. For example, FDA and NIH categorizes them into prognostic, predictive, responsive, monitoring, safety, diagnostic and susceptibility/risk biomarkers (BEST Resource 2018). Within the meaning of the present invention, a biomarker is used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. This is in line with the definition given by an NIH study group in 1998. More specifically, a biomarker indicates a change that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a surrogate endpoint for evaluating clinical benefit. The term “sample“ as used herein refers to a tissue sample or a bodily fluid sample, such as a blood sample. Preferably, said sample is a blood, blood plasma, or blood serum sample. A tissue sample is a section of an organ or a tissue of the body, which typically includes several cell types, optionally with cytoskeletal structures that hold the cells together. A tissue sample can be obtained by a biopsy, for example, including by cutting, slicing, or a punch. lt involves extraction of sample cells or tissue for examination. However, the terms “providing a sample“, “a sample from a patient“ or “a sample obtained from a patient“ do not include the active step of extraction of the tissue or blood, but rather refer to the provision of an already extracted sample, i.e., the provision of an ex vivo sample from a patient. The term “a sample obtained from a patient“ as used herein refers to the sample ex vivo, i.e., after collection, and is synonymous to “providing a sample from a patient“ or “providing an ex vivo sample from a patient“. Further, a tissue sample may be a tumor sample or the respective control sample, preferably from the same tissue. A blood sample may be a serum or plasma sample and is preferably a plasma sample. However, a blood sample may also include the cell fraction, e.g., for complete blood count and blood cell exam, such as a peripheral blood smear. Other bodily fluid samples in addition to blood include, without being limited thereto, mucous, seminal fluid, saliva, sputum, bronchial lavage, breast milk, bile and urine. A sample may further be a bone marrow biopsy or aspirate or a cerebrospinal fluid. The sample may be analysed using any method known in the art including, for example, without being limited thereto, by cytochemistry, such as chemical stains (dyes) that react with certain substances found in or on different kind of cells, flow cytometry and immunohistochemistry (IHC), such as by using antibody staining, fluorescent in situ hybridization (FISH), Polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), MSD® S-PLEX technology or Western Blot. Preferably, the analysis is carried out by ELISA or the MSD® S- PLEX technology. In any one of the methods described above, the level of the biomarker Survivin in the second (or nth +1) sample is decreased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, or 100%, as compared to the level in the first (or nth) sample. The Survivin-specific assay, in particular when it is an assay comprising a Western Blot, Dot Blot, ELISA (Enzyme-linked immunosorbent assay), RIA (radio immuno assay), RIST (radio immunosorbent assay), MSD® S-PLEX technology, or FACS (Fluorescence activated cell sorter), might be based on an antibody, in particular a monoclonal antibody. General principles of Western Blot, Dot Blot, ELISA, RIA, RIST, the MSD® S-PLEX technology and FACS are known to the person skilled in the art (Coligan 2011). Antibodies and monoclonal antibodies directed to Survivin have been described (Fenstermaker et al.2018; Watanuki-Miyauchi et al.2005; Arora et al.2012). Survivin-specific assays are known in the prior art (Naumunik et al.2009; Derin et al.2008). As used herein, the term “antibody” refers to a protein consisting of one or more polypeptide chains encoded by native or recombinant immunoglobulin genes or fragments of immunoglobulin genes or cDNAs derived from the same. Said immunoglobulin genes include the light chain kappa, lambda and heavy chain alpha, delta, epsilon, gamma and mu constant region genes as well as any of the many different variable region genes. The basic immunoglobulin (antibody) structural unit is usually a tetramer composed of two identical pairs of polypeptide chains, the light chains (L, having a molecular weight of about 25 kDa) and the heavy chains (H, having a molecular weight of about 50-70 kDa). Each heavy chain is comprised of a heavy chain variable region (abbreviated as VH or V_H) and a heavy chain constant region (abbreviated as CH or CH). The heavy chain constant region is comprised of three domains, namely CH1, CH2 and CH3. Each light chain contains a light chain variable region (abbreviated as VL or V_L) and a light chain constant region (abbreviated as CL or C_L). The VH and VL regions can be further subdivided into regions of hypervariability, which are also called complementarity determining regions (CDR) interspersed with regions that are more conserved called framework regions (FR). Each VH and VL region is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains form a binding domain that interacts with an antigen. The CDRs are most important for binding of the antibody or the antigen binding portion thereof. The FRs can be replaced by other sequences, provided the three-dimensional structure which is required for binding of the antigen is retained. Structural changes of the construct most often lead to a loss of sufficient binding to the antigen. The term “antigen-binding“ of the (monoclonal) antibody, antigen-binding fragment or derivative thereof, and antigen-binding antibody-like protein, refers to one or more portions or fragments of an antibody which retain the ability to specifically bind to the antigen in its native form. Examples of antigen binding portions of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, an F(ab’)₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfid bridge at the hinge region, an Fd fragment consisting of the VH and CH1 domain, an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, and a dAb fragment which consists of a VH domain and an isolated complementarity determining region (CDR). As used herein, the term “monoclonal antibody (mAb)” shall refer to an antibody composition having a homogenous antibody population, i.e., a homogeneous population consisting of a whole immunoglobulin, or a fragment or derivative thereof. Such antibody may be selected from the group consisting of IgG, IgD, IgE, IgA and/or IgM, or a fragment or derivative thereof. Particularly preferred, said antibody is an IgG. As used herein, the term antibody “fragment” shall refer to fragments of such an antibody retaining target binding capacities, e.g., a CDR (complementarity determining region), a hypervariable region, a variable domain (Fv), an IgG heavy chain (consisting of VH, CH1, hinge, CH2 and CH3 regions), an IgG light chain (consisting of VL and CL regions), and/or a Fab and/or F(ab)₂. As used herein, the term antibody “derivative” shall refer to protein constructs being structurally different from, but still having some structural relationship to, the common antibody concept, e.g., scFv, Fab and/or F(ab)₂, as well as bi-, tri- or higher specific antibody constructs. The term “KRAS dependent cancer” as used herein refers to a cancer, cancer cell or cancer tissue, wherein said cancer, cancer cell or cancer tissue either comprises (i) one or more mutations in the K-ras oncogene, either alone or together with one or more co-mutations which may influence the function of the KRAS protein and the occurrence and development of tumors, and/or wherein said cancer, cancer cell or cancer tissue formation is caused by said one or more mutations in the K-ras oncogene, or (ii) an amplification of the wild type (WT) K-Ras protooncogene. K-ras mutations are considered to be the most common oncogenic gene driver in human cancers. The profile of K-ras mutations may differ significantly among different cancer types. K-ras mutations are dominated by single-base missense mutations, 98% of which are found at codon 12 (G12), codon 13 (G13) or codon 61 (Q61). Alterations in KRAS proteins caused by mutations have been shown to impede the interaction of KRAS with GAPs and the hydrolysis of GTP bound to KRAS, leaving KRAS in a constitutively active state (Huang et al. 2021). As used herein, the term “KRAS mutants“ relates to K-ras genes or KRAS proteins comprising any kind of mutation in the K-ras gene and at any amino acid position of the KRAS protein, respectively. In particular, K-Ras mutants are KRAS proteins comprising mutations at codon 12 (G12), codon 13 (G13) or codon 61 (Q61) in the K-ras gene. Further in particular, a K-Ras mutant is KRAS(G12C) protein. Prominent amplification of the wildtype (WT) KRAS proto-oncogene has been observed in a subset of tumor indications such as gastric cancer, gastroesophageal junction cancer and oesophageal cancer, as described herein above. As used herein, the term “KRAS inhibitors“ or “K-Ras inhibitors“ refers to any compounds, agents, small molecules, peptides, polypeptides or proteins capable of inhibiting the activity of K-Ras, including degraders of KRAS protein. KRAS inhibitors in accordance with the present invention are preferably compounds inhibiting KRAS wildtype, preferably amplified. KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A and KRAS G12R, preferably inhibiting KRAS G12C and/or KRAS G12D, as well as compounds inhibiting KRAS mutated at residue 13, such as KRAS G13D, or KRAS mutated at residue 61, such as KRAS Q61H. Said inhibition might be directly or indirectly, competitively or allosterically. Indirect inhibitors include, without limitation, compounds that inhibit K-Ras activity by interfering with signalling molecules upstream of the KRAS signaling pathway, such as e.g. the receptor tyrosine kinases of the EGFR family, including EGFR (also known as ERBB1 or HER1), ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4. Preferably, the indirect KRAS inhibitor is a HER2 inhibitor. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. The family of ERBB transmembrane receptor tyrosine kinases (RTKs) consists of the four members EGFR (ERBB1), HER2 (Neu, ERBB2), HER3 (ERBB3) and HER4 (ERBB4), which fulfill essential functions during development (Citri et al. 2006; Wang, Z. 2017). ERBB signaling is initiated upon binding of the extracellular domains of EGFR, HER3 or HER4 to their respective ligands and subsequent homo- or heterodimerization of ERBB family members. HER2, for which no ligand has been identified, is the preferred dimerization partner for the other ERBB members. Once an active ligand-receptor complex has been formed, the intracellular tyrosine kinase domains of EGFR, HER2, HER3 or HER4 are activated by auto- or transphosphorylation and subsequently elicit a signal transduction cascade most notably engaging the mitogen-activated protein (MAP) kinase and/or the phosphoinositide 3-kinase (PI3K) pathways (Citri et al.2006; Wang, Z. 2017), wherein K-Ras is involved, as described above. In cancer, ERBB signaling is hyper-activated through mutations that render the RTK constitutively active by promoting dimerization or shifting the equilibrium towards the active conformer of the kinase and/or through amplification and consequent over-expression of the RTK. Both oncogenic mechanisms increase the net output of ERBB signaling and thereby promote cell survival, cell growth and proliferation. Aberrant HER2 signaling is observed in a wide variety of human malignancies. Oncogenic mutations are described for the extracellular, (juxta-) membrane and intracellular regions of the protein. Collectively these mutations render HER2 constitutively active, fueling cancer initiation, tumor maintenance and growth. Similarly, HER2 overexpression increases HER2 signaling and underlies neoplastic transformation and tumor maintenance in a variety of indications including breast, gastric or lung cancer. Consequently, interference with HER2 oncogenic signaling results in inhibition of tumor growth. Targeted therapies include HER2 directed antibodies (e.g., trastuzumab and pertuzumab), HER2 directed antibody-drug conjugates (trastuzumab-DM1 (T-DM1, ado- trastuzumab emtansine)) and small molecules inhibiting the HER2 kinase domain (afatinib, neratinib, lapatinib). Tumors driven by HER2 oncogenic mutations or HER2 wild type over-expression (for example due to gene amplification) might benefit from a HER2 specific tyrosine kinase inhibitor (TKI). Collectively, HER2 alterations affect up to 6-7% of all human cancers and an EGFR wild type sparing TKI (tyrosine kinase inhibitor) could emerge as an effective therapeutic option. HER2 exon 20 mutations constitute a subset of HER2 gain-of-function mutations that result in enhanced kinase activity. This enhanced HER2 kinase activity feeds into downstream signaling cascades that stimulate neoplastic transformation through promoting growth, proliferation and survival of the mutant cells. Selective inhibitors of HER2 exon 20 have been developed and show an improved wild type EGFR sparing efficacy profile in addition to high selectivity over EGFR wild type compared to prior art compounds. Furthermore, some compounds of that kind have shown an improved pharmacokinetic and pharmacological profile, such as good metabolic stability (WO2021/213800). KRAS inhibitors include, but are not limited to, compounds known in the art such as e.g. sotorasib (AMG510) and adagrasip (MRTX849), as well as the compounds detailed herein. KRAS inhibitors preferably include annulated 2-amino-3-cyano thiophenes and derivatives of formula (A): wherein R1a, R1b, R2a, R2b, Z, R3 to R5 , A, p, U, V, W, L and E have the following meanings: [A0] R1a and R1b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; R2a and R2b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R1a or R1b and one of R2a or R2b together with the carbon atoms they are attached form a cyclopropane ring; [B0] Z is -(CR6aR6b)n-; each R6a and R6b is independently selected from the group consisting of hydrogen, C_1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halogen, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; n is selected from the group consisting 0, 1 and 2; [C0] R3 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-6alkyl, halogen, -OH, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocyclyl; [D0] ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; [E0] each R4, if present, is independently selected from the group consisting of C1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-6alkyl, halogen, -OH, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting 0, 1, 2 and 3; [F0] U is selected from the group consisting of nitrogen (=N–) and carbon substituted with RA (=C(RA)-); V is selected from the group consisting of nitrogen (=N–) and carbon substituted with RB (=C(RB)-); W is selected from the group consisting of nitrogen (=N–) and carbon substituted with RC (=C(RC)-); RA, RB and RC is each independently selected from the group consisting of hydrogen, C_1-6haloalkyl, C_2-6alkynyl optionally substituted with C_3-5cycloalkyl, C_1-6alkoxy, C1-6haloalkoxy, halogen, -CN, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -C(=O)NH2, -C(=O)NH(C_1-4alkyl), -C(=O)N(C_1-4alkyl)₂, -S-C_1-6alkyl, -S(=O)₂-C_1-6alkyl, C_3-5cycloalkyl, 3- 5 membered heterocyclyl and C_1-6alkyl optionally substituted with a substituent selected from the group consisting of C1-6alkoxy, -CN, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -C(=O)NH2, -C(=O)NH(C1-4alkyl) and -C(=O)N(C1-4alkyl)2; [G0] R5 is selected from the group consisting of Ra1 and Rb1; Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb1 and/or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C(=O)Rc1, -C(=O)ORc1, -C(=O)NRc1Rc1, -S(=O)₂Rc1, -S(=O)₂NRc1Rc1, -NHC(=O)Rc1, -N(C_1-4alkyl)C(=O)Rc1, -NHS(=O)₂Rc1, -N(C_1-4alkyl)S(=O)₂Rc1, -NHC(=O)ORc1, -N(C alkyl)C c1 1-4 (=O)OR and the bivalent substituent =O; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, wherein the C_1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rd1 and/or Re1; each Rd1 is independently selected from the group consisting of -ORe1, -NRe1Re1, halogen, -CN, -C(=O)Re1, -C(=O)ORe1, -C(=O)NRe1Re1, -S(=O) e1 e1 e1 2R , -S(=O)2NR R , -NHC(=O)Re1, -N(C_1-4alkyl)C(=O)Re1, -NHS(=O)₂Rc1, -N(C_1-4alkyl)S(=O)₂Rc1, -NHC(=O)ORe1, -N(C e1 1-4alkyl)C(=O)OR and the bivalent substituent =O; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C_1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C1-4alkyl, C6-10aryl, 5-10 membered heteroaryl, -OH, C1- 6alkoxy, C_1-4alkoxy-C_1-4alkyl, hydroxy-C_1-4alkyl, halogen, -CN, -NH₂, -C(=O)C_1-4alkyl, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂ and the bivalent substituent =O; wherein 1 L is linked to E; L1 is selected from the group consisting of a bond, -NH-, -N(C_1-4alkyl)-, -O-, -C(=O)-, -NH-C(=O)-, -N(C1-4alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C1-4alkyl)-, -C(=O)-, C1-6alkylen, C3-7cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene; L2 is selected from the group consisting of C1-6alkylen, C3-7cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene; L3 is selected from the group consisting of a bond, -NH-, -N(C1-4alkyl)-, -O-, -C(=O)-, -NH-C(=O)-, -N(C_1-4alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C_1-4alkyl)-, -C(=O)-, C_1-6alkylen, C3-7cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene; wherein each C_1-6alkylen, C_3-7cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene in L1, L2 and L3 is optionally and independently substituted with one or more, identical or different substituent(s) selected from the group consisting of C_2-6alkinyl, C_1-6haloalkyl, C_3-7cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, -OH, - CN, C_1-6alkoxy, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -C(=O)OH, -C(=O)-OC1-6alkyl, -C(=O)NH2, -C(=O)NH(C1-4alkyl), -C(=O)N(C1-4alkyl)2, the bivalent substituent =O and C_1-6alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of halogen, -OH, -CN, C_1-4alkoxy, -NH₂, -NH(C1-4alkyl), -N(C1-4alkyl)2, -C(=O)OH, -C(=O)-OC1-6alkyl, -C(=O)NH2, -C(=O)NH(C1-4alkyl) and -C(=O)N(C1-4alkyl)2; [I0] E is represents a double or a triple bond; Q1 is selected from the group consisting of a bond, -CH₂-, -CH(OH)-, -C(=O)-, -C(=O)N(RG1)-, -C(=O)O-, -S(=O)₂-, -S(=O)₂N(RG1)- and -C(=NRH1)-; each RG1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, hydroxy-C_1-6alkyl, H₂N-C_1-6alkyl, cyano-C_1-6alkyl, (C_1-4alkyl)HN-C_1-6alkyl, (C_1-4alkyl)₂N-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_3-7cycloalkyl and 3-11 membered heterocyclyl; each RH1 is independently selected from the group consisting of hydrogen, -OH, C1-6alkoxy, - CN and C1-6alkyl; represents a double bond then RD is selected from the group consisting of hydrogen, C_3-7cycloalkyl, phenyl, halogen, -CN, C1-6alkoxy, -C(=O)O-C1-6alkyl, -NHC(=O)-C1-6alkyl and C1-6alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of phenyl, 3-11 membered heterocyclyl, C_1-6alkoxy, halogen, -OH, -NH₂, -NH(C_1-6alkyl), -N(C_1-6alkyl)₂, -C(=O)OH, -C(=O)O-C_1-6alkyl,-C(=O)NH(C_1-6alkyl), -NHC(=O)-C1-6alkyl, -OC(=O)-C1-6alkyl and phenyl-C1-6alkoxy; RE and RF is each independently selected from the group consisting of Ra2 and Rb2; Ra2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb2 and/or Rc2; each Rb2 is independently selected from the group consisting of -ORc2, -NRc2Rc2, halogen, -CN, -C(=O)Rc2, -C(=O)ORc2, -C(=O)NRc2Rc2, -S(=O)₂Rc2, -S(=O)₂NRc2Rc2, -NHC(=O)Rc2, -N(C al c2 c2 c2 1-4 kyl)C(=O)R , -NHC(=O)OR , -N(C1-4alkyl)C(=O)OR and the bivalent substituent =O; each Rc2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, -OH, -C(=O)OH, -C(=O)O-C1-6alkyl, -C(=O)C1-6alkyl, -C(=O)NH₂, -C(=O)NH(C_1-6alkyl), -C(=O)N(C_1-6alkyl)₂, and the bivalent substituent =O; or RD and RE taken together with the carbon atoms they are attached form a 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle, wherein this 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle is optionally, in addition to RF, substituted with one or more identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6haloalkyl, -OH, C1-6alkoxy, C1-4alkoxy-C1-4alkyl, - NH2, -CN, -NH(C1-4alkyl), -N(C1-4alkyl)2, halogen, -C(=O)O-C1-6alkyl and the bivalent substituent =O; or if Q1 is -C(=O)N(RG1)-, then RG1 of -C(=O)N(RG1)- and RF together form a linker selected from the group consisting of -C(=O)-, -CH₂-, -CH₂-C(=O)-, -C(=O)-CH₂- and -C₂H₄-; represents a triple bond then RD and RE are both absent; RF is Ra2; Ra2 is selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb2 and/or Rc2; each Rb2 is independently selected from the group consisting of -ORc2, -NRc2Rc2, halogen, -CN, -C(=O)Rc2, -C(=O)ORc2, -C(=O)NRc2Rc2, -S(=O) c2 c2 c2 2R , -S(=O)2NR R , -NHC(=O)Rc2, -N(C_1-4alkyl)C(=O)Rc2, -NHC(=O)ORc2, -N(C_1-4alkyl)C(=O)ORc2 and the bivalent substituent =O; each Rc2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl; or E is Q2 is selected from the group consisting of a bond, -CH₂-, -CH(OH)-, -C(=O)-, -C(=O)N(RG2)-, -C(=O)O-, -S(=O)₂-, -S(=O)₂N(RG2)- and -C(=NRH2)-; each RG2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, hydroxy-C_1-6alkyl, H₂N-C_1-6alkyl, cyano-C_1-6alkyl, (C_1-4alkyl)HN-C_1-6alkyl, (C_1-4alkyl)₂N-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_3-7cycloalkyl and 3-11 membered heterocyclyl; each RH2 is independently selected from the group consisting of hydrogen, -OH, C1-6alkoxy, - CN and C1-6alkyl; RI is selected from the group consisting of hydrogen and halogen; RJ is hydrogen; or RI and RJ together with the carbon atoms they are attached form a cyclopropane or oxirane ring; RK is selected from the group consisting of hydrogen, C1-6alkyl, -CN and halogen; RL is selected from the group consisting of hydrogen, C1-6alkyl, -CN, halogen and -C(=O)-C1-6alkyl; or E is Q3 is selected from the group consisting of -C(=O)-, -C(=O)N(RG3)-, -C(=O)O-, -S(=O)₂-, -S(=O)₂N(RG3)- and -C(=NRH3)-; each RG3 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, hydroxy-C1-6alkyl, H2N-C1-6alkyl, cyano-C1-6alkyl, (C1-4alkyl)HN-C1-6alkyl, (C_1-4alkyl)₂N-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_3-7cycloalkyl and 3-11 membered heterocyclyl; each RH3 is independently selected from the group consisting of hydrogen, -OH, C1-6alkoxy, - CN and C1-6alkyl; RM is selected from the group consisting of halogen, -CN and -O-C(=O)-C_1-6alkyl; or E is Q4 is selected from the group consisting of a bond, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C_1-4alkyl)-, -S(=O)₂- and -S(=O)₂NH-; ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and 5-membered heteroaryl; q is selected from the group consisting 1, 2, 3 and 4; each RN is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, vinyl, ethinyl, halogen, -CN, nitro and C1-4alkoxy; or a salt thereof. KRAS inhibitors preferably also include compounds of formula (B): wherein R1a and R1b are both independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halogen, -NH2, -NH(C1-4alkyl), -N(C_1-4alkyl)₂, C_3-5cycloalkyl and 3-5 membered heterocyclyl; R2a and R2b are both independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halogen, -NH2, -NH(C1-4alkyl), -N(C_1-4alkyl)₂, C_3-5cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R1a or R1b and one of R2a or R2b together with the carbon atoms they are attached form a cyclopropane ring; Z is -(CR6aR6b)_n-; each R6a and R6b is independently selected from the group consisting of hydrogen, C_1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halogen, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; or R6a and R6b together with the carbon atom they are attached form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; -L- is a bond or is selected from -O-, -S- and -N(R13)-, wherein R13 is hydrogen or C_1-6alkyl; R3 is substituted with E and when -L- is selected from -O-, -S- and -N(R13)-, then R3 is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, 5-10 membered heteroaryl and 3-11 membered heterocyclyl, wherein the C1-6alkyl, 5-10 membered heteroaryl, C1-6alkoxy and 3-11 membered heterocyclyl are all optionally and independently substituted with one or more, identical or different substituent(s) selected from the group consisting of halogen, C_1-6alkyl, -OH, -NH₂, -NH(C_1-4alkyl), - N(C1-4alkyl)2, C3-5cycloalkyl and 3-11 membered heterocyclyl; when -L- is a bond, then R3 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more, identical or different R7 and/or R8 each R7 is independently selected from the group consisting of halogen, -CN, -OH, C1-6alkoxy, -NR8R8, -C(=O)R8, -C(=O)OR8, -C(=O)NR8R8, -NHC(=O)OR8 and the bivalent substituent =O; each R8 is independently selected from the group consisting of hydrogen, C_1-6alkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, phenyl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R9 and/or R10; each R9 is independently -OR10; each R10 is independently selected from the group consisting of hydrogen, C_1-6alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R11)=; R11 is selected from hydrogen, halogen and C1-4alkoxy; ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-6alkyl, halogen, -OH, -NH2, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R5 is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different C1-6alkyl, C1-6alkoxy or a 5-6 membered heterocyclyl, wherein the C1-6alkyl is optionally substituted with cyclopropyl; or R5 is -O-C_1-6alkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R12; each R12 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen and 3-11 membered heterocyclyl; E is represents a double or a triple bond; Q1 is selected from the group consisting of a bond, -CH₂-, -CH(OH)-, -C(=O)-, -C(=O)N(RG1)-, -C(=O)O-, -S(=O) G1 H1 2-, -S(=O)2N(R )- and -C(=NR )-; each RG1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, hydroxy-C_1-6alkyl, H₂N-C_1-6alkyl, cyano-C_1-6alkyl, (C_1-4alkyl)HN-C_1-6alkyl, (C_1-4alkyl)₂N-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_3-7cycloalkyl and 3-11 membered heterocyclyl; each RH1 is independently selected from the group consisting of hydrogen, -OH, C1-6alkoxy, - CN and C_1-6alkyl; represents a double bond then RD is selected from the group consisting of hydrogen, C3-7cycloalkyl, phenyl, halogen, -CN, C_1-6alkoxy, -C(=O)O-C_1-6alkyl, -NHC(=O)-C_1-6alkyl and C_1-6alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of phenyl, 3-11 membered heterocyclyl, C1-6alkoxy, halogen, -OH, -NH2, -NH(C_1-6alkyl), -N(C_1-6alkyl)₂, -C(=O)OH, -C(=O)O-C_1-6alkyl,-C(=O)NH(C_1-6alkyl), -NHC(=O)-C_1-6alkyl, -OC(=O)-C_1-6alkyl and phenyl-C_1-6alkoxy; RE and RF is each independently selected from the group consisting of Ra2 and Rb2; Ra2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb2 and/or Rc2; each Rb2 is independently selected from the group consisting of -ORc2, -NRc2Rc2, halogen, -CN, -C(=O)Rc2, -C(=O)ORc2, -C(=O)NRc2Rc2, -S(=O)₂Rc2, -S(=O)₂NRc2Rc2, -NHC(=O)Rc2, -N(C_1-4alkyl)C(=O)Rc2, -NHC(=O)ORc2, -N(C_1-4alkyl)C(=O)ORc2 and the bivalent substituent =O; each Rc2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, -OH, -C(=O)OH, -C(=O)O-C1-6alkyl, -C(=O)C1-6alkyl, -C(=O)NH2, -C(=O)NH(C1-6alkyl), -C(=O)N(C1-6alkyl)2, and the bivalent substituent =O; or RD and RE taken together with the carbon atoms they are attached form a 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle, wherein this 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle is optionally, in addition to RF, substituted with one or more identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6haloalkyl, -OH, C1-6alkoxy, C1-4alkoxy-C1-4alkyl, -NH2, -CN, - NH(C_1-4alkyl), -N(C_1-4alkyl)₂, halogen, -C(=O)O-C_1-6alkyl and the bivalent substituent =O; or if Q1 is -C(=O)N(RG1)-, then RG1 of -C(=O)N(RG1)- and RF together form a linker selected from the group consisting of -C(=O)-, -CH₂-, -CH₂-C(=O)-, -C(=O)-CH₂- and -C₂H₄-; represents a triple bond then RD and RE are both absent; RF is Ra2; Ra2 is selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C_1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb2 and/or Rc2; each Rb2 is independently selected from the group consisting of -ORc2, -NRc2Rc2, halogen, -CN, -C(=O)Rc2, -C(=O)ORc2, -C(=O)NRc2Rc2, -S(=O)₂Rc2, -S(=O)₂NRc2Rc2, -NHC(=O)Rc2, -N(C_1-4alkyl)C(=O)Rc2, -NHC(=O)ORc2, -N(C_1-4alkyl)C(=O)ORc2 and the bivalent substituent =O; each Rc2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl; or E is Q2 is selected from the group consisting of a bond, -CH₂-, -CH(OH)-, -C(=O)-, -C(=O)N(RG2)-, -C(=O)O-, -S(=O)₂-, -S(=O)₂N(RG2)- and -C(=NRH2)-; each RG2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, hydroxy-C1-6alkyl, H2N-C1-6alkyl, cyano-C1-6alkyl, (C1-4alkyl)HN-C1-6alkyl, (C_1-4alkyl)₂N-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_3-7cycloalkyl and 3-11 membered heterocyclyl; each RH2 is independently selected from the group consisting of hydrogen, -OH, C1-6alkoxy, - CN and C1-6alkyl; RI is selected from the group consisting of hydrogen and halogen; RJ is hydrogen; or RI and RJ together with the carbon atoms they are attached form a cyclopropane or oxirane ring; RK is selected from the group consisting of hydrogen, C_1-6alkyl, -CN and halogen; RL is selected from the group consisting of hydrogen, C1-6alkyl, -CN, halogen and -C(=O)-C1-6alkyl; or E is Q3 is selected from the group consisting of -C(=O)-, -C(=O)N(RG3)-, -C(=O)O-, -S(=O)2-, -S(=O)₂N(RG3)- and -C(=NRH3)-; each RG3 is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, hydroxy-C_1-6alkyl, H₂N-C_1-6alkyl, cyano-C_1-6alkyl, (C_1-4alkyl)HN-C_1-6alkyl, (C1-4alkyl)2N-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C3-7cycloalkyl and 3-11 membered heterocyclyl; each RH3 is independently selected from the group consisting of hydrogen, -OH, C_1-6alkoxy, - CN and C_1-6alkyl; RM is selected from the group consisting of halogen, -CN and -O-C(=O)-C1-6alkyl; or E is Q4 is selected from the group consisting of a bond, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C_1-4alkyl)-, -S(=O)₂- and -S(=O)₂NH-; ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and 5-membered heteroaryl; q is selected from the group consisting 1, 2, 3 and 4; each RN is independently selected from the group consisting of C_1-4alkyl, C_1-4haloalkyl, vinyl, ethinyl, halogen, -CN, nitro and C_1-4alkoxy; or a salt thereof. KRAS inhibitors preferably also include compounds of formula (C): wherein R1a and R1b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; R2a and R2b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R1a or R1b and one of R2a or R2b together with the carbon atoms they are attached form a cyclopropane ring; Z is -(CR6aR6b)n-; each R6a and R6b is independently selected from the group consisting of hydrogen, C1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, C3-5cycloalkyl and 3-5 membered heterocyclyl; or R6a and R6b together with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; R3 is selected from the group consisting of halogen, C_1-6alkyl, C_1-6haloalkyl, -N₃, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C_1-6alkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more, identical or different R7 and/or R8; each R7 is independently selected from the group consisting of halogen, -CN, -OR8, -NR8R8, -C(=O)R8, -C(=O)OR8, -C(=O)NR8R8, -NHC(=O)OR8 and the bivalent substituent =O; each R8 is independently selected from the group consisting of hydrogen, C_1-6alkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 3-11 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R9 and/or R10; each R9 is independently selected from the group consisting of -OR10, -NR10R10 and -C(O)NR10R10; each R10 is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with a substituent selected from the group consisting of C1-6alkoxy, C3-10cycloalkyl and 3-11 membered heterocyclyl optionally substituted with C1-6alkyl; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R11)=; R11 is selected from hydrogen, halogen and C1-4alkoxy; ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-6alkyl, halogen, -OH, -NH2, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R5 is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different C_1-6alkyl, C_1-6alkoxy or a 5-6 membered heterocyclyl, wherein the C_1-6alkyl is optionally substituted with cyclopropyl; or R5 is -O-C1-6alkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R12, each R12 is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, halogen and 3-11 membered heterocyclyl; or a salt thereof. KRAS inhibitors preferably also include compounds of formula (D): wherein R1a and R1b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halogen, -NH2, -NH(C1-4alkyl), -N(C_1-4alkyl)₂, C_3-5cycloalkyl and 3-5 membered heterocycloalkyl; R2a and R2b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C1-4alkyl)2, C3-5cycloalkyl and 3-5 membered heterocycloalkyl; and/or, optionally, one of R1a or R1b and one of R2a or R2b together with the carbon atoms they are attached to form a cyclopropane ring; Z is -(CR3aR3b)n-; each R3a and R3b is independently selected from the group consisting of hydrogen, C1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, C3-5cycloalkyl and 3-5 membered heterocycloalkyl; or R3a and R3b together with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; R4 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-6alkyl, halogen, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CN, C3-5cycloalkyl and 3-5 membered heterocycloalkyl; ring A is a 5 membered heteroarylene; each R5, if present, is independently selected from the group consisting of C1-6alkyl, C1- ₆haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-6alkyl, halogen, -OH, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocycloalkyl; m is selected from the group consisting of 0, 1, 2 and 3; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R11)=; R11 is selected from hydrogen, halogen and C1-4alkoxy; ring B is a 3-11 membered heterocycloalkylene optionally substituted with one or more identical or different C_1-6alkyl, C_1-6alkoxy or a 5-6 membered heterocycloalkyl, wherein the C_1- 6alkyl is optionally substituted with cyclopropyl; L is selected from the group consisting of a bond, C1-8alkylene, C2-8alkenylene, C2-8alkynylene and C_1-8alkoxylene; X is -(CH2)- or -O-; Y is a 5 membered heteroarylene or -C(O)(NR12)-, wherein said 5 membered heteroarylene comprises at least one nitrogen atom and wherein said -C(O)(NR12)- is linked to X via the C atom; R9 is C1-4 alkyl; R10 is selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, -C(O)R12 and -C(O)OR12, wherein said C_1-6alkyl is optionally substituted by -OH or -OP(O)(OH)₂; each R12 is independently hydrogen or C1-4 alkyl; q is selected from the group consisting of 0, 1 and 2; each R6, if present, is independently at each occurrence halogen or C_1-3alkyl; R7 is selected from the group consisting of halogen, C1-3alkyl, -CN and 5 membered heteroaryl, wherein said 5 membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with R8; R8 is C1-3alkyl or C1-3hydroxyalkyl; or a salt thereof. KRAS inhibitors preferably also include compounds of formula (E): wherein R1a and R1b are both independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, C_3- 5cycloalkyl and 3-5 membered heterocyclyl; R2a and R2b are both independently selected from the group consisting of hydrogen, C1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, C_3-5cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R1a or R1b and one of R2a or R2b together with the carbon atoms they are attached form a cyclopropane ring; Z is -(CR6aR6b)_n-; each R6a and R6b is independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, halogen, -NH₂, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, C3-5cycloalkyl and 3-5 membered heterocyclyl; or R6a and R6b together with the carbon atom they are attached form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; L is selected from -O-, -S- and -N(R7)-, wherein R7 is hydrogen or C1-6alkyl; R3 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, 5-10 membered heteroaryl and 3-11 membered heterocyclyl, wherein the C_1-6alkyl, 5-10 membered heteroaryl, C1-6alkoxy and 3-11 membered heterocyclyl are all optionally and independently substituted with one or more, identical or different halogen, C1-6alkyl, C1-6alkoxy, -OH, -NH2, -NH(C1- ₄alkyl), -N(C_1-4alkyl)₂, -C(O)O-C_1-6alkyl, C_3-5cycloalkyl or 3-11 membered heterocyclyl optionally substituted with - N(C1-4alkyl)2; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R11)=; R11 is selected from hydrogen, halogen and C1-4alkoxy; ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-6alkyl, halogen, -OH, -NH2, -NH(C_1-4alkyl), -N(C_1-4alkyl)₂, -CN, C_3-5cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R5 is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different C_1-6alkyl, C_1-6alkoxy or a 5-6 membered heterocyclyl, wherein the C_1-6alkyl is optionally substituted with cyclopropyl; or R5 is -O-C1-6alkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R12, each R12 is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, halogen and 3-11 membered heterocyclyl; or a salt thereof. HER2 inhibitors preferably include [1,3]diazino[5,4-d]pyrimidines and derivatives of formula (F):

wherein R1 is selected from the group consisting of hydrogen, -CH3, -CCH, -OCH3 and halogen; R2 is hydrogen or halogen; R3 is selected from the group consisting of formula (i.1), (i.2), (i.3) and (i.4); R4 is selected from the group consisting of R4.a and R4.b or wherein Q denotes 4-6 membered heterocyclyl containing 1 N-atom, wherein one carbon atom of the ring is optionally substituted by methyl; Z denotes 4-6 membered heterocyclyl containing 1 N-atom, wherein one carbon atom of the ring is optionally substituted by methyl; R5 is -H or -CH₃; and at least one of R1 and R2 is not hydrogen. Statistical Methods for predicting the clinical outcome are known in the art and can readily be adapted to the methods according to the invention. As used herein, the term “monitoring of the treatment” or “monitoring” refers to monitoring the extent of the response, monitoring the duration of response, monitoring the response rate, monitoring the stabilisation rate, monitoring the duration of stabilisation, monitoring the time to disease progression, monitoring the progression free survival or monitoring the overall survival. According to a third aspect, the present invention relates to a method of treating cancer in a patient with a compound inhibiting KRAS protein or a mutant of a KRAS protein, wherein the patient has been determined to be responsive to the treatment with said compound according to any of the methods described above. Similarly, the present invention relates to a method of treating cancer in a patient with a compound inhibiting the interaction between MDM2 and p53, wherein the patient has been determined to be responsive to the treatment with said compound according to any of the methods described above. The present invention further relates to a method for the treatment of a KRAS-dependent cancer in a patient with a KRAS inhibitor or degrader, comprising - determining that said patient exhibits the molecular biomarker Survivin, and - administering to the patient a pharmaceutically effective amount of a KRAS inhibitor or degrader. The present invention further relates to a method for the treatment of cancer in a patient with a compound inhibiting the interaction between MDM2 and p53, comprising - determining that said patient exhibits the molecular biomarker Survivin, and - administering to the patient a pharmaceutically effective amount of a compound inhibiting the interaction between MDM2 and p53. The present invention further relates to a method for the treatment of a KRAS-dependent cancer in a patient with a KRAS inhibitor or degrader, comprising - having measured the level of Survivin in a first sample obtained from said patient, - having compared the level of Survivin in at least a second sample obtained from said patient during treatment to the level of Survivin in the first sample, and - having determined that the level of Survivin in the second sample obtained from said patient during treatment is decreased as compared to the level of Survivin in the first sample, or that the level of Survivin in any further sample obtained from said patient during treatment after the second sample is decreased as compared to the level of Survivin in the penultimate sample obtained from said patient during treatment, and - continuing administering to the patient a pharmaceutically effective amount of a KRAS inhibitor or degrader. The present invention further relates to a method for the treatment of cancer in a patient with a compound inhibiting the interaction between MDM2 and p53, comprising - having measured the level of Survivin in a first sample obtained from said patient, - having compared the level of Survivin in at least a second sample obtained from said patient during treatment to the level of Survivin in the first sample, and - having determined that the level of Survivin in the second sample obtained from said patient during treatment is decreased as compared to the level of Survivin in the first sample, or that the level of Survivin in any further sample obtained from said patient during treatment after the second sample is decreased as compared to the level of Survivin in the penultimate sample obtained from said patient during treatment, and - continuing administering to the patient a pharmaceutically effective amount of a compound inhibiting the interaction between MDM2 and p53. Said cancer patient may be a patient who has been selected according to any of the methods for determining the responsiveness of a cancer patient to a KRAS inhibitor, or the responsiveness of a cancer patient to a compound inhibiting the interaction between MDM2 and p53, as described above. As used herein, the term “monotherapy“ refers to a treatment with a compound of the invention without an additional anticancer therapy such as radiotherapy or chemotherapy. As used herein, the term “combination therapy“ as defined herein may be achieved by way of the simultaneous, sequential or separate administration of the individual components of said treatment. A combination treatment as defined herein may be applied as a sole therapy or may involve surgery or radiotherapy or an additional chemotherapeutic or targeted agent in addition to a combination treatment of the invention. Surgery may comprise the step of partial or complete tumor resection, prior to, during or after the administration of a combination treatment as described herein. Said treatment of a KRAS dependent cancer in a patient may be a combination therapy with said KRAS inhibitor and an additional anticancer therapeutic, e.g., an immune checkpoint inhibitor. Furthermore, also the treatment of a cancer responsive to a compound inhibiting the interaction between MDM2 and p53 may be a combination therapy with said compound inhibiting the interaction between MDM2 and p53 and an additional anticancer therapeutic, e.g., an immune checkpoint inhibitor. “Immune checkpoints“ are receptors on the cell membrane of T lymphocytes which modulate the immune reactivity of said cells. There are anti-inflammatory (suppressing) and pro- inflammatory (activating) immune checkpoints which are expressed on the cell membrane of T cells, and which are interacting with respective ligands, either soluble or cell-bound ligands. Tumor cells often activate anti-inflammatory immune checkpoint pathways via respective ligands that suppress anti-tumor immune responses, thus evading immuno-surveillance and progessing tumor growth. “Immune checkpoint inhibitors (ICIs)“ are agents, in particular monoclonal antibodies, which bind to anti-inflammatory immune checkpoints or their ligands and can interrupt this tumor suppression strategy by reactivating the immune system and, hence, reestablishing its capacity to combat tumors. ICIs have been shown to be clinically effective in a variety of tumor types (Dyck and Mills, 2017). In other words, immune checkpoint inhibitors are comprising antagonists of an immune inhibitory receptor, such as PD-1, which inhibit, in this case, the PD-1 or PD-L1 in the PD- 1/PD-L1 pathway. Examples of PD-1 or PD-L1 inhibitors include, without limitation, (human or humanized) antibodies blocking human PD-1 such as pembrolizumab or pidilizumab, or blocking PD-L1 such as avelumab, durvalumab and atezolizumab, as well as fully human antibodies such as the PD-1 blocking nivolumab. The term “therapeutically effective amount“ is used to refer to an amount of an active agent that relieves or ameliorates one or more of the symptoms of the disorder being treated. In another aspect, the therapeutically effective amount refers to a target serum concentration of an active agent that has been shown to be effective in, for example, slowing disease progression. Efficacy can be measured in conventional ways, depending on the condition to be treated. The terms “treatment“ and “therapy“ and the like, as used herein, are meant to include therapeutic as well as prophylactic, or suppressive measures for a disease or disorder leading to any clinically desirable or beneficial effect, including but not limited to alleviation or relief of one or more symptoms, regression, slowing or cessation of progression of the disease or disorder. Thus, for example, the term treatment includes the administration of an agent prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes the administration of an agent after clinical manifestation of the disease to combat the symptoms of the disease. Further, administration of an agent after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises “treatment“ or “therapy“ as used herein. Moreover, as long as a therapeutic agent either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of a respective agent, the result should be considered an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not. According to a fourth aspect, the present invention relates to a use of Survivin in a method for determining the ability of a compound to inhibit KRAS protein or a mutant of a KRAS protein, or of a pharmaceutical formulation comprising said compound inhibiting KRAS protein or a mutant of a KRAS protein, to treat cancer. The present invention further relates to the use as described above, wherein the level of Survivin is determined in a sample obtained from the patient prior to the treatment, and in at least one sample obtained from the patient after treatment with said compound inhibiting KRAS protein or a mutant of a KRAS protein, and wherein a decrease in the level of Survivin after treatment with said compound inhibiting KRAS protein or a mutant of a KRAS protein is indicative of the compound’s ability to treat said cancer. Further in accordance with this aspect of the invention, the present invention also relates to a use of Survivin in a method for determining the ability of a compound inhibiting the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, to treat cancer. Preferably in accordance with said use, the level of Survivin is determined in a sample obtained from the patient prior to the treatment, and in at least one sample obtained from the patient after treatment with said compound inhibiting the interaction between MDM2 and p53, and wherein a decrease in the level of Survivin after treatment with said compound inhibiting the interaction between MDM2 and p53 is indicative of the compound’s ability to treat said cancer. The present invention further relates to the use of a molecular biomarker for selecting a patient suffering from a KRAS-dependent cancer for treatment with a KRAS inhibitor or degrader, or a pharmaceutical formulation comprising said KRAS inhibitor or degrader, wherein the molecular biomarker is Survivin. The present invention further relates to the use of a molecular biomarker for selecting a patient suffering from cancer for treatment with a compound inhibiting the interaction between MDM2 and p53, or a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, wherein the molecular biomarker is Survivin. The present invention further relates to the use of a molecular biomarker in a method for determining or confirming the ability of a KRAS inhibitor or degrader, or of a pharmaceutical formulation comprising said KRAS inhibitor or degrader, to inhibit a KRAS-dependent cancer, wherein the molecular biomarker is Survivin. The present invention further relates to the use of a molecular biomarker in a method for determining or confirming the ability of a compound inhibiting the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, to inhibit a cancer, wherein the molecular biomarker is Survivin. The present invention further relates to said use of a molecular biomarker as described above, wherein the level of the molecular biomarker Survivin is determined in a sample provided by the patient prior to the treatment, and in at least one sample provided by the patient after treatment with said KRAS inhibitor or degrader, and wherein the level of Survivin is identified as having decreased after treatment with said KRAS inhibitor or degrader. The present invention further relates to said use of a molecular biomarker as described above, wherein the level of the molecular biomarker Survivin is determined in a sample provided by the patient prior to the treatment, and in at least one sample provided by the patient after treatment with said compound inhibiting the interaction between MDM2 and p53, and wherein the level of Survivin is identified as having decreased after treatment with said compound inhibiting the interaction between MDM2 and p53. The present invention further relates to said use of a molecular biomarker as described above, wherein the use is an in-vitro use. In a preferred embodiment of any of the uses as described above, said sample(s) is/are blood, blood plasma, or serum sample(s). In further preferred embodiments of any of the uses as described above, the compound inhibiting KRAS protein or a mutant of a KRAS protein is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP- KRAS inhibitors or degraders, and HER2 inhibitors and degraders. In yet further preferred embodiments of any of the uses as described above, the compound inhibiting the interaction between MDM2 and p53 is MDM2i-cpd#1. The person skilled in the art will understand that depending on the type of compound, the KRAS-dependent cancer will vary. In further preferred embodiments of any of the uses as described above, the KRAS(G12C) inhibitor or degrader is selected from the group consisting of: sotorasib (AMG510), adagrasip (MRTX849), G12C-cpd#1, G12C-cpd#2, G12C-cpd#3, G12C-cpd#4, G12C-cpd#5, G12C- cpd#6, G12C-cpd#7, G12C-cpd#8, G12C-cpd#9, G12C-cpd#10, and G12C-cpd#11. In further preferred embodiments of any of the uses as described above, the KRAS(G12D) inhibitor or degrader is selected from the group consisting of MRTX1133, G12D-cpd#2, G12D- cpd#3, G12D-cpd#4, G12D-cpd#5, G12D-cpd#6, G12D-cpd#7, G12D-cpd#8, and G12D- cpd#9. In further preferred embodiments of any of the uses as described above, the GDP-KRAS inhibitor or degrader is selected from the group consisting of GDP-cpd#1, GDP-cpd#2, GDP- cpd#3, GDP-cpd#4, GDP-cpd#5, GDP-cpd#6, GDP-cpd#7, GDP-cpd#8, GDP-cpd#9, GDP- cpd#10, GDP-cpd#11, GDP-cpd#12, and GDP-cpd#13. In further preferred embodiments of any of the uses as described above, the HER2 inhibitor or degrader is a compound according to formula (F) (see above), more preferably the HER2 inhibitor or degrader is the compound HER2-cpd#1. In preferred embodiment(s) of the present invention, said compound inhibiting KRAS protein or a mutant of a KRAS protein may be a compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, wherein the compound inhibiting or degrading the HER2 protein, or a mutant of said HER2 protein, acts as an indirect inhibitor of the KRAS protein, or a mutant of a KRAS protein, which is located downstream from the HER2 protein, or mutant of HER2 protein, in signal transduction pathways. In further preferred embodiments of any of the uses as described above, said Survivin is comprised in exosomes. In further preferred embodiments of any of the uses as described above, said KRAS dependent cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), non- small-cell lung cancer (NSCLC), and colorectal cancer (CRC). In yet further preferred embodiments of any of the uses as described above, the cancer to be treated with a compound inhibiting the interaction between MDM2 and p53 is selected from any of the cancers defined herein above as preferred cancer types for the treatment with such an MDM2 inhibitor. In further preferred embodiments of any of the uses as described above, determining the level of Survivin comprises a Survivin-specific assay selected from the group consisting of Western Blot, ELISA, RIA, the MSD® S-PLEX technology and FACS. In further preferred embodiments of any of the uses as described above, said treatment is a combination therapy of said KRAS inhibitor or degrader, or of said compound inhibiting the interaction between MDM2 and p53, and an additional anticancer therapeutic and/or standard of care. According to a fifth aspect, the present invention relates to a kit of parts, comprising the means for determining the level of Survivin in samples provided from a patient suffering from cancer, such as e.g. a KRAS-dependent cancer, and instructions for how to perform any of said methods as described above. The present invention further relates to a kit of parts, comprising the means for determining the level of Survivin in samples provided from a patient suffering from cancer, such as e.g. a KRAS-dependent cancer, for performing any of the methods described above. Examples While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. All amino acid sequences disclosed herein are shown from N-terminus to C-terminus; all nucleic acid sequences disclosed herein are shown from 5' end to 3' end. Materials and Methods Example 1: Compounds KRAS- inhibiting compounds and HER2-inhibiting compounds, respectively, are shown in Table 1 above. Synthesis of Compounds Example 2: Synthesis of compounds according to formula (A) The synthesis of compounds according to formula (A) has been described in WO2021/245051. Example 3: Synthesis of compounds according to formula (B) List of abbreviations (Table 3) Ac acetyl ACN acetonitrile aq. aquatic, aqueous ATP adenosine triphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butyl c concentration Cbz carboxybenzyl CDI 1,1´-carbonyldiimidazole d day(s) TLC thin layer chromatography Davephos 2-dimethylamino-2'-dicyclohexylaminophosphinobiphenyl DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DCE dichloro ethane DCM dichloro methane DEA diethyl amine DIPEA N-ethyl-N,N-diisopropylamine (Hünig´s base) DMA dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulphoxide DPPA diphenylphosphorylazide dppf 1.1´-bis(diphenylphosphino)ferrocene EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid eq. equivalent(s) ESI electron spray ionization Et ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol h hour O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium HATU hexafluorophosphate HPLC high performance liquid chromatography i iso conc. concentrated LC liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide sln. solution Me methyl MeOH methanol min minutes MPLC medium pressure liquid chromatography MS mass spectrometry MTBE methyl tert-butyl ether NMM N-methylmorpholine NMP N-methylpyrrolidone NP normal phase n.a. not available PBS phosphate-buffered saline Ph phenyl Pr propyl PTSA p-toluenesulfonic acid Py pyridine rac racemic red. reduction Rf (Rf) retention factor RP reversed phase RRLC Rapid resolution liquid chromatography rt ambient temperature SFC supercritical fluid chromatography SN nucleophilic substitution TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium TBTU tetrafluoroborate tBu tert-butyl TEA triethyl amine temp. temperature tert tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl t_Ret. retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane TsOH p-toluenesulphonic acid UPLC ultra performance liquid chromatography UV ultraviolet wt weight Examples Features and advantages of the present invention will become apparent from the following detailed examples which illustrate the principles of the invention by way of example without restricting its scope: Preparation of the compounds according to the invention Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 µm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 µm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 µm, 50 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm). Different gradients of H2O/acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H₂O/acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH. For the chromatography under basic conditions for Agilent systems H2O/acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH₄HCO₃ + 50 mL NH₃ (25 % in H₂O) to 1 L with H₂O). For Gilson systems the water is made alkaline as follows: 5mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28 % in H2O) are replenished to 1 L with H2O. The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), Phenomenex Lux C2 (250 x 20 mm, 5 µm). The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridgeTM C18, 2.5 µm, 2.1 x 20 mm or XBridgeTM C18, 2.5 µm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 µm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 µm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 µm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy/UV-spectrometry The retention times/MS-ESI+ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time tRet. = 0.00. SFC-Method (preparative) Preparative SFC is performed in Waters Thar SFC 80 system Column: Chiralpak AD-H (21 x 250 mm), 5µm Flow: 25 g/min Mobile Phase: 75 % CO₂ + 25 % MeOH ( 0.5 % isopropylamine) ABPR: 120 bar Temp: 35 ºC UV: 220 nm Stack Time: 8 min HPLC-Methods (analytic) Method A Samples were analyzed on an Agilent 1200 series LC system coupled with an Agilent 6140 mass spectrometer. Purity was determined via UV detection with a bandwidth of 170 nm in the range from 230-400 nm. LC parameters were as follows: column Waters Xbridge C18 column 3.5 µm particle size, 2.1 x 30 mm; flow 1 mL/min; column temperature 60 °C; injection 5 µL injections; solvent A: 20 mM NH₄HCO₃/NH₃ pH 9 B: MS grade acetonitrile; gradient 0.0 - 1.5 min 10 % - 95 % B 1.5 - 2.0 min 95 % B 2.0 - 2.1min 95 % - 10 % B Method B HPLC Agilent 1100/1200 Series MS Agilent LC/MSD SL column Waters X-Bridge BEH C18, 2.5 µm, 2.1 x 30 mm XP solvent A: 20 mM NH4HCO3 / 28 mM NH3 in H2O; B: acetonitrile (HPLC grade) detection MS: positive and negative mode mass range 100 – 750 m/z flow 1.40 mL/min column temperature 45 °C gradient: 0.00 – 1.00 min: 15 % B ^ 95 % B 1.00 – 1.30 min: 95 % B Method F HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (API-ES +/- 3000/3500 V, Quadrupol, G6140A) MSD signal settings Scan pos/neg 150 – 750 column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 µm, 12 nm; 30 x 2.0 mm column eluant A: H₂O + 0.11 % formic acid B: MeCN + 0.1 % formic acid (HPLC grade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 10, reference off) spectrum range: 190 – 400 nm; slit: 4 nm peak width > 0.0031 min (0.063 s response time, 80Hz) injection 0.5 µL standard injection flow 1.4 mL/min column temperature 45 °C gradient 0.0 – 1.0 min 1.0 – 1.1 min 95 % B Stop time: 1.23 min The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist). Experimental procedure for the synthesis of A-2a To a suspension of 5-chloropentanenitrile (22.9 g, 194.8 mmol, 1.0 eq.) in dry EtOH (136 mL) is added acetyl chloride (111.3 mL, 1.558 mol, 8.0 eq.) dropwise at 0°C. The reaction mixture is allowed to reach rt and stirred for 12 h. The mixture is concentrated under reduced pressure and washed with Et₂O and the crude product A-2a is used as the HCl salt directly in the next step without further purification. Experimental procedure for the synthesis of A-3a Crude A-2a (HCl salt) (28 g, 139.9 mmol, 1.0 eq.) and ethylene glycol (7.382 g, 118.94 mmol, 0.9 eq.) are dissolved in DCM (300 mL) and stirred at rt for 6 d. The resulting suspension is concentrated under reduced pressure, diluted with Et₂O (200 mL) and filtered. The filtrate is concentrated under reduced pressure, taken up in DCM (200 mL) and treated with a 2N KOH solution (150 mL). The mixture is stirred at rt overnight keeping the phases intact. The phases are separated, the water phase is extracted twice with DCM and the combined organic phases are dried over MgSO₄, filtered and concentrated under reduced pressure. The crude orthoester A-3a is used for the next step without further purification. Experimental procedure for the synthesis of A-4a Crude A-3a (22.3 g, 106.9 mmol, 1.0 eq.), 1-cyclohexenyloxytrimethylsilane (16.42 mL, 82.3 mmol, 0.8 eq.) and zinc chloride (10.195 g, 74.8 mmol, 0.7 eq.) are dissolved in DCM (120 mL) and stirred at rt for 5 h. The reaction mixture is treated by addition of saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography (gradient elution: 0 % to 50 % EtOAc in cHexane) to give the desired compound A-4a. Experimental procedure for the synthesis of A-5a A-4a (14.9 g, 57.14 mmol, 1.0 eq.) and sodium iodide (25.954 g, 171.4 mmol, 3.0 eq.) are dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium thiosulfate solution. The organic phase is separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product A-5a is used for the next step without further purification. Experimental procedure for the synthesis of A-6b A-5a (30 g, 85.0 mmol, 1.0 eq.) is dissolved in THF. The mixture is treated with potassium tert.-butoxide (28.67 g, 256.0 mmol, 3.0 eq.) at 0°C and stirred at rt overnight. The reaction mixture is quenched by addition of water (2 mL), diluted by addition of Et₂O and a saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography (gradient elution: 0 % to 50 % EtOAc in cHexane) to give (racemic) compound A-6a (the reaction sequence A-1a A-6a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem.2004, 19:3962-3967). Desired enantiomer A-6b can then be obtained after chiral separation via SFC (e.g. using a CHIRACEL OX-3 column and acetonitrile as cosolvent). Experimental procedure for the synthesis of E-4c (Method C) To a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL) is added piperazine-1- carboxylic acid tert-butyl ester (11.22 g, 57.22 mmol, 1.0 eq.). Then DIPEA (20.71 g, 160.21 mmol, 2.8 eq.) is added and the reaction mixture is stirred at 60 °C for 1 h. After complete conversion the mixture is dissolved in EtOAc and washed with water (3 x). The organic phase is dried, filtered and concentrated under reduced pressure. The crude product is purified via column chromatography (DCM/MeOH) yielding E-4c. The following (additional) intermediates E-4 (table 4) are available in an analogous manner using different amines PG-L-H and intermediates E-1 according to methods A to E. The crude products E-4 can be purified by chromatography if necessary. Table 4 # metho structure tret [min] [M+H] HPLC d + method E-4c C 0.72 324 F Boc N E-4s C ^N N _Cl 1.49 352 A N CN Experimental procedure for the synthesis of E-8d

To a solution of E-1a (600 mg, 3.21 mmol, 93 % purity, 1.0 eq.) in anhydrous DMSO (6 mL) is added cesium fluoride (1.218 g, 8.02 mmol, 2.5 eq.) and the resulting mixture is stirred at rt for 1 h until full conversion of the staring material is observed. The resulting suspension is filtered and the filtered solid is washed with anhydrous DMSO (2 mL). The filtrate (8 mL) is added to (S)‐1‐((S)‐1‐methylpyrrolidin‐2‐yl)ethan‐1‐ol (453 mg, 3.51 mmol, 1.1 eq.) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) is added. The mixture is stirred at rt for 1 h. After full conversion of the starting materials is observed a solution of tert-butyl piperazine-1-carboxylate (674 mg, 3.51 mmol, 97 % purity, 1.1.eq.) in anhydrous DMSO (3 mL) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) is added to the mixture. The mixture is stirred at rt for 30 min. After full conversion is observed the reaction is diluted with acetonitrile and water, filtered and purified by basic reversed phase chromatography (gradient elution: 30 % to 98 % acetonitrile in water) to give the desired product E-8d. The following intermediates E-8 (table 5) are available in an analogous manner without isolation of the corresponding intermediates E-5 and E-7, respectivley. The crude product E-8 is purified by chromatography if necessary. # structure t_ret [min] [M+H]+ HPLC method E-8d 1.55 417 A E-8e 1.67 445 A Experimental procedure for the synthesis of E-8p (Method J) To a mixture of E-4r (200 mg, 0.59 mmol, 1.0 eq.) and (S)‐1‐((S)‐1‐methylpyrrolidin‐2‐ yl)ethan‐1‐ol (91.8 mg, 0.71 mmol, 1.2 eq.) in acetonitrile (1.5 mL) is added trimethylamine (149.8 mg, 1.48 mmol, 2.5 eq.).The mixture is stirred at 40 °C for 2 h. The mixture is stirred at 80 °C for 16 h. The solvent is removed under reduced pressure and the crude product is purified by normal phase chromatography (gradient elution: 0 % to 90 % MeOH in DCM + ammonia) to give the desired product E-8p. Intermediates E-8 marked “J” (table 6) are available in an analogous manner. The crude product E-8 is purified by chromatography if necessary. Experimental procedure for the synthesis of E-8ch (Method M) E-6h (100.0 mg, 0.31 mmol, 1.0 eq.) and (S)-1,3-dimethylpiperazine (42.5 mg, 0.37 mmol, 1.2 eq.) are dissolved in DMSO (1 mL) at rt and DIPEA (115.0 µL, 0.62 mmol, 2.0 eq.) is added and the mixture is stirred for 1 h. The mixture is diluted with acetonitrile and water and purified by acidic reversed phase chromatography to give E-8ch. Intermediates E-8 marked “M“ (table 7) are available in an analogous manner. The crude product E-8 is purified by chromatography if necessary. Table 7 # method structure t [min] [M+ + ret H] HPLC method E-8ch M 1.55 417 A E-8cj L 1.66 432 A Additional nitrile building blocks E-8 not explicitly disclosed herein are disclosed in WO 2021/245051 and WO 2021/245055 (incl. synthesis) which are both herewith incorporated by reference in respect of the disclosure of such building blocks E-8, their synthesis and their synthetic use. Those building blocks can also be used in the synthesis of additional compounds of formula (I) according to the invention not specifically disclosed herein. Scheme 3a: Experimental procedure for the synthesis of E-12a To a solution of E-8aq (1.776 g, 4.26 mmol, 1 eq.) in MeOH (35 mL) is added a solution of sodium hydroxide in water (16 mL, 4 M, 63.96 mmol, 15.0 eq.) and the resulting mixture is stirred at 65 °C for 1.5 h. The reaction volume is reduced under reduced pressure to remove large parts of the MeOH and the remaining aqueous solution is carefully neutralized with an aqueous solution of HCl (8 M). The mixture is diluted with acetonitrile and purified by acidic reversed phase chromatography (gradient elution: 10 % to 85 % acetonitrile in water) to give the desired product E-12a. Experimental procedure for the synthesis of E-12e To a solution of E-8c (2.2 g, 4.97 mmol, 1 eq.) in MeOH is added a solution of sodium hydroxide in water (6.2 mL, 4 M, 40 mmol, 5.0 eq.) and the resulting mixture is stirred at 65 °C for 4 h. The reaction mixture is concentrated under reduced pressure, suspended in MeOH, filtrated and purified by acidic reversed phase chromatography (gradient elution: 10 % to 85 % acetonitrile in water). The product containing fractions are combined, concentrated under reduced pressure and lyophilized to give the desired product E-12e. The following intermediates E-12/E-12* (table 8) are available in an analogous manner starting from different intermediates E-8/E-8*. The crude product E-8/E-8* is purified by chromatography if necessary. # structure t_ret [min] [M+H]+ HPLC method E-12d 1.02 464 A Boc ^N _N E-12i ^N N _O 0.99 464 A N COOH Scheme 4a: Experimental procedure for the synthesis of B-1a CDI (18.781 g, 112.352 mmol, 2.0 eq.) is dissolved in dry THF and heated to 50°C. In a second flask E-12d (13.021 g, 28.088 mmol, 0.5 eq.) and activated molsieve in dry THF are stirred for 10 min at rt before being added to the CDI solution. The reaction mixture is stirred at 50°C for 15 min. In a third flask A-6b (15 g, 56.176 mmol, 1.0 eq.) is dissolved in a 1M LiHMDS solution in THF (117.969 mL, 117.969 mmol, 2.1 eq.) and stirred at rt for 10 min before being added to the active ester. The reaction mixture is stirred at 50°C overnight. After cooling down to rt the reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium hydrogencarbonate solution. The water phase is extracted with EtOAx (3 x 100 mL). The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography (using an MeOH/DCM 0-10% gradient under basic conditions). The product containing fractions are combined and freeze dried to yield B-1a. The following intermediates B-1/B-1* (table 9) are available in an analogous manner starting from different intermediates E-12/E-12* *. The crude product B-1/B-1* is purified by chromatography if necessary. Table 9 [M+H] HPLC # structure t_ret [min] + method Boc N N N O 1.01, 1.06, N N B-1a 1.19 670 A OH O O (tautomers) O [M+H] HPLC # structure t_ret [min] + method Boc N N N N O N 1.02, 1.10 B-1c 670 B OH (tautomers) O O O Scheme 5a: Experimental procedure for the synthesis of B-6a and B-7a

To a solution of B-1a (12.7 g, 19 mmol, 1.0 eq.) in EtOH/water is added hydroxylamine hydrochloride (50% content in water, 3.131 g, 47 mmol, 2.5 eq.) and the reaction mixture is heated to 50°C for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in MeOH (40 mL) and treated with conc. HCl (40 mL). The reaction mixture is stirred at 60°C for 1 h, concentrated under reduced pressure, dissolved in EtOAc and neutralized by careful addition of a saturated solution of sodium carbonate. The water phase is extracted with EtOAc (three times), the combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by RP-chromatography (using an ACN/water 30-80% gradient under basic conditions). The product containing fractions are combined and freeze dried to yield B-6a as well as the other isoxazole isomer B-7a. The following intermediates B-6/B-6*, B-7/B-7* (table 10) are available in an analogous manner starting from different intermediates B-1/B-1* The crude products are purified by chromatography if necessary. Table 10 t_ret [M+H HPLC # structure [min] ]+ method B-6a 1.45 523 A tret [M+H HPLC # structure [min] ]+ method B-6c 1.60 523 A B-7a 1.35 523 A B-7c 1.34 523 A Scheme 6a:

To a solution of B-6a (1.2 g, 2.3 mmol, 1.0 eq.) in EtOH (10 mL) is added under nitrogen gas malononitrile (95% purity, 798.2 mg, 11 mmol, 5.0 eq.), beta-alanine (95% purity, 646 mg, 6.9 mmol, 3.0 eq.) and activated molecular sieve (from Roth, 200 mg) at rt. The reaction mixture is heated to 80°C for 3 h. Upon complete condensation reaction monitored by HPLC-MS sulfur (220.9 mg, 6.9 mmol, 3.0 eq.) is added and the reaction mixture is stirred at 80°C for 15 min. The reaction mixture is cooled down to rt, dissolved with water and EtOAc and filtered. The layers are separated. To the water phase is added a 4N NaOH solution (10 mL) and extracted 3 x with EtOAc. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by chromatography over silica gel using a gradient under basic conditions. The product containing fractions are combined and freeze dried to yield C-3a. The following intermediates C-3/C-3* and C-4/C-4* (table 11) are available in an analogous manner starting from different intermediates B-6/B-6* and B-7/B-7*. The crude products are purified by chromatography if necessary. Table 11 tret [M+H] HPLC # structure [min] + method C-3a 1.51 603 A C-3c 1.46 603 A C-4a 1.41 603 A C-4c 1.41 603 A tret [M+H] HPLC # structure [min] + method C-4d 1.51 575 A C-4e 1.41 603 A Synthesis of compounds (I) according to the invention: Scheme 7: Experimental procedure for the synthesis of compound Ia-1

To a solution of 2-fluoroacrylic acid (136 mg, 1.51 mmol, 2.6 eq.) and HATU (552 mg, 1.452 mmol, 2.5 eq.) in DMF (0.6 mL) is added TEA (353 mg, 3.484 mmol, 6.0 eq.) and the reaction mixture is stirred for 2 min at rt. To the reaction mixture is added a solution of C-3a (350 mg, 581 µmol, 1.0 eq) dissolved in DMF (3 mL) and the mixture is stirred for 15 min at rt. After completion of the reaction the mixture is diluted with acetonitrile and water, filtered and purified by basic reversed phase chromatography (gradient elution: 30 % to 98 % acetonitrile in water) to give the desired compound Ia-1. Experimental procedure for the synthesis of compound Ia-2 To a solution of sodium carbonate (154 mg, 1.45 mmol, 2.5 eq.) in acetone/water (8:1) and C- 3a (350 mg, 581 µmol, 1.0 eq.) is added a freshly prepared solution of acryloyl chloride in acetone (81.3 mg, 871 µmol, 1.5 eq.). After completion of the reaction the mixture is diluted with acetonitrile and water, filtered and purified by basic reversed phase chromatography (gradient elution: 30 % to 98 % acetonitrile in water) to give the desired compound Ia-2. Table 12 tret HPLC # structure [M+H]+ [min] method Ia-1 1.60 675 A Ia-2 1.52 657 A Ia-4 1.47 657 A Ib-3 1.47 657 A

tret HPLC # structure [M+H]+ [min] method Ib-5 1.55 675 A Ib-6 1.55 675 A Example 4: Synthesis of compounds according to formula (C) List of abbreviations (Table 13) Ac acetyl ACN acetonitrile aq. aquatic, aqueous ATP adenosine triphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butyl c concentration CDI 1,1´-carbonyldiimidazole d day(s) TLC thin layer chromatography DCM dichloromethane DIPEA N-ethyl-N,N-diisopropylamine (Hünig´s base) DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide dppf 1.1´-bis(diphenylphosphino)ferrocene equiv. equivalent(s) ESI electron spray ionization Et ethyl Et₂O diethyl ether EtOAc ethyl acetate EtOH ethanol h hour(s) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium HATU hexafluorophosphate HPLC high performance liquid chromatography i iso conc. concentrated LC liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide m-CPBA meta-chloroperoxybenzoic acid Me methyl MeOH methanol min minute(s) MS mass spectrometry NP normal phase n.a. not available PBS phosphate-buffered saline Ph phenyl Pr propyl Py pyridine rac racemic red. reduction Rf (Rf) retention factor RP reversed phase rt ambient temperature s second(s) SFC supercritical fluid chromatography SN nucleophilic substitution tBu tert-butyl TEA triethyl amine temp. temperature tert tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography tRet. retention time (HPLC) Ts tosylate UPLC ultra performance liquid chromatography UV ultraviolet Wt weight Examples Features and advantages of the present invention will become apparent from the following detailed examples which illustrate the principles of the invention by way of example without restricting its scope: Preparation of the compounds according to the invention Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 µm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 µm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 µm, 50 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm). Different gradients of H2O/ACN are used to elute the compounds, while for Agilent systems 5% acidic modifier (20 mL HCOOH to 1 L H2O/ACN (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH. For the chromatography under basic conditions for Agilent systems H2O/ACN gradients are used as well, while the water is made alkaline by addition of 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) to 1 L with H2O). For Gilson systems the water is made alkaline as follows: 5 mL NH₄HCO₃ solution (158 g in 1 L H₂O) and 2 mL NH₃ (28% in H₂O) are replenished to 1 L with H2O. The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), Phenomenex Lux C2 (250 x 20 mm, 5 µm). The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridgeTM C18, 2.5 µm, 2.1 x 20 mm or XBridgeTM C18, 2.5 µm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 µm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 µm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 µm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy/UV-spectrometry The retention times/MS-ESI+ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time t_Ret. = 0.00. Method A HPLC Agilent 1100 system MS 1200Series LC/MSD(API-ES+/-3000V, Quadrupol, G6140) MSD signal settings Scan pos/neg 120 - 900m/z Detection signal 315 nm (bandwidth 170nm, reference off) Spectrum range 230 – 400 nm Peak width <0.01 min Column Waters, Xbridge C18, 2.5 µm, 2.1x20 mm column Column temperature 60°C Solvent A: 20mM aq. NH4HCO3/ NH3 pH 9 B: ACN HPLC grade Flow 1.00 mL/min Gradient 0.00 – 1.50 min 10 % to 95 % B 1.50 – 2.00 min 95 % B 2.00 – 2.10 min 95 % to 10 % B Method B HPLC Agilent 1260 system MS 1200 Series LC/MSD (MM-ES+APCI +/- 3000 V, Quadrupol, G6130) Detection UV: 254 nm (bandwidth 8, reference off) UV: 230 nm (bandwidth 8, reference off) UV spectrum range: 190 – 400 nm; step: 4 nm MS: positive and negative mode Mass range 100 – 800 m/z Column Waters; Part. No. 186003389; XBridge BEH C18, 2,5 µm, 30 x 2.1 mm Column temperature 45 °C Solvent A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: ACN (HPLC grade) Flow 1.40 mL/min Gradient 0.00 – 1.00 min: 5 % B to 100 % B 1.00 – 1.37 min: 100 % B 1.37 – 1.40 min: 100 % B to 5 % B Method C HPLC Agilent 1260 Series MS Agilent LC/MSD Quadrupole Detection MS: positive and negative mode Mass range 100 – 750 m/z Column Waters X-Bridge BEH C18, 2.5 µm, 2.1 x 30 mm XP Column temperature 45 °C Solvent A: 20 mM NH₄HCO₃/30 mM NH₃ in H₂O; B: ACN (HPLC grade) Flow 1.40 mL/min Gradient 0.00 – 1.00 min: 15% B to 95% B 1.00 – 1.30 min: 95 % B Method E HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/- 3000 V, Quadrupol, G6130B) MSD signal settings Scan pos/neg 150 – 750 Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) Spectrum range: 190 – 400 nm; slit: 4 nm Peak width > 0.0031 min (0.063 s response time, 80Hz) Column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 µm, 2.1 x 30 mm) column Column temperature 45 °C Solvent A: 5 mM NH₄HCO₃/18 mM NH3 in H2O (pH = 9.2) B: ACN (HPLC grade) Flow 1.4 mL/min Gradient 0.0 – 1.0 min 15 % to 95 % B 1.0 – 1.1 min 95 % B Stop time: 1.3 min Method SFC-1 Make Waters UPC2-MS Soft Empower3 MS QDa Column CHIRALCEL OX-3(4.6*150MM) 3µm A-Solvent CO2 B-solvent ACN Total Flow 3g/min % of Co-Solvent 15 ABPR 1500psi Colum temp 30°C PDA range 200nm to 400nm Resolution 1.2nm MS Parameters - QDa MS scan range 100Da to 1000Da Cone voltage Positive scan 20V Negative Scan 15V Negative Scan 15V The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist). Synthesis of spiroketone intermediates A Experimental procedure for the synthesis of A-2a To a suspension of 5-chloropentanenitrile (22.9 g, 195 mmol, 1.00 equiv.) in EtOH (136 mL) is added acetyl chloride (111 mL, 1.56 mol, 8.00 equiv.) dropwise at 0 °C. The reaction mixture is allowed to warm to rt and stirred for 12 h. The mixture is concentrated under reduced pressure and washed with Et₂O and the crude product A-2a is used as the HCl salt directly in the next step without further purification (HPLC method: A; t + ret = 1.03 min; [M+H] = 164). Experimental procedure for the synthesis of A-3a Crude A-2a (HCl salt) (28.0 g, 140 mmol, 1.00 equiv.) and ethylene glycol (7.38 g, 119 mmol, 0.90 equiv.) are dissolved in DCM (300 mL) and stirred at rt for 6 d. The resulting suspension is concentrated under reduced pressure, diluted with Et2O (200 mL) and filtered. The filtrate is concentrated under reduced pressure, taken up in DCM (200 mL) and treated with a KOH solution (2 M in water, 150 mL). The mixture is stirred at rt overnight keeping the phases intact. The phases are separated, the water phase is extracted with DCM (2 x) and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude orthoester A-3a is used for the next step without further purification (HPLC method: A; t_ret = 1.37 min; [M+H]+ = 163). Experimental procedure for the synthesis of A-4a Crude A-3a (22.3 g, 107 mmol, 1.00 equiv.), 1-cyclohexenyloxytrimethylsilane (16.4 mL, 82.3 mmol, 0.80 equiv.) and zinc chloride (10.2 g, 74.8 mmol, 0.70 equiv.) are dissolved in DCM (120 mL) and stirred at rt for 5 h. The reaction mixture is treated by addition of saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography to give the desired compound A-4a (HPLC method: A; t + ret = 1.25 min; [M+H] = 283). Experimental procedure for the synthesis of A-5a A-4a (14.9 g, 57.1 mmol, 1.00 equiv.) and sodium iodide (25.9 g, 171 mmol, 3.00 equiv.) are dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium thiosulfate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product A-5a is used for the next step without further purification. Experimental procedure for the synthesis of A-6b A-5a (30.0 g, 85.0 mmol, 1.00 equiv.) is dissolved in THF. The mixture is treated with potassium tert.-butoxide (28.7 g, 256 mmol, 3.0 equiv.) at 0 °C and stirred at rt overnight. The reaction mixture is quenched by addition of water (2 mL), diluted by addition of Et₂O and saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography to give (racemic) compound A-6a (HPLC method: A; t = 1.17 min; [M+ + ret H] = 225). Reaction sequence A-1a ^ A-6a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem.2004, 19:3962-3967. Enantiomer A-6b can then be obtained after chiral separation via SFC (using a Lux Cellulose- 4 column (250x30mm, 5µm), 30 °C column temperature, 90 % CO2, 10% ACN as cosolvent) with enantiomer A-6b (HPLC method: A; t_ret = 1.17 min; [M+H]+ = 225 / SFC method: SFC- 1; t = 2.99 min) elutin nd ret g as the 2 peak after the other enantiomer. Alternative procedure for the synthesis of A-6b Step 1 A dry and clean reactor is charged with toluene (234 L) under nitrogen (note: 2.5V toluene in total for this reaction). Water (1.56 kg, 85.5 mol, keep H₂O : Pd = 160:1) is added followed by rinsing the charging line with 1,1,3,3-tetramethylguanidine (175.5 kg, 1527.6 mol, 2.0 equiv.) under nitrogen and then toluene (13 L). A-7a (130.0 kg, 763.8 mol) is added under nitrogen followed by rinsing with toluene (13 L). Allyl acetate (98.8 kg, 992.9 mol, 1.3 equiv.) is added under nitrogen and rinsed with toluene (13 L). Under agitation, the mixture is cooled to 10 °C in 0.5 h. The batch is degassed by sparging the solution with nitrogen for ~30 min. (S,S)- DACH-Ph Trost ligand (0.429 kg, 0.619 mol, 0.081 mol%) in degassed toluene (13 L) (note: keep Pd : ligand = 1 : 1.15) is added followed by rinsing with degassed toluene (13 L). Allylpalladium(II) chloride dimer (97.5 g, 267 mol, 0.035 mol%) in degassed toluene (13 L) is added followed by rinsing with degassed toluene (13 L). The batch is kept at 10-15 °C at least 8 h. After the reaction is complete by HPLC, a solution of N-acetyl-L-cysteine (3.9 kg, 22.9 mol, 0.03 equiv.) in water (260 L) below 25 °C is added. The resulting solution is warmed to 20-25 °C and kept at 20-25 °C at least for 1 h. After phase cut to discard the bottom aqueous layer, 10 wt% NH₄Cl aqueous solution (260 L) is added. After the mixture is agitated for 10 min, the bottom aqueous layer is drained. The organic phase is further washed with water (130 L). The organic layer is filtered through a very short pad of Celite and the reactor and Celite bed is rinsed with toluene (65 L). The filtrate is charged into a clean reactor and then toluene is distilled off under vacuum at 40-50 °C. The crude product is directly used for the next step or the product is drained into a container with the help of minimum amount of toluene (65 L) and stored at 20-23 °C.150 kg of A-8a is usually obtained as a light yellow oil in 96 % yield with ≥ 90:10 enantimeric ratio. 1H NMR (500 MHz, CDCl3): δ 5.75 (ddt, J = 14.8, 9.4, 7.5 Hz, 1H), 5.06-5.00 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.61 (dd, J = 13.9, 7.1 Hz, 1H), 2.51-2.43 (m, 3H), 2.33 (dd, J = 13.9, 7.9 Hz, 1H), 2.03-1.98 (m, 1H), 1.78-1.60 (m, 3H), 1.50-1.42 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz, CDCl3): δ 207.7, 171.6, 133.5, 118.4, 61.3, 61.0, 41.3, 39.4, 35.9, 27.7, 22.6, 14.3. ESI-MS: m/z 211 [M+H]+. Step 2 To the reactor containing A-8a (150 kg, 713.4 mol) from step 1 (less than 1V toluene if used) is added ethylene glycol (600 L) to give a yellow biphasic mixture. After the mixture is cooled to 10-15 °C, TMSCl (193.5 kg, 1783.5 mol, 2.5 equiv.) is added over not less than 15 min, at a rate to maintain the internal temperature between 20-30 °C (orange biphasic mixture obtained). Sufficient agitation is needed to achieve mixing. After the batch is kept at 20-25 °C for 2 h, agitation is stopped and kept for at least 15 min at 20-25 °C. The batch is cooled to 0-5 °C. NaOH (96 kg, 1854.8 mol, 2.6 equiv.) in water (600 L) is added at a rate to maintain the internal temperature below 20 °C (light yellow cloudy biphasic mixture obtained). Toluene (300 L) is added and then the batch is agitated for 10 min. After phase cut to drain the bottom aqueous layer (note: some precipitate may form at interphase), the organic layer is washed with water (300 L) two times. The organic phase is filtered through a short pad of Celite to remove insoluble solids/interphase. The organic solution is charged into a clean and dry reactor and then the solvent is distilled off at 40-50 °C to a minimum stirrable volume. The crude product A-9a (189 kg, 95.2 wt%, 100 % yield) is drained to a container with the help of minimum amount of toluene. 1H NMR (500 MHz, CDCl3): δ 5.65 (ddt, J = 14.7, 8.1, 6.6 Hz, 1H), 5.07-4.98 (m, 2H), 4.20- 4.10 (m, 2H), 3.97-3.88 (m, 4H), 2.81 (dd, J = 13.9, 6.6 Hz, 1H), 2.35 (dd, J = 13.9, 8.1 Hz, 1H), 2.04-1.98 (m, 1H), 1.75-1.35 (m, 7H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl₃): δ 173.7, 134.3, 117.6, 110.9, 65.0, 64.7, 60.5, 54.6, 36.2, 32.3, 30.3, 23.3, 20.9, 14.4. ESI-MS: m/z 255 [M+H]+. Step 3 To a dry and clean reactor is added 9-BBN (688.5 kg, 401 mol,1.2 equiv.) under nitrogen. The solution is cooled to 0-5 °C to obtain a slurry. A-9a (85.0 kg, 334.2 mol) from step 2 is added at 0-5 °C and rinsed with THF (40 L). The mixture is warmed to 20-23 °C in 1 h and kept at 20-23 °C for not less than 1 h. After that the mixture is cooled to -45 to -40 °C, methyl chloroacetate (69.6 kg, 1.3 equiv) is added in one portion followed by dropwise addition of LiHMDS (909.5 kg, 1102.9 mol) while keeping temperature below -35 °C. The batch is then warmed to 20-23 °C in 1 h and then kept at 20-23 °C at least for 18 h. ~12-13 V solvent is removed by distillation under vacuum with heating (35 °C). EtOH (255 kg) is added followed by a solution of NaOH (13.4 kg) in H₂O (212.5 L). The mixture is heated at reflux (at 66-70 °C) for at least 14 h. After that ~5-6 V solvent is removed by distillation at reflux, the batch is cooled to 20-25 °C and then filtered through a short pad of Celite to remove insoluble material and rinsed with heptane (160 L). ~5-6 V solvent (or most of the residual THF and ethanol) is distilled under vacuum at 40-50 °C. The batch is cooled to 20-25 °C. After that, water (255 L) is added, the crude product is extracted twice with heptane (2364.8 kg). The combined heptane layers are washed once with water (85 L). After solvent removal by distillation under vacuum at 40-50 °C, the crude product (52.7 kg, 87.5 wt%) is obtained as a yellow oil in 52.6 % assay yield. The crude product A-6b is used for next step directly. 1H NMR (500 MHz, CDCl₃): δ 4.01-3.82 (m, 4H), 2.50-2.44 (m, 1H), 2.382.34 (m, 1H), 2.28- 2.22 (m, 1H), 2.11-2.05 (m, 1H), 2.01-1.95 (m, 1H), 1.92-1.86 (m, 1H), 1.81-1.58 (m, 6H), 1.54-1.43 (m, 3H), 1.27-1.18 (m, 1H). ESI-MS: m/z 225 [M+H]+. Synthesis of alcohol-, pyrazole-, and tosylate-intermediates B Experimental procedure for the synthesis of B-2a B-1a (4.92 g, 19.1 mmol, 1.00 equiv.), N,N’-carbonyldiimidazole (5.14 g, 28.6 mmol, 1.50 equiv.) and molecular sieves (3A, 500 mg) are dissolved in DCM (29.5 mL) and stirred for 40 min at rt. After complete activation, N,O-Dimethylhydroxylamine hydrochloride (2.79 g, 28.6 mmol, 1.50 equiv.) is added and the reaction is stirred again for 2 h at rt. After complete conversion, water (100 mL) and DCM (150 mL) are added and the phases are separated, the water phase is extracted with DCM (2x). The combined organic phase is washed with brine and concentrated under reduced pressure. The residue is purified by NP chromatography to give the product B-2a. The following intermediates B-2 (Table 14) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 14 tret HPLC # structure [M+H]+ [min] method 189 B-2a 0.43 ([M+H- C Boc]+) 177 B-2b 0.47 ([M+H- C Boc]+) 189 B-2d 0.44 ([M+H- C Boc]+) Experimental procedure for the synthesis of B-3a B-2a (4.88 g, 16.9 mmol, 1.00 equiv.) is dissolved in THF (15 mL) under an argon atmosphere and cooled to -10 °C. Bromo(methyl)magnesium (3.4 M in MeTHF, 6.46 mL, 22.0 mmol, 1.3 equiv.) is added and stirred for 1 h at -10 °C. After complete conversion, the reaction mixture is cooled to -20 °C and quenched by addition of brine. The resulting mixture is extracted with DCM (3x). The combined organic phase is concentrated under reduced pressure to obtain B- 3a. The following intermediates B-3 (Table 15) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 15 + HPLC # structure t_ret [min] [M+H] method 144 B-3a 0.97 ([M+H- A Boc]+) 132 B-3b 0.50 ([M+H- C Boc]+) 144 B-3d 0.48 ([M+H- C Boc]+) Experimental procedure for the synthesis of B-4a (R)-Methyl oxazaborolidine (0.99 g, 3.3 mmol, 0.20 equiv.) is dissolved in THF (2 mL) under an argon atmosphere and cooled to -5 °C. Borane-dimethyl sulfide complex (1.0 M, 22 mL 22.0 mmol, 1.3 equiv.) is added. The mixture is stirred for 30 min at rt. The mixture is cooled to -5 °C and B-3a (4.1 g, 17 mmol, 1 equiv.) is added slowly, dropwise. The reaction is stirred at rt for 1 h. After complete conversion of starting material, the reaction is cooled to -10 °C and quenched by addition of MeOH. The mixture is concentrated under reduced pressure. The residue is dissolved in water (150 mL) and formic acid (0.5 mL) and extracted with DCM (3x). The combined organic phase is concentrated under reduced pressure and purified by NP chromatography to give the product B-4a. The following intermediates B-4 (Table 16) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 16 + HPLC # structure tret [min] [M+H] method O O 190 B-4a N O 0.44 C ([M+H-tBu]+) OH 178 B-4b 0.46 C ([M+H- tBu]+) B-4d 190 0.44 + C ([M+H- tBu] ) Experimental procedure for the synthesis of B-5a B-4a (306 mg, 12.5 mmol, 1.00 equiv.) is dissolved in THF, (30.6 mL) under an argon atmosphere. Lithium aluminium hydride (1 M in THF, 24.9 mL, 25.0 mmol, 2.00 equiv.) is added slowly. The reaction is stirred at 60 °C for 1h. After complete conversion, the reaction is cooled to rt, Rochelle salt solution and KOH is added and stirred for 1 h. The existing suspension is extracted with DCM (3x), the combined organic phase is concentrated under reduced pressure to yield B-5a. The following intermediates B-5 (Table 17) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 17 tret # structure [M+H]+ HPLC method [min] B-5a 0.92 160 A B-5b 0.92 148 A B-5d 0.07 160 C Synthesis of alcohol-, pyrazole-, and tosylate-intermediates B Experimental procedure for the synthesis of B-11a 1H-Pyrazole-3-carboxylic acid (500 mg, 4.46 mmol, 1.00 equiv.) is dissolved in ACN (4.5 mL). Pyrrolidine (745 µL, 8.92 mmol, 2.00 equiv.), DIPEA (1.50 mL, 8.92 mmol, 2.00 equiv.) and 1-propanephosphonic anhydride (2.00 mL, 6.69 mmol, 1.50 equiv.) are added and the reaction mixture is stirred at rt for 1 h until complete conversion. The reaction mixture is diluted with saturated NaHCO3 and extracted with DCM and the organic phase is dried, filtered and solvent is removed under vacuum. The crude product is purified via NP chromatography to obtain B- 11a (HPLC method: C, t_ret = 0.14 min; [M+H]+ = 166). Experimental procedure for the synthesis of B-15a 3-Ethynyloxetan-3-ol (120 mg, 1.16 mmol, 1.00 equiv.) and (trimethylsilyl)diazomethane (2M solution in hexanes, 2.00 mL, 4.00 mmol, 3.46 equiv.) are combined and stirred in a closed vial for 3h at 50°C until complete conversion. The reaction mixture is cooled to rt diluted with MeOH, and solvent is removed under vacuum to obtain crude B-15a (HPLC method: C, t_ret = 0.08 min; [M+H]+ = 141). The crude product is used for the next step without purification. Synthesis of esters and acids E Experimental procedure for the synthesis of intermediates E-9a: 4,6-Dichloropyrimidine-2-carboxylic acid E-8a (900 mg, 4.66 mmol, 1.00 equiv.) is dissolved in DMSO (2 mL) and DIPEA (1.5 mL, 8.8 mmol, 2.0 equiv.) and (S)-tert-butyl 3-methyl-1,4- diazepane-1-carboxylate (1.04 g, 4.896 mmol, 95 % purity, 1.05 equiv.) is added dropwise. The reaction mixture is then stirred at 40 °C for 18 h. The mixture is diluted with ACN and purified by RP chromatography to give the desired product E-9a (HPLC method: A, t_ret = 0.82 min; [M+H]+ = 371). Experimental procedure for the synthesis of intermediates E-11a: E-10a B-5b E-11a E-10a (3.00 g, 14.5 mmol, 1.00 equiv.) is dissolved in DCM (30 mL) and DIPEA (5.34 mL, 29 mmol, 2.0 equiv.) and B-5b (3.20 g, 21.8 mmol, 1.5 equiv.) is added. The reaction mixture is then stirred at rt for 18 h. After complete conversion, the mixture is concentrated, water is added, and the mixture is extracted with EtOAc and the organic phases are washed with brine, dried, filtered and concentrated. The crude product is purified by NP chromatography yielding E-11a. The following intermediates E-11 (Table 18) are available in an analogous manner. The crude product E-11 is purified by chromatography if necessary. Table 18 [M+H] HPLC # structure tret [min] + method E-11a 1.13 318 A E-11c 0.67 207 A Experimental procedure for the synthesis of E-11e: B-5a (100 mg, 0.48 mmol, 1.00 equiv.) is dissolved in THF (500 µL), LiHMDS (591 µL, 0.59 mmol, 1.10 equiv.) is added and stirred for 5 min. Meanwhile methyl 4,6- dichloropyrimidine- 2-carboxylate (170mg, 0.81mmol, 1.5 equiv.) is dissolved in THF (500µL). The solution of B-5a is added dropwise over 5 min to the methyl 4,6- dichloropyrimidine-2-carboxylate solution. The reaction is stirred for 25min. After complete conversion of starting material is observed, the reaction is filtered and purified by RP chromatography to give E-11e (HPLC method: A, t + ret = 1.08 min; [M+H] = 330). Synthesis of diketones F When multiple HPLC retention times are reported it means that different tautomers are present. Experimental procedure for the synthesis of F-4a A-6b (1.4 g, 5.31 mmol, 1.1 equiv.) and magnesium bromide diethyl etherate (2.5 g, 9.66 mmol, 2.0 equiv.) are dissolved in DCM (10.0 mL). F-3a (1.0 g, 4.83 mmol, 1.0 equiv.), dissolved in DCM (10 mL), is added dropwise. DIPEA (2.1 mL, 12.08 mmol, 2.5 equiv.) is added and the reaction mixture is stirred 7 h at rt. The reaction is quenched with 1 M HCl, diluted with DCM and water. The organic phase is separated, evaporated and the resulting residue is purified by RP chromatography to afford F-4a (HPLC method: C, t + ret = 0.633 min; [M+H] = 399). Experimental procedure for the synthesis of F-5a 4,6-Dichloropyrimidine-2-carboxylic acid methyl ester (2.00 g, 9.67 mmol, 1.00 equiv.) is dissolved in dry ACN (5 mL) under nitrogen atmosphere. Magnesium bromide diethyl etherate (2.99 g, 11.6 mmol, 1.20 equiv.), a solution of A-6b (2.38 g, 10.6 mmol, 1.10 equiv.) in ACN (5 mL), and DIPEA (2.67 mL, 14.5 mmol, 1.50 equiv.) is added, and the reaction mixture is stirred at 50 °C for 20 h. After complete conversion, the reaction mixture is carefully quenched with HCl (1 M), diluted with water, extracted with DCM, and the organic phases are dried, filtered, and concentrated to obtain crude F-5a. The crude compound is purified by normal phase chromatography (HPLC-Method: H, tret = 2.50min; [M+H] = 399/401). Experimental procedure for the synthesis of F-8a F-4a (1.27 g, 2.77 mmol, 1.0 equiv.) is dissolved in dioxane (10 mL) and an aqueous cesium carbonate solution (2 M, 3.46 mL, 6.93 mmol, 2.5 equiv.) is added and stirred at 80 °C for 15 min. Then pyridine-4-boronic acid (357 mg, 2.91 mmol, 1.1 equiv.) and Pd(dppf)Cl₂ CH₂Cl₂ (238 mg, 0.28mmol, 0.1 equiv.) are added to the reaction mixture and stirred for 30 min at 90 °C until complete conversion of the starting material is observed. The reaction mixture is filtered and diluted with water and extracted three times with DCM. The organic phase is evaporated, and the residue is dissolved in DMF and purified by RP chromatography to give the desired product F-8a (HPLC-Method: C, tret = 0.80 / 86 min; [M+H] = 440). Experimental procedure for the synthesis of F-9a F-5a (10.0 g, 19.4 mmol, 1.00 equiv.) is dissolved in DMSO (10 mL), (1S)-1-[(2S)-1- methylpyrorolidin-2-yl]ethanol (2.76 g, 21.4 mmol, 1.10 equiv.) and DIPEA (6.78 mL, 38.8 mmol, 2.0 equiv.) are added and the solution is stirred at rt overnight. The reaction mixture is diluted with DCM and water. The organic phase is separated, evaporated and the resulting residue is purified by RP chromatography to afford F-9a. (HPLC-method: A, tret = 1.58/1.66 min; [M+H] = 492). Experimental procedure for the synthesis of F-11a F-11a E-9a (1.05 g, 2.83 mmol, 1.00 equiv.) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (918 mg, 5.66 mmol, 2.00 equiv.) under argon atmosphere are dissolved in THF (5 mL) and stirred 1h at rt. After complete activation of the acid, a solution of A-6b (1.34 mg, 5.98 mmol, 2.00 equiv.) and LiHMDS (1.0 M in THF, 5.95 mL, 5.95 mmol, 2.10 equiv.) is added to the reaction mixture and washed with THF (5 mL). The resulting mixture is stirred overnight at 60 °C. After full conversion, the reaction mixture is diluted with an aqueous saturated NaHCO₃ solution and extracted three times with DCM. The organic phases are combined, dried, filtered and concentrated under reduced pressure. The crude product is dissolved in ACN and water, filtered and purified by basic RP chromatography to give the desired product F-11a (HPLC- Method: C, t_ret = 0.888/0.936/0.978 min; [M+H] = 557). Experimental procedure for the synthesis of F-12a E-11e (1.80 g, 0.01 mol, 1 equiv.) is dissolved in THF (18 mL), activated molecular sieves 3 Å are added (200 mg pro 1 ml solvent) and stirred at 50 °C for 20 min under an argon atomsphere. Then magnesium bromide ethyl etherate (2.11 g, 0.01 mol, 1.5 equiv.) is added and further stirred at 50 °C for 30 min. Meanwhile a second solution is prepared using the A-6b (1.47 g, 0.01 mol, 1.5 equiv.), which is also predried using activated molecular sieves 3Å at 50 °C for 20 min in THF (8 ml). Then LiHMDS (1 M in THF, 13.7 mL, 0.01 mol, 2.5 equiv.) is added and stirred for 15 min. After that the second solution is added to the first solution and stirred for 1 h at 50 °C. After complete conversion, the reaction mixture is carefully quenched with water, THF is removed under reduced pressure. The residue pH is adjusted to 7-8 by using 1N HCl and extracted with 5% MeOH in DCM (2 x), the combined organic layer is washed with brine solution dried over Na2SO4 filtered and concentrated to obtain crude F-12a. The crude compound is purified by NP chromatography. The following intermediates F-12 (Table 19) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 19 tret # structure [M+H]+ HPLC method [min] 5.69 F-12a 6.00 522 I 6.13 1.61 F-12b 510 H 1.78 1.62 F-12c 510 H 1.75 Synthesis of isoxazole-intermediates G Experimental procedure for the synthesis of G-9a and G-10a F-11a (1.10 g, 1.91 mmol, 1.0 equiv.) is dissolved in 1,4-dioxane (3 mL) and hydroxylamine is added (50% in water, 140 µL, 2.29 mmol, 1.2 equiv.). The reaction mixture is stirred overnight at rt. After full conversion, the reaction mixture is diluted with aq. satd. NaHCO3 solution and extracted three times with DCM. The organic phase is combined, dried, filtered and concentrated under reduced pressure to give the crude product. The crude mixture of G-9a and G-10a (1.0 g, 1.68 mmol,1.0 equiv.) is dissolved in 1,4-dioxane (6 mL) and HCl (4 M in water, 2.11 mL, 8.44 mmol, 5.0 equiv.) is added. The reaction mixture is stirred 3 h at rt. After full conversion, the reaction is diluted with aq. satd. NaHCO₃ solution and extracted three times with DCM. The organic phase is combined, dried, filtered and concentrated under reduced pressure to give the crude product. The crude product is dissolved in ACN and water, filtered and purified by basic RP chromatography to give the desired products G-11a and G-12a. The following intermediates G-11 and G-12 (Table 20) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 20 [M+H] HPLC # structure tret [min] + method G-11a 0.67 430 C G-11b 1.57 445 A G-11c 1.52 463 A G-12b 1.62 445 A G-11e 3.01 475 K Experimental procedure for the synthesis of G-35a G-12b (140 mg, 0.31 mmol, 1.0 equiv.) is dissolved in dioxane (2mL). [1-(oxetan-3-yl)- 1Hpyrazol-3-yl] boronic acid (B-9c) (66.3 mg, 0,38 mmol, 1.19 equiv.), XPHOS PD G3 (29.9 mg, 0.03 mmol, 0.1 equiv.) and cesium carbonate (400 µl, 0.80 mmol, 2.54 equiv.) are added. The reaction is stirred for 10min at 80 °C under an argon atmosphere. After complete conversion is observed the reaction is extracted with DCM/water. The combined organic phase is concentrated under reduced pressure, dissolved in ACN/water and purified by RP chromatography to give the desired product G-35a. Experimental procedure for the synthesis of A-10a A dry and clean reactor is charged with 9-BBN (387 mL, 193.5 mmol, 1.2 equiv., 0.5 M in THF) under nitrogen. The solution is cooled to 0-5 °C to obtain a slurry. A-9a (41.0 g, 161.2 mmol) is added at 0-5 °C and rinsed with THF (20.5 mL). The mixture is warmed to 20-23 °C in 1 h and kept at 20-23 °C for not less than 1 h. After the mixture is cooled to -45 to -40 °C, methyl chloroacetate is added in one portion followed by dropwise addition of LiHMDS (355 mL, 532.0 mmol, 3.3 equiv.) while keeping temperature below -35 °C. The batch is then warmed to 20-23 °C in 1 h and then kept at 20-23 °C at least for 18 h. The batch is cooled to 5- 10 °C, AcOH (30.4 mL, 3.3 equiv.) is added below 20 °C followed by water (41 mL) below 20 °C. AcOH (30.4 mL, 3.3 equiv) is added below 20 °C to reach pH ~6-7. ~15-16 V of THF is removed under vacuum below 35 °C. MTBE (246 mL) and water (205 mL) are added. After phase cut to discard the bottom aqueous layer, the mixture is cooled to 0-5 °C, a solution of sodium percarbonate (37.2 g, 322.4 mmol, 2.0 equiv.) in water (320 mL) is added below 20 °C. After 1 h at 20-23 °C, 20 wt% sodium sulfite solution (31 mL) is added. After 15 min at 20- 23 °C, the bottom aqueous layer is separated and discarded. The organic layer is washed with 5 wt% ammonium chloride solution (123 mL) and water (328 mL). The organic layer is treated with 5 % activated carbon for 30 min prior to filtration. After ~4-5 V of solvent is removed under vacuum below 35 °C the crude product A-10a (80 % yield, HPLC method: C, t_ret = 0.84 min; [M+H]+ = 283) is obtained as orange-brown oil. Experimental procedure for the synthesis of G-70a A reactor is charged with A-10a (45.5 g, 161.2 mmol), ethanol (91.0 mL), NaOAc (39.7 g, 483.6 mmol, 3.0 equiv.), water (45.5 mL) and NH2OH·HCl (33.6 g, 483.6 mmol, 3.0 equiv.). The mixture is heated at 73-78 °C for not less than 16 h. After the batch is cooled to 20-23 °C, water (227.6 mL) is added over 0.5 h. Then MTBE (136.5 mL) is added over 0.5 h followed by heptane (113.8 mL) over 1 h. After 0.5 h at 20-23 °C, the solid is collected by filtration. The solid is washed successively with MTBE (45 mL) and water (91.0 mL). The solid is dried under vacuum to give the product G-70a as an off-white solid (18.27 g, 93.2 wt%) in 40 % yield. 1H NMR (500 MHz, DMSO-d6): δ 11.48 (br s, 1H), 4.04 (q, J = 6.0 Hz, 1H), 3.89-3.80 (m, 2H), 3.60 (q, J = 6.8 Hz, 1H), 2.10-1.95 (m, 2H), 1.92-1.76 (m, 4H), 1.69-1.39 (m, 8H). ESI- MS: m/z 266 [M+H]+. Experimental procedure for the synthesis of G-71a A clean reactor is charged with G-70a (100.0 g, 376.9 mmol, 1.0 equiv.), and K3PO4 (240.0 g, 1130.8 mmol, 3.0 equiv.) in water (499.0 g, 500.0 mL) and toluene (432.5 g, 500.0 mL). The bi-phase mixture is agitated to sufficient mixing. After the mixture is cooled to 0~5 °C, Tf₂O (186.0 g, 110.9 mL, 659.6 mmol, 1.750 equiv.) is added with a syringe pump over 2 h below 5 °C. After phase cut, the organic layer is filtered through a Celite bed with Na2SO4. After rinsing with toluene (50 mL), the crude product G-71a (149.8 g, 100 % yield) is used for the next step directly. 1H NMR (500 MHz, CDCl3): δ 3.95-3.91(m, 3H), 3.77-3.74 (m, 1H), 2.51-2.44 (m, 2H), 2.16- 1.80 (m, 4H), 1.77-1.48 (m, 8H). ESI-MS: m/z 398 [M+H]+. Experimental procedure for the synthesis of G-72a A dry and clean autoclave reactor is charged with G-71a (750 g, 1.89 mol, 1 equiv.), Pd(OAc)₂ (8.48 g, 37.7 mmol, 0.02 equiv.), rac-BINAP (23.5 g, 37.7 mmol, 0.02 equiv), 2-MeTHF (3 L), EtOH (870 g, 18.9 mol, 10 equiv.) and DIPEA (293 g, 2.26 mol, 1.2 equiv.). The reactor is purged with nitrogen (100 psi) two times and then purged with CO (100 psi) two times. The reactor is pressurized to 200 psi CO and heated at 55-60 °C for not less than 12 h. The mixture is transferred to a reactor and the autoclave reactor is rinsed with 2-MeTHF (0.75 L) into the reactor. The mixture is washed with water (3.75 L). After filtration through a short Celite pad, the solvent is removed by vacuum distill to give the crude product G-72a (531.9 g, 87.7 % yield) which is used for the next step without purification. 1H NMR (400 MHz, CDCl3): δ 4.38 (q, J = 7.1 Hz, 2H), 3.95-3.85 (m, 3H), 3.76-3.73 (m, 1H), 2.85 (dt, J = 17.5, 5.5 Hz, 1H), 2.64 (ddd, J = 17.5, 9.6, 6.0 Hz, 1H), 2.22-2.14 (m, 1H), 2.04- 1.88 (m, 3H), 1.78-1.45 (m, 8H), 1.37 (t, J = 7.1 Hz, 3H). ESI-MS: m/z 322 [M+H]+. Experimental procedure for the synthesis of G-73a A dry and clean reactor is charged with G-72a (482.0 g, 1.5 mol, 1 equiv.) and EtOH (3 V) and vacuum distilled ~3 V to remove residual 2-MeTHF from the previous carbonylation step. EtOH (1.45 L) and NH₄OH (1.93 L) are added. The mixture is kept at 20-25 °C for not less than 15 h. Water (1.69 L) is added over 30 min. After 30 min at 20-25 °C, the solid is collected and washed with 1:2 EtOH/water (0.96 L) and water (0.48 L). The solid is slurried in 1:1 MTBE/hexane (0.96 L) for 1 h. The solid is collected by filtration and dried under vacuum at 40-45 °C overnight to give the product G-73a (332.4 g, 75.8 % yield, water content ≤ 0.5 % based on Karl Fischer titration) as a tan solid. 1H NMR (500 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.78 (s, 1H), 3.94-3.72 (m, 4H), 2.78 (dt, J = 17.1, 5.0 Hz, 1H), 2.54-2.48 (m, 1H), 2.20-2.14 (m, 1H), 1.93-1.78 (m, 3H), 1.70-1.42 (m, 8H). ESI-MS: m/z 293 [M+H]+. Experimental procedure for the synthesis of G-74a A dry and clean reactor is charged with G-73a (383 g, 86.7 wt%, 1.137 mol, 1 equiv.), MeCN (1.15 L) and pyridine (216 g, 0.19 L, 2.4 equiv.). After the mixture is cooled to 0-5 °C, trifluoroacetic anhydride (287 g, 1.36 mol, 1.2 equiv.) is added below 5 °C. After 5 min at 0-5 °C, water (1.54 L) is added below 15 °C. The product is extracted with MTBE (1.92 L) and washed with 5 % sodium bicarbonate solution (1.15 L). The organic layer is filtered through silica gel pad (380 g) and rinsed with MTBE (0.58 L). After resolvent removal by distillation under vacuum, the product G-74a (421.8 g, 97.8 % yield) is obtained as an orange-brown oil. 1H NMR (500 MHz, CDCl₃): δ 3.98-3.85 (m, 3H), 3.80-3.75 (m, 1H), 2.72 (dt, J = 17.0, 5.2 Hz, 1H), 2.60 (ddd, J = 17.0, 9.5, 5.8 Hz, 1H), 2.20-2.12 (m, 1H), 2.07-1.94 (m, 3H), 1.82-1.48 (m, 8H). ESI-MS: m/z 275 [M+H]+. Experimental procedure for the synthesis of G-76a A dry flask is charged with crude G-74a (265 g, 72.3 wt%, 698.4 mmol) in MeOH (1590 mL) and cat. NaOMe (8.0 mL, 25 % in MeOH, 34.9 mmol). The mixture is stirred at rt for 1 h to achieve > 99 % conversion. After solid NH₄Cl (52.0 g, 977.8 mmol, 1.4 equiv.) is added, the resulting mixture is stirred at rt to achieve > 95 % conversion (if not, more NH₄Cl is added). After dimethyl malonate (168 g, 1047.7 mmol, 1.5 equiv.) is added at rt, NaOMe (377 g, 25 % in MeOH, 2.5 equiv.) is added. The resulting mixture is heated to reflux for 4 h to achieve > 95 % conversion. After the mixture is cooled to 23 °C, water (795 mL) is added followed by addition of 6N HCl (349 mL) slowly below 20 °C to reach pH ~3. To the slurry is added MTBE (530 mL). After 1 h at rt, the solid is collected by filtration, washed with 3V water (796 mL) and MTBE (530 mL) to give the product G-76a (178 g) as an off-white solid with 71 % crude yield. The crude product is used for next step directly. 1H NMR (500 MHz, CDCl3): δ 5.82 (s, 1H), 3.96-3.74 (m, 4H), 2.74-2.70 (m, 1H), 2.62-2.59 (m, 1H), 2.22-2.10 (m, 1H), 2.12-1.90 (m, 3H), 1.80-1.48 (m, 8H). ESI-MS: m/z 360 [M+H]+. Experimental procedure for the synthesis of G-77a A dry flask is charged with G-76a (80.0 g, 253.7 mmol), DMAP (4.0 g), tetramethyl ammonium chloride (4.0 g), and POCl3 (400 mL). The mixture is heated at 80 °C for 1.5 h to achieve > 99 % conv. POCl3 is removed under vacuum to get a thick light-yellow slurry. MTBE (160 mL) is added. Then the mixture is cooled to 5 °C. Water (800 mL) is slowly added. The resulting white slurry is stirred at 23 °C for 1 h. The solid is collected by filtration and then washed successively with water (480 mL) and MTBE (160 mL). After drying under vacuum at 60 °C overnight, 84.3 g of the product G-77a are isolated as a white solid in > 99 purity% and ~93 % yield. 1H NMR (600 MHz, DMSO-d6): δ 8.05(s, 1H),2.96-2.91 (m, 1H), 2.76-2.69 (m, 2H), 2.53- 2.48 (m, 2H), 2.37-2.34 (m, 1H), 1.97-1.96 (m, 2H), 1.88-1.82 (m, 4H), 1.70-1.61 (m,1H), 1.52- 1.41(m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 209.8, 164.3,161.4, 157.3, 155.7, 120.8, 120.2, 50.3, 38.1, 37.5, 31.0, 26.6, 20.7,19.9, 18.0. ESI-MS: m/z 353 [M+H]+. A dry and clean reactor is charged with LiHMDS (1 M in THF) (406.4 kg, 456.1 mol, 1.1 equiv). The solution is cooled to 0-5 °C, crude A-6b (93.0 kg, 414.6 mol) is added below 5 °C and rinsed with THF (46.5 kg) to aid transfer. After 30 min at 0-5 °C, diethyl oxalate (72.5 kg, 497.5 mol, 1.2 equiv) is added below 5 °C. After the mixture is warmed to 20-25 °C in 1 h, the mixture is kept at 20-25 °C for not less than 3 h. After the batch is cooled to 10-15 °C, cooled HCl solution [prepare by adding acetyl chloride (73.6 kg, 932.9 mol, 2.25 equiv) to EtOH (293.9 kg) at 0-5 °C] is added to the batch below 25 °C to reach final pH ~6-7of the yellow slurry. Solid NH2OH·HCl (28.8 kg, 414.4 mol, 1.05 equiv.) is added in one portion and the resulting mixture is heated to reflux 66-70 °C for 6-10 h. After that 5V of solvent is removed by distillation at reflux 66-70 °C. EtOH (73.5 kg) is used to remove residual THF. Water (372.0 kg) and EtOH (293.9 kg) are added. After 3-6 h at 70-75 °C, the mixture is cooled to 30- 35 °C.0.5-1 % G-78a crystals are seeded. After 2-4 h at 30-35 °C, heptane (63.2 kg) is added in not less than 1 h. After 60 min at 20-25 °C, water (279.0 kg) is added over 4-6 h. After 1 h at 20-25 °C, the solid is collected and washed with 1:2 EtOH/water (51.2 kg EtOH and 130.2 kg water) and then heptane (63.2 kg) two times. The solid is dried under vacuum under nitrogen stream to give the product G-78a (93.0 kg) with 65 % yield. 1H NMR (500 MHz, CDCl3): δ 4.42 (q, J = 7.1 Hz, 2H), 2.73 (dt, J = 16.8, 5.1 Hz, 1H), 2.64 (dt, J = 14.3, 6.0 Hz, 1H), 2.60-2.51 (m, 2H), 2.43-2.30 (m, 2H), 2.09-1.96 (m, 3H), 1.91-1.81 (m, 3H), 1.76-1.67 (m, 1H), 1.65-1.58 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H). ESI-MS: m/z 278 [M+H]+. Experimental procedure for the synthesis of G-79a A dry and clean reactor is charged with G-78a (72.0 kg, 259.6 mol), EtOH (56.9 kg) and NH₄OH (aq) (280.8 kg). The mixture was kept at 20-25 °C for not less than 16 h. After water (144.0 kg) is added over 30 min, the slurry is kept at 20-25 °C for 30 min. The solid is collected by filtration, washed with 1:3 EtOH/water (28.5 kg EtOH and 108 kg water) and then heptane (97.9 kg). After drying, under vacuum over 1 h at 23 °C, the solid was dried under vacuum at 50-55 °C overnight to give the product G-79a (61.4 kg, 87.2 % yield, enantiomeric ratio ≥ 95:5 (254 nm), water content ≤ 0.5 % based on Karl Fischer titration). A dry and clean reactor is charged with crude G-79a (60.0 kg, 1.0 equiv.), 1,4-dioxane (240.0 kg) and activated carbon (3.0 kg, 5 wt%). The mixture is stirred at 55-65 °C for 2-4 h. After filtration at high temperature (55~65 °C), the filter cake is washed with 1,4-dioxane (33.0 kg). The filtrate is transferred into a clean reactor. The temperature is adjusted to 45-55 °C and stirred at 45-55 °C for 1-2 h. Water (240.0 kg) is added over 2 h. The temperature is adjusted to 45-55 °C and stirred at 45-55 °C for 1-2 h. The mixture is cooled down to 35-45 °C and stirred at 35~45 °C for 2-4 h. Water (87.0 kg) is added over 4 h. The mixture is cooled down to 15-25 °C and stirred at 15-25 °C for 12-14 h. The solid is collected by a centrifuge, washed with water (120.0 kg) and dried under vacuum at 50-55 °C overnight to give the product G-79a (44.8 kg, 71 % yield) as a light yellow to off-white solid. The undesired isomer should be less than 0.5 %. 1H NMR (500 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.71 (s, 1H), 2.80-2.69 (m, 1H), 2.60-2.53 (m, 1H), 2.50-2.42 (m, 1H), 2.40-2.28 (m, 2H), 2.26-2.18 (m, 1H), 2.05-1.70 (m, 7H), 1.48-1.39 (m, 1H). ESI-MS: m/z 249 [M+H]+. Experimental procedure for the synthesis of G-80a A dry and clean reactor is charged with G-79a (40.0 kg, 161.1 mol), MeCN (96.0 kg) and pyridine (30.8 kg, 386.6 mol, 2.4 equiv.). After the mixture is cooled to 0-5 °C, TFAA (40.8 kg, 193.3 mol, 1.2 equiv.) is added slowly below 5 °C. After 5 min at 0-5 °C, water (120.0 kg) is added over 30 min at 0-5 °C and seeded with 0.5 % G-80a crystals. After 15 min at 0-5 °C, water (120.0 kg) is added over 30 min. After 30 min at 0-5 °C for 30 min, the solid is collected by filtration, washed with 1:3 MeCN/water (15.6 acetonitrile and 60.0 kg water) and then water (80.0 kg). The solid is dried under vacuum to give the crude product (33.0 kg, 93.6 % yield) as a tan solid. A dry and clean reactor is charged with crude G-80a (32.5 kg, 1.0 equiv.) and MTBE (48.1 kg), the slurry is agitated at 20-25 °C for 30 min. Heptane (132.6 kg) is added over 1 h. After 30 min at 20-25 °C, the solid is collected, dried under vacuum to give the product G-80a (26.6 kg, 82.0 % yield) as a white solid with > 99:1 enantiomeric ratio (254 nm) and > 98 % purity (220 nm). 1H NMR (500 MHz, DMSO-d6): δ 2.83-2.73 (m, 1H), 2.60-2.40 (m, 3H), 2.34-2.20 (m, 2H), 2.06-1.75 (m, 7H), 1.53-1.43 (m, 1H). ESI-MS: m/z 231 [M+H]+. Experimental procedure for the synthesis of G-82a To a stirred solution of G-80a (25.0 g, 108.6 mmol, 1.0 equiv.) in MeOH (150 mL), is added NaOMe (30 % in MeOH, 4.89 g, 27.1 mmol, 0.25 equiv.) and the resulting mixture is stirred for 2 h at rt. Then NH4Cl (6.39 g, 119.4 mmol, 1.1 equiv.) is added and the mixture is stirred for 16 h at rt. After complete conversion to the desired amidine, the mixture is filtered through a Celite bed and concentrated. The residue is dissolved in DMF (125 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (32.3 g, 212.3 mmol, 2.1 equiv.) and diethyl malonate (13.4 g, 101.1 mmol, 1.0 equiv.) are added at 0 °C and the resulting mixture is stirred for 16 h at 90 °C. After complete conversion, ice cold water is added, the mixture is acidified with 1N HCl and the precipitate is collected by filtration. The precipitate is dried under reduced pressure yielding crude G-82a (HPLC-Method: H, tret = 1.51 min; [M+H] = 316) which is used for the next step without purification. Experimental procedure for the synthesis of G-83a G-82a (10.0 g, 30.1 mmol, 1.0 equiv.) and POCl₃ (48.0 g, 310.0 mmol, 10.3 equiv.) are combined at 0 °C and stirred for 5 min. DIPEA (8.2 g, 63.2 mmol, 2.1 equiv.) is added and the resulting mixture is stirred for 3 h at 80 °C. After complete conversion ice cold water (1 L) is slowly added to the mixture at 0 °C and afterwards the mixture allowed to reach rt and stirred for 1 h. The precipitate is collected by filtration, washed with water and hexane, and dried under vacuum to yield G-83a (HPLC-Method: H, tret = 2.22 min; [M+H] = 352/354). The crude product is used for the next step without purification. Experimental procedure for the synthesis of G-84a B-5d (694 mg, 4.09 mmol, 1.2 equiv.) is dissolved in dry THF (13 mL) and cooled to 0 °C. LiHMDS (1.0 M in THF, 5.11 mL, 5.11 mmol, 1.5 equiv.) is added dropwise at 0 °C and the mixture is stirred for additional 15 min. G-77a (1.20 g, 3.41 mmol, 1.0 equiv.) is dissolved in dry THF (13 mL) and added dropwise at 0 °C. The mixture is stirred for 1.5 h at 65 °C. After complete conversion, the mixture is diluted with aq. satd. NaHCO₃ solution and extracted three times with DCM. The organic phases are combined, filtered and concentrated under reduced pressure to obtain G-84a. The crude product is used for the next step without purification. The following intermediates G-84 (Table 21) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 21 t_ret HPLC # Structure [M+H]+ [min] method G-84a 0.89 475 C G-84b 1.52 475 A G-84c 1.52 475 A Cl D C N O N _N ^F G-84d N 2.10 466 G O ^O Experimental procedure for the synthesis of G-15a

F-8a (356 mg, 0.804 mmol, 1.0 equiv.) is dissolved in dioxane (2 mL) and hydroxylamine solution (50% in water, 98.6 µL, 1.61 mmol, 2.0 equiv.) is added. The resulting solution is stirred at 40 °C until complete conversion is observed. The solvents are evaporated, the resulting residue is purified by RP chromatography to afford G-13a (G-14a is observed as a side product and separated by chromatography). G-13a (136.0 mg, 0.29 mmol 1.0 equiv.) is dissolved in DCM (2 mL) and DIPEA (114.38 µL, 0.65 mmol, 2.2 equiv.) and methanesulfonyl chloride (34.2 µL, 0.45 mmol, 1.5 equiv.) is added. The resulting solution is stirred at rt until complete conversion is observed. The reaction mixture is concentrated under reduced pressure and extracted with DCM (3x) and water. The organic solvent is evaporated, the resulting residue is purified by RP chromatography to afford G-15a. The following intermediates G-15 (Table 22) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 22 tret HPLC # structure [M+H]+ [min] method G-15a 1.64 439 A G-15b 1.89 572 A Experimental procedure for the synthesis of G-29a (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethan-1-ol (122 µL mg, 0.865 mmol, 3.0 equiv.) and potassium tert.-butoxide (97.0 mg, 0.865 mmol, 3.0 equiv.) are dissolved in THF (2 mL) and stirred at 50 °C for 30 min. G-15b (165 mg, 0.28 mmol, 1 equiv.) is added and the solution is stirred at 85 °C for 3 h. The solvent is evaporated and the resulting residue is purified by RP chromatography to afford G-29a (HPLC-Method: C, tret = 1.12 min; [M+H] = 665). Experimental procedure for the synthesis of G-30a G-29a (183 mg, 275 µmol, 1.0 equiv.) and HCl (8 M, 172 µL, 1.38 mmol, 5.0 equiv.) are dissolved in MeOH (2.0 mL) and stirred at 60 °C until total conversion. The reaction mixture is concentrated under reduced pressure and extracted with EtOAc / NaHCO₃. The combined organic phase is concentrated under reduced pressure to give G-30a (HPLC-Method: A, tret = 1.41 min; [M+H] = 521). Experimental procedure for the synthesis of G-34a G-12b (100 mg, 0.22 mmol, 1.0 equiv.), (S)-5-methyl-4,7-diazaspiro[2.5]octane 2HCl (141 mg, 0.67 mmol, 3.0 equiv.) and DIPEA (230 µL, 0.67 mmol, 6.0 equiv.) are dissolved in DMSO (1 mL). The reaction is stirred for 18h at 90 °C. After the reaction is completed, the solvent is removed under reduced pressure and the residue purified by basic RP chromatography to give the desired product G-34a. The following intermediates G-34 (Table 23) are available in an analogous manner. The crude product is purified by chromatography if necessary. The diastereomeric mixture G-34c can be separated via chiral HPLC (Chiralpack IE, 250X20mm, 5µ; solvent: ethanol/heptane 60:40 + 0.1% diethyl amine) to obtain G-34c1 (eluting 1st as peak1) and G-34c2 (eluting afterwards as peak2). Table 23 t_ret HPLC # Structure [M+H]+ [min] method G-34a 1.51 535 A N O N N O N N F G-34h 1.01 569 B O O ^N G-34k 1.02 551 B G-34i 1.24 639 B Experimental procedure for the synthesis of G-45a G-11a (217 mg, 0.505 mmol, 1.0 equiv.) is dissolved in DMSO (2 mL) and DIPEA (172 µL, 1.01 mmol, 2.0 equiv.) and N-methylpiperazine (75.8 mg, 0.757 mmol, 1.5 equiv.) is added. The reaction mixture is stirred at 90 °C until complete conversion is observed. The mixture is diluted with aq. satd. NaHCO3 solution and extracted three times with DCM. The organic phase are combined, filtered and concentrated under reduced pressure. The resulting residue is dissolved in ACN and purified by basic RP chromatography to give the desired product G-45a. The following intermediates G-45 (Table 24) are available in an analogous manner. The crude product is purified by chromatography if necessary. The diastereomeric mixture G-45l is separated via chiral HPLC (Colum: Chiralpack IE, 250X20mm, 5µ; solvent: ethanol/heptane 1:1 + 0.1% diethyl amine) to obtain G-45I1 (eluting 1st as peak 1) and G-45I2 (eluting afterwards as peak 2). Table 24 + HPLC # Structure tret [min] [M+H] method G-45a 1.38 494 A O O N N N O G-45y N N F 1.21 639 B N O ^O G-45z 1.04 553 B Experimental procedure for the synthesis of G-46a 4-(1H-pyrazol-3-yl)pyridine (73.4 mg, 0.51 mmol, 1.50 equiv.) is dissolved in DMF (1 mL), NaH (51.7 mg, 1.35 mmol 4.0 equiv.) is added and stirred for 20 min at rt. G-11b (150 mg, 0.34 mmol, 1.0 equiv.) is added and the reaction is stirred for 1 h at 40 °C. After complete conversion, the reaction is extracted with EtOAc/water. The organic phase is concentrated under reduced pressure and purified by RP chromatography to give the desired product G-46a. The following intermediates G-46 (Table 25) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 25 tret + HPLC # Structure [M+H] [min] method G-46a 1.60 554 A G-46b 1.59 555 A G-46d 1.74 555 A Experimental procedure for the synthesis of G-48a G-11d (150 mg, 0.32 mmol, 1.0 equiv.) is dissolved in dioxane (1.5 mL).1-Methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (82.7 mg, 0.39 mmol, 1.2 equiv.), XPHOS PD G3 (26.0 mg, 0.03 mmol, 0.09 equiv.) and cesium carbonate (0.4 ml, 0.80 mmol, 2.46 equiv.) are added. The reaction is stirred for 2 h at 80 °C. After complete conversion is observed the reaction is extracted with DCM/water. The combined organic phase is concentrated under reduced pressure, dissolved in ACN/water and purified by RP chromatography to give the desired product G-48a. The following intermediates G-48 (Table 26) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 26 tret HPLC # Structure [M+H]+ [min] method G-48a 0.75 509 C G-48g 1.54 494 A G-48s 1.50 492 A Experimental procedure for the synthesis of G-51a G-11b (150 mg, 0.34 mmol, 1.0 equiv.) is dissolved in dioxane (18mL), 2-oxazolidone (59.9 mg, 0.67 mmol, 2.0 equiv.), Pd(dppf)Cl2 (24.7 mg, 0.03 mmol, 0.1 equiv.) and NaOtBu (2.0M in THF, 185 µL, 0.37 mmol, 1.1 equiv.) are added. The reaction is stirred 3 d at 60 °C. after complete conversion is observed the reaction is filtered and concentrated under reduced pressure. The residue is extracted with DCM/water. The combined organic phase is concentrated under reduced pressure and purified by RP chromatography to afford G-51a (HPLC-method: C, t_ret = 0.78 min; [M+H] = 496). Experimental procedure for the synthesis of G-63a G-45a (124 mg, 0.251 mmol, 1.0 equiv.) is dissolved in DCM (1 mL) under argon and cooled to 0°C. Formaldehyde (22.5 µL, 0.301 mmol, 1.2 equiv.) is added followed by the addition of sodium triacetoxyborohydride (224 mg, 1.01 mmol, 4.0 equiv.). The solution is stirred for 30 min at 0 °C. After complete consumption of starting material, the reaction is quenched by the addition of water. The aqueous phase is extracted with DCM. The combined organic phases are dried, filtered, and concentrated under reduced pressure. The residue is purified by RP chromatography to give the desired product G-63a. The following intermediates G-63 (Table 27) are available in an analogous manner. Deuterated intermediates G-63 are obtained analogously but sodium triacetoxyborohydride is exchanged by sodium triacetoxyborodeuteride. The crude product is purified by chromatography if necessary. Table 27 # Structure tret [min] [M+H]+ HPLC method G-63a 0.70 508 C Experimental procedure for the synthesis of G-86a G-12b (2.00 g, 4.23 mmol, 1 equiv.), ethyl 1H-pyrazole-5-carboxylate (936 mg, 6.34 mmol, 1.5 equiv.) and cesium carbonate (4.59 g, 8.46 mmol, 2 equiv.) are dissolved in THF (20 mL). The reaction is stirred for 2 h at 70 °C. After complete conversion, DCM is added, and the solution is washed with water. The organic phase is concentrated under reduced pressure and purified by RP chromatography to obtain G-86a. The following intermediates G-86 (Table 28) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 28 t_ret + HPLC # Structure [M+H] [min] method G-86a 0.96 549 C G-86b 0.92 579 C G-86c 0.88 579 C G-86d 0.69 550 C Experimental procedure for the synthesis of G-88a G-11b (4.00 g, 8.99 mmol, 1 equiv.), 2-(1H-pyrazol-3-yl)acetic acid hydrochloride (1.73 g, 10.34 mmol, 1.15 equiv.) and cesium carbonate (8.79 g, 26.97 mmol, 3 equiv.) are dissolved in DMSO (20 mL). The reaction is stirred for 1.5 h at 90 °C. After complete conversion to the desired intermediate, the reaction mixture is cooled to RT, isopropylamine (1.55 mL, 17.98 mmol, 2.0 equiv.), 1-methylimidazole (1.43 mL, 17.98 mmol, 2.0 equiv.), and chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5.15 g, 17.98 mmol, 2.0 equiv.) are added and the mixture is stirred for 15 min. at RT. After complete conversion, DCM is added, and the solution is washed with water and brine. The organic phase is concentrated under reduced pressure and purified by RP chromatography to obtain G-88a. The following intermediates G-88 (Table 29) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 29 t_ret + HPLC # Structure [M+H] [min] method G-88a 0.78 576 C Experimental procedure for the synthesis of I-2 G-30a (80.0 mg, 154 µmol, 1.00 equiv.), malononitrile (64.2 mg, 953 µmol, 6.20 equiv.), sulfur (23.1 mg, 791 µmol, 4.70 equiv.) ß-Alanine (60.9 mg, 684 µmol, 4.50 equiv.) and magnesium sulfate (23.5 mg, 195 µmol, 1.30 equiv.) are suspended in EtOH (2.0 mL) and stirred at 80 °C for 18h. The reaction mixture is diluted with EtOAc, filtered and washed with aq. saturated NaHCO3. The organic phase is separated and the remaining aq. phase is extracted with EtOAc (2x). The combined organic phases are dried with magnesium sulfate, evaporated and the resulting residue is purified by RP chromatography to afford I-2. The following final compounds I (Table 30) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 30 # structure t + ret [min] [M+H] HPLC method I-2 1.41 601 A I-34 1.51 613 A Experimental procedure for the synthesis of I-37 G-34h (91.0 mg, 0.160 mmol, 1.00 equiv.), ammonium acetate (26.3 mg, 0.320 mmol, 2.00 equiv.) and sulfur (10.3 mg, 0.320 mmol, 2.00 equiv.) is suspended in EtOH (1.0 mL) and stirred at 60 °C for 15 min. Malonitrile (22.3 mg, 0.320 mmol, 2.00 equiv.) is added. The reaction is stirred for 5 h at 80 °C. After full conversion the mixture is diluted with DMSO, filtered and purified with RP chromatography to afford I-37. The following final compounds I (Table 31) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 31 t_ret + HPLC # structure [M+H] [min] method I-37 1.44 649 A I-38 1.23 719 B I-39 1.57 633 A I-46 0.92 659 C I-47 0.94 629 C HN N I-49 N O N N N O 1.45 631 A O N H2N S I-50 1.53 645 A Experimental procedure for the synthesis of I-45 O HN O N N N N O N O N N F N N F N N O O N N H2N H2N S S I-45 I-38 I-38 (225 mg, 0.31 mmol, 1.0 equiv.) is dissolved in DCM/TFA (1:1, 2.0 mL) and the reaction is stirred at rt for 3 h. After complete conversion, the reaction mixture is concentrated under vacuum and purified with RP chromatography yielding I-45 (HPLC-Method: A, tret = 1.47 min; [M+H] = 619). Experimental procedure for the synthesis of I-51 H O O O O N N N N N N O O N N N N O N O N O O N N H N H N S S I-46 I-51 To a suspension of I-46 (2.73 g, 4.14 mmol, 1.0 equiv.) in ethanol (47 mL) is added potassium hydroxide (1.91 g, 29.0 mmol, 7.0 equiv.) dissolved in water (53 mL) and the mixture is stirred for 2h at rt. After complete conversion the mixture is acidified to pH6, ethanol is removed under reduced pressure and the resulting precipitate is collected by repeated centrifuging and washing with water and dried under reduced pressure to give the desired product I-51. The crude product is used without further purification. The following final compounds I (Table 32) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 32 t_ret + HPLC # structure [M+H] [min] method I-51 0.56 631 C I-52 1.08 601 A Experimental procedure for the synthesis of I-53 To a solution of I-51 (90.1 mg, 0.14 mmol, 1.0 equiv.) in DMSO (0.7 mL) is added (R)- tetrahydrofuran-3-amine hydrochloride (21.9 mg, 0.17 mmol, 1.2 equiv.), 1-methylimidazole (45.6 µL, 0.57 mmol, 4.0 equiv.) and chlor-N,N,N’,N’-tetramethylformamidinium- hexafluorophosphat (57.3 mg, 0.20 mmol, 1.4 equiv.) and the mixture is stirred for 1 h at rt. After complete conversion, the mixture is diluted with ACN and the product is isolated via RP chromatography to give the desired product I-53. The following final compounds I (Table 33) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 33 tret HPLC # structure [M+H]+ [min] method O HN O N I-53 N N O N 1.46 700 A N N O O N H N S I-58 1.51 658 A Experimental procedure for the synthesis of II-1 G-11c (1.20 g, 2.59 mmol, 1.00 equiv.), ammonium acetate (319 mg, 4.15 mmol, 1.60 equiv.), sulfur (133 mg, 4.15 mmol, 1.60 equiv.) is dissolved in EtOH (12 mL) and stirred at 60 °C for 15 min. Malonitrile as a solution in EtOH (3.77 mL, 4.28 mmol, 1.65 equiv.) is added slowly dropwise (8mL/h). Reaction is stirred for 5 h at 80 °C. After full conversion reaction is concentrated and purified by NP chromatography. Product fractions are concentrated and extracted with DCM and saturated NaHCO₃. The organic phase is concentrated under reduced pressure to obtain II-1. The following final compounds II (Table 34) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 34 tret HPLC # structure [M+H]+ [min] method II-1 1.59 543 A II-3 0.83 525 E II-179 1.11 556 B II-180 1.54 556 A II-182 1.50 656 A Experimental procedure for the synthesis of II-17 II-1 (0.10 g, 0.18 mmol, 1.0 equiv.) is suspended in DMSO (0.50 ml). DIPEA (0.11 mL, 0.57 mmol, 3.1 equiv.) and (R)-5-methyl-4,7-diazaspiro[2.5]octane dihydrochloride (42 mg, 0.20 mmol, 1.1 equiv.) is added and the reaction mixture is stirred for 2 h at 80 °C. After full conversion the reaction mixture is purified with RP chromatography. The following final compounds II (Table 35) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 35 tret [M+H] HPLC # structure [min] + method II-17 1.50 633 A II-184 1.43 631 A II-187 1.41 631 A Experimental procedure for the synthesis of II-19 II-3 (80 mg, 0.15 mmol, 1.0 equiv.) and B-11a (50.3 mg, 0.31 mmol, 2.0 equiv.) are dissolved in THF (1.0 mL), cesium carbonate (123 mg, 0.38 mmol, 2.5 equiv.) is added and the mixture is stirred for 3 h at 65°C. After complete conversion saturated NaHCO3 solution is added and the product is extracted with DCM. The organic phase is dried, filtered and concentrated under reduced pressure. The crude product is purified by RP chromatography to yield the desired final product II-19. The following final compounds II (Table 36) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 36 tret HPLC # structure [M+H]+ [min] method II-19 1.58 654 A II-20 1.46 614 A II-21 1.39 600 A II-23 1.66 629 A II-189 1.42 629 A Experimental procedure for the synthesis of II-24 To a solution of II-23 (100 mg, 0.159 mmol, 1.0 equiv.) in 1-propanol (1 mL) is added sodium hydroxide (4 M in water, 99.4 µL, 0.40 mmol, 2.5 equiv.) and the mixture is stirred for 30 min at rt. After complete conversion, saturated NaHCO3 is added, the mixture is washed with DCM, then the aqueous phase is acidified with HCl and extracted with DCM. The organic phases are dried, filtered and concentrated and the crude product is purified via RP chromatography to give the desired product II-24. The following final compounds II (Table 37) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 37 t_ret HPLC # structure [M+H]+ [min] method II-24 1.11 601 A Experimental procedure for the synthesis of II-25 To a solution of II-24 (40 mg, 0.067 mmol, 1.0 equiv.) in DMF (0.4 mL) is added oxetan-3- amine hydrochloride (15 mg, 0.133 mmol, 2.0 equiv.), DIPEA (22.3 µL, 0.166 mmol, 2.5 equiv.) and 1-propanephosphonic anhydride (29.7 µL, 1.00 mmol, 1.5 equiv.) and the mixture is stirred for 3 h at rt. After complete conversion, saturated NaHCO₃ is added and the mixture is extracted with DCM. The organic phases are dried, filtered and concentrated and the crude product is purified via RP chromatography to give the desired product II-25. The following final compounds II (Table 38) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 38 tret HPLC # structure [M+H]+ [min] method II-25 1.44 656 A II-26 1.49 670 A II-191 1.57 705 A O H_N ^O N N II-192 N O N 1.48 670 A N N N O H N S II-194 1.46 670 A Experimental procedure for the synthesis of II-30 To a solution of G-63a (94.0 mg, 0.18 mmol, 1.0 equiv.) and molecular sieves (3 Å) in anhydrous EtOH (2 mL) under an argon atmosphere are added malononitrile (64.4 mg, 0.97 mmol, 5.0 equiv.), sulfur (23.8 mg, 0.74 mmol, 4.0 equiv.) and ß-Alanine (69.5 mg, 0.78 mmol, 4.0 equiv.). The reaction mixture is stirred at 80 °C overnight. After complete conversion, the mixture is cooled to the rt, filtered and extracted with DCM and aq. sat. NaHCO₃. The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in ACN and water and purified by basic RP chromatography to give the desired product II-30. The following final compounds II (Table 39) are available in an analogous manner. The crude product is purified by chromatography if necessary. In the case of II-87, Boc-deprotection is observed during the reaction using G-48r as the starting material. Table 39 tret HPLC # structure [M+H]+ [min] method II-30 1.39 588 A II-86 1.55 572 A II-110 1.35 635 A II-111 1.56 574 A II-130 1.63 635 A Experimental procedure for the synthesis of II-143 G-51a (90 mg, 0.18 mmol, 1.0 equiv.), ammonium acetate (22.4 mg, 0.29 mmol, 1.6 equiv.), and sulfur (9.32 mg, 0.29 mmol, 1.6 equiv.) are dissolved in EtOH (1.20 mL) and stirred at 60 °C for 15 min. Malonitrile as a solution in EtOH (0.26 mL, 0.3 mmol, 1.65 equiv.) is added slowly, dropwise. The reaction is stirred for 5 h at 80 °C. After full conversion, DCM is added and extracted 3 times with water. The combined organic phases are concentrated under reduced pressure, dissolved in DMF/ACN/water and purified with RP chromatography to afford II-143. The following final compounds II (Table 40) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 40 t_ret # structure [M+H]+ HPLC method [min] II-143 1.45 576 A II-146 1.60 717 A O O _N N N _O F II-147 ^N _N 1.21 719 B N N O H N S II-149 1.56 633 A N N N O N O II-152 N N 1.52 645 A N O H N S II-201 1.38 630 A Experimental procedure for the synthesis of II-160 To a solution of II-146 (210 mg, 0.29 mmol, 1.0 equiv.) in dioxane (3 mL), HCl (4 M in dioxane, 0.29 mL, 1.17 mmol, 4.0 eq) is added and the reaction mixture is stirred for 18 h at rt. The reaction mixture is heated to 50 °C and stirred for 6 h. The solvent is removed, and the residue is purified by RP chromatography to obtain II-160. The following final compounds II (Table 41) are available in an analogous manner. The crude product is purified by chromatography if necessary. Table 41 tret + HPLC # Structure [M+H] [min] method II-160 1.30 617 A II-165 1.44 619 A Example 5: Synthesis of compounds according to formula (D) List of abbreviations (Table 42) Ac Acetyl ACN Acetonitrile aq. aquatic, aqueous ATP adenosine triphosphate Bn Benzyl Boc tert-butyloxycarbonyl Bu Butyl C Concentration c Concentration Cbz Carboxybenzyl CDI 1,1´-carbonyldiimidazole cHexane cyclohexane D day(s) d day(s) TLC thin layer chromatography Davephos 2-dimethylamino-2'-dicyclohexylaminophosphinobiphenyl DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DCE dichloro ethane DCM dichloro methane de diastereomeric excess DEA diethyl amine DIPEA N-ethyl-N,N-diisopropylamine (Hünig´s base) DMA Dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO Dimethylsulphoxide DPPA Diphenylphosphorylazide dppf 1.1´-bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid eq. equivalent(s) eq equivalent(s) ESI electron spray ionization Et Ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH Ethanol h Hour O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium HATU hexafluorophosphate HOBT 1-hydroxybenzotriazole hydrate HPLC high performance liquid chromatography i Iso conc. Concentrated LC liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide sln. Solution Me Methyl MeOH Methanol min Minutes MPLC medium pressure liquid chromatography MS mass spectrometry MTBE methyl tert-butyl ether NMM N-methylmorpholine NMP N-methylpyrrolidone NP normal phase n.a. not available PBS phosphate-buffered saline Ph Phenyl Pr Propyl PTSA p-toluenesulfonic acid Py Pyridine rac Racemic red. Reduction Rf (R_f) retention factor RP reversed phase RRLC Rapid resolution liquid chromatography RT ambient temperature rt ambient temperature SFC supercritical fluid chromatography SN nucleophilic substitution TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate tBu tert-butyl TEA triethyl amine temp. Temperature tert Tertiary Tf Triflate TFA trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl tRet. retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane TsOH p-toluenesulphonic acid UPLC ultra performance liquid chromatography UV Ultraviolet wt Weight Chemical Examples Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Chromatography The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 µm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 µm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 µm, 50 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm) and Chiralpak IE (5 µm, 250 x 20 mm) Different gradients of H2O/acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H2O/acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH. For the chromatography under basic conditions for Agilent systems H₂O/acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH₄HCO₃ + 50 mL NH₃ (25 % in H₂O) to 1 L with H₂O). For Gilson systems the water is made alkaline as follows: 5mL NH₄HCO₃ solution (158 g in 1 L H₂O) and 2 mL NH₃ (28 % in H₂O) are replenished to 1 L with H2O. The Gilson system was also used under isocratic conditions (60% EtOH/40% EtOH + 0.1% DEA) The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a Agilent 1260 SFC-system, JASCO SFC-system or Sepiatec SFC-system or Waters Thar SFC-System or Waters UPC2-MS SFC-System with the following colums: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD-H (21 x 250 mm), 5 µm, Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), Chiralcel OX-3 (150 x 4.6 mm, 3 µm), Phenomenex Lux C2 (250 x 20 mm, 5 µm). Analytical SFC/UV-spectrometry Methods SFC Method: SFC-1 SFC: Agilent 1260 (binary pump) SFC Column: Chiralpak AD-H (250 x 4,6 mm), 5 µm Flow: 2 ml/min Mobile Phase: A: CO2 + B: MeOH ABPR: 120 Bar Temp: 37.5 °C UV: 220 nm Gradient 80% A + 20% B (isocratic) Stop time 10 min The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridgeTM C18, 2.5 µm, 2.1 x 20 mm or XBridgeTM C18, 2.5 µm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 µm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 µm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 µm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy/UV-spectrometry The retention times/MS-ESI+ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time t_Ret. = 0.00. Method A HPLC Agilent 1100 system MS 1200Series LC/MSD(API-ES+/-3000V, Quadrupol, G6140) MSD signal settings Scan pos/neg 120 – 1500 m/z Detection signal 315 nm (bandwidth 170nm, reference off) Spectrum range 230 – 400 nm Peak width <0.01 min Column Waters, Xbridge C18, 2.5 µm, 2.1x20 mm column Column temperature 60°C Solvent A: 20mM aq. NH4HCO3/ NH3 pH 9 B: ACN HPLC grade Flow 1.00 mL/min Gradient 0.00 – 1.50 min 10 % to 95 % B 1.50 – 2.00 min 95 % B 2.00 – 2.10 min 95 % to 10 % B Method E UPLC-MS Waters Acquity-UPLC-SQ Detector-2 MSD signal settings Scan pos & Neg 100 – 1500, Source Voltage: Capillary Vol(kV)- 3.50, Cone(V): 50 Source Temp: Desolvation Temp(°C): 350 Source Gas Flow: Desolvation(L/Hr): 750, Cone(L/Hr): 50 Detection signal Diode Array Spectrum Range: 200 – 400 nm; Resolution: 1.2nm Sampling rate 10 point/sec Column AQUITY UPLC BEH C181.7µm, 2.1X50mm Column temperature 35 °C Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow 0.6 mL/min Gradient 0.0 – 0.30 min 97% B 0.30 – 2.20 min 97 % to 2 % B 2.20 – 3.30 min 2 % B 3.30 – 4.50 min 2 % to 97 % B 4.50 – 4.51 min 97 % B Method H HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/- 3000 V, Quadrupol, G6130B) MSD signal settings Scan pos 700 - 1350 Column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 µm, 2.1 x 30 mm) column eluant A: 5 mM NH4HCO3/18 mM NH3 (pH = 9.2) B: acetonitrile (HPLC grade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) spectrum range: 190 – 400 nm; slit: 4 nm peak width > 0.0031 min (0.063 s response time, 80Hz) injection 0,5 µL standard injection flow 1.4 mL/min column temperature 45 °C gradient 0.0 – 1.0 min 15 % à 95 % B 1.0 – 1.1 min 95 % B Stop time: 1.3 min HPLC/UV-spectrometry Method I HPLC Agilent 1100/1200 system Column Chiralpak; Part. No.85394; IE, 5 µm; 150 x 2.1 mm eluant A: n-Heptan B: EtOH + 0.1 % DEA detection signal UV 315 nm (bandwidth 170, reference off) spectrum range: 190 – 400 nm; slit: 4 nm peak width > 0.0031 min (0.063 s response time, 80Hz) injection 0,5 µL standard injection flow 1.2 mL/min column temperature 45 °C isocrat 70 % B Stop time: 5 min The compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art. If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist).

Scheme 1: Scheme 2: Experimental procedure for the synthesis of K-1a To a solution of ethyl 1‐methyl‐2‐oxocyclohexane‐1‐carboxylate (108.00 g, 586.2 mmol) in toluene (1.03 L) is added malononitrile (58.04 g, 879.3 mmol, 1.5 eq.) followed by ammonium acetate (9.04 g, 117.2 mmol, 0.2 eq.) and acetic acid (13.41 mL, 234.5 mmol, 0.4 eq.) at rt. The mixture is stirred at 110 °C for 16 h. After complete conversion the mixture is diluted with EtOAc and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product K-1a. This crude material is used for the next step without further purification (see also Naumann et al., Pharmazie 51 (1996), 4). Table 43 + HPLC # structure t_ret [min] [M+H] method K-1a n.a. n.a. - Experimental procedure for the synthesis of K-2a To a solution of K-1a (250.0 g, 1.1 mol) in DMF (3.0 L) is added sulphur (68.9 g, 2.2 mol, 2.0 eq.) and L-proline (24.8 g, 0.22 mol, 0.2 eq.) and the resulting mixture is stirred at 80 °C for 12 h. After complete conversion the mixture is partitioned between EtOAc and water and the organic layer is collected. The aqueous layer is further extracted with EtOAc and the combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product is purified through column chromatography yielding K-2a. Table 44 + HPLC # structure tret [min] [M+H] method K-2a 1.08 265 A Experimental procedure for the synthesis of K-3a K-2a (78.0 mg, 0.3 mmol, 1.0 eq.) is dissolved in EtOH (1.5 mL) and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 eq.) is added. The mixture is stirred for 16 h at 78 °C. After complete conversion, water and EtOAc is added to the reaction mixture, the pH of the aqueous phase is set to pH 4 using KHSO4 solution (10 % in water), and the product is extracted using EtOAc. The combined organic layers are dried, filtered and concentrated. The crude product is purified via acidic reversed phase chromatography (gradient elution: 20 % to 90 % acetonitrile in water) yielding K-3a. The enantiomers can be separated with preparative SFC chromatography. For example K-3a into K-3b and its enantiomer. (Analytical SFC-Method SFC-1: t_ret = 4.9 min for K-3b, 7.9 min for other enantiomer). Table 45 + HPLC # structure t_ret [min] [M+H] method K-3a 0.22 237 A K-3b 0.25 237 A Experimental procedure for the synthesis of K-9a To a solution of (S)-tert-butyl-3-methyl-1,4-diazepane-1-carboxylate (846.0 mg, 214.30 mmol, 1.0 eq.) and 2-chloropyrimidine-4-carbonitrile (528.9 mg, 139.54 mmol, 1.0 eq) in DMSO (4 ml, 4,5 V) is added TEA (1.1 ml, 101.19 mmol, 2.0 eq.) at rt. The reaction mixture is stirred at 80 °C for 1 h. After complete conversion the reaction mixture is cooled to rt and water and EtOAc is added. The phases are separated. The organic layer is washed with water, dried over sodium sulfate, then filtered and concentrated under reduced pressure to the get crude product which is purified by chromatography to obtain K-9a. Table 46 # structure t_ret [min] [M+H]+ HPLC method 262 [M+H- K-9a 1.38 + A isobutene] Experimental procedure for the synthesis of K-10a To a solution of K-9a (33.85 g, 106.65 mmol, 1.0 eq) in EtOH (270 ml) is added hydroxylamine solution 50 % in water (13.05 ml, 213.30 mmol, 2.0 eq) at rt. The reaction mixture is stirred at 60 °C for 1 h. After complete conversion the reaction mixture is concentrated under reduced pressure to afford K-10a which is used for the next step without further purification. Table 47 # Structure tret [min] [M+H]+ HPLC method K-10a 1,12 351 A Experimental procedure for the synthesis of K-11a To a stirred solution of K-3b (2.53 g, 10.70 mmol, 1.0 eq.) in DMSO (10 ml) are added TEA (2.17 g, 21.40 mmol, 2.0 eq.) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium- hexafluorphosphat (HATU, 4.27 g, 11.24 mmol, 1.10 eq.) at rt. The mixture is stirred for 15 min at rt. K-10a (3.75 g, 10.70 mmol, 1.0 eq) is added at rt and stirred overnight. After complete conversion the reaction mixture is diluted with water and EtOAc. The phases are separated. The organic layer is washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to get the crude product. The crude product K-11 is purified by chromatography if necessary. Table 48 tret HPLC # Structure [M+H]+ [min] method O N N N O N 513 K- N NH 1.43 [M+H- A 11a ₂ N O O isobutene]+ H₂N S Experimental procedure for the synthesis of K-12a To a stirred solution of K-11a (2.00 g, 3.51 mmol, 1.0 eq) in THF (40 mL) is added DBU (1.98 mL, 14.04 mmol, 4.0 eq) at rt. The reaction mixture is stirred at 70 °C overnight. After complete conversion the reaction mixture is concentrated under reduced pressure to get the crude product. The crude product is purified by column chromatography to afford K-12a. The crude product K-12 is purified by chromatography if necessary. Table 49 # structure t [min] [M+ + ret H] HPLC method K-12a 1.51 551 A K-12b 1.54 537 A Experimental procedure for the synthesis of K-13a To a stirred solution of K-12a (20.00 g, 34.52 mmol, 1.0 eq.) in MeOH (350 mL) is added conc. HCl (32.88 mL, 345.21 mmol, 10.0 eq.) at rt. The reaction mixture is stirred at 50 °C for 2 h. After complete conversion the reaction mixture is concentrated under reduced pressure and diluted with water. The aqueous phase is extracted with DCM. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure to afford K-13a which is used for the next step without further purification. The crude product K-13 is purified by chromatography if necessary. Table 50 tret # structure [M+H]+ HPLC method [min] K-13a 1.21 451 A Experimental procedure for the synthesis of E-1a To a stirred solution of methyl 2‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)‐3‐methylbutanoate (15.00 g, 0.08 mol, 1.0 eq.) in DMF (75.0 mL) is added potassium carbonate (31.17 g, 0.23 mol, 3.0 eq.) at 0 °C.1,3-Dibromopropane (15.20 g, 0.08 mol, 1.0 eq) is added dropwise and the reaction mixture is stirred at 0 °C for 9 hours. After complete conversion the reaction mixture is quenched with water and extracted with EtOAc. The organic layer is washed with ice water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The obtained crude compound is purified by chromatography to yield E-1a. The following intermediates E-1 (table 43) are available in an analogous manner. The crude products E-1 are purified by chromatography if necessary. Table 51 # structure t_ret [min] [M+H]+ HPLC method E-1a 1.96 320 A E-1c 2.48 334/336 E Experimental procedure for the synthesis of E-2a

To a stirred solution of K-13a (4.50 g, 9.99 mmol, 1.0 eq.) and E-1a (3.72 g, 11.03 mmol, 1.1 eq) in acetonitrile (45.0 mL) is added potassium carbonate (2.76 g, 19.98 mmol, 2.0 eq) and the mixture is stirred at 60 °C under argon for 22 h. After complete conversion the reaction mixture is allowed to cool to rt, filtered and the solid is washed with acetonitrile. The combined solution is concentrated under reduced pressure and purified by chromatography to give E-2a. The following intermediates E-2 (Table 52) are available in an analogous manner starting from different intermediates K-13 and E-1 or alternative bromides. The crude products E-2 are purified by chromatography if necessary. Table 52 t_ret + HPLC # structure [M+H] [min] method E-2a 1.63 690 A O O N ^N _O O N N E-2c N 1.72 704 A N N N O H N S Experimental procedure for the synthesis of E-3a To a stirred solution of E-2a (4.26 g, 6.18 mmol, 1.0 eq.) in methanol (21.0 mL) is added sodium hydroxide solution (2 M in water, 6.18 mL, 12.35 mmol, 2.0 eq) and the reaction mixture is stirred at 45 °C for 1 h. After complete conversion the reaction mixture is concentrated under reduced pressure. The crude product is purified by chromatography yielding E-3a. The following intermediates E-3 (Table 53) are available in an analogous manner starting from different intermediates E-2. The crude products E-3 are purified by chromatography if necessary. Table 53 tret [M+H HPLC # structure [min] ]+ method E-3a 1.14 676 A E-3c 1.16 690 A Experimental procedure for the synthesis of I-1 To a stirred solution of E-3a (219 mg, 0.32 mmol, 1.0 eq.), (2S,4R)‐4‐hydroxy‐N‐{[4‐(4‐ methyl‐1,3‐thiazol‐5‐yl)phenyl]methyl}pyrrolidine‐2‐carboxamide (113 mg, 0.36 mmol, 1.1 eq.) and HATU (184 mg, 0.48 mmol, 1.3 eq.) in DMF (1.0 mL) is added DIPEA (0.16 mL, 0.97 mmol, 3.0 eq) and the reaction mixture is stirred at rt for 30 min. After complete conversion the reaction mixture is quenched with water, diluted with acetonitrile and purified by chromatography. The following compounds I (Table 54) are available in an analogous manner starting from different intermediates E-3 and A-4. Table 54 tret HPLC # structure [M+H]+ [min] method OH O N N _{N N} ^{N O} O O NH I-1 N N 0.78 975 H H₂ ^{N N} _N S O S N I-2 1.41 961 A OH O N N N O O N O NH I-3 N N S 1.47 989 A N N N N O H2N S Chiral Separation via chiral column chromatography of compounds I: If compounds I are obtained as mixtures of diastereomers they can be separated to single stereoisomers by chiral chromatography, e.g. as shown for I-3 which was separated into I-26 and I-27 (Table 55). Table 55 tret + HPLC # structure [M+H] [min] method S ^N HO HN 1.47 989 A N O O O N I-26 O N N ^N N 2.36 - I N N N HN O S I-27 1.47 989 A tret HPLC # structure [M+H]+ [min] method 3.22 - I Example 6: Synthesis of compounds according to formula (E) List of abbreviations (Table 56) Ac acetyl ACN acetonitrile aq. aqueous ATP adenosine triphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butyl c concentration CDI 1,1´-carbonyldiimidazole d day(s) TLC thin layer chromatography Davephos 2-dimethylamino-2'-dicyclohexylaminophosphinobiphenyl DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DCE dichloroethane DCM dichloromethane DEA diethyl amine DIPEA N-ethyl-N,N-diisopropylamine (Hünig´s base) DMA dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulphoxide DPPA diphenylphosphorylazide dppf 1.1´-bis(diphenylphosphino)ferrocene EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid equiv. equivalent(s) ESI electron spray ionization Et ethyl Et₂O diethyl ether EtOAc ethyl acetate EtOH ethanol h hour(s) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium HATU hexafluorophosphate HPLC high performance liquid chromatography i iso conc. concentrated LC liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide sln. solution Me methyl MeOH methanol min minute(s) MPLC medium pressure liquid chromatography MS mass spectrometry MTBE methyl tert-butyl ether NMM N-methylmorpholine NMP N-methylpyrrolidone NP normal phase n.a. not available PBS phosphate-buffered saline Ph phenyl Pr propyl PTSA p-toluenesulfonic acid Py pyridine rac racemic red. reduction Rf (R_f) retention factor RP reversed phase RRLC Rapid resolution liquid chromatography rt ambient temperature SFC supercritical fluid chromatography S_N nucleophilic substitution TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium TBTU tetrafluoroborate tBu tert-butyl TEA triethyl amine temp. temperature tert tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran t_Ret. retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane TsOH p-toluenesulphonic acid UPLC ultra performance liquid chromatography UV ultraviolet wt weight Preparation of the compounds according to the invention Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 µm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 µm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 µm, 50 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 µm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm). Different gradients of H₂O/acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H₂O/acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH. For the chromatography under basic conditions for Agilent systems H₂O/acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH4HCO3 + 50 mL NH3 (25 % in H2O) to 1 L with H2O). For Gilson systems the water is made alkaline as follows: 5mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28 % in H2O) are replenished to 1 L with H₂O. The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), Phenomenex Lux C2 (250 x 20 mm, 5 µm). The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridgeTM C18, 2.5 µm, 2.1 x 20 mm or XBridgeTM C18, 2.5 µm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 µm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 µm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 µm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy/UV-spectrometry The retention times/MS-ESI+ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time t_Ret. = 0.00. Method A HPLC Agilent 1100 system MS 1200Series LC/MSD(API-ES+/-3000V, Quadrupol, G6140) MSD signal settings Scan pos/neg 120 - 900m/z Detection signal 315 nm (bandwidth 170nm, reference off) Spectrum range 230 – 400 nm Peak width <0.01 min Column Waters, Xbridge C18, 2.5 µm, 2.1x20 mm column Column temperature 60°C Solvent A: 20mM NH₄HCO₃/ NH₃ in H₂O pH 9 B: ACN HPLC grade Flow 1.00 mL/min Gradient 0.00 – 1.50 min 10 % to 95 % B 1.50 – 2.00 min 95 % B 2.00 – 2.10 min 95 % to 10 % B Method C HPLC Agilent 1260 Series MS Agilent LC/MSD Quadrupole Detection MS: positive and negative mode Mass range 100 – 750 m/z Column Waters X-Bridge BEH C18, 2.5 µm, 2.1 x 30 mm XP Column temperature 45 °C Solvent A: 20 mM NH4HCO3/30 mM NH3 in H2O; B: ACN (HPLC grade) Flow 1.40 mL/min Gradient 0.00 – 1.00 min: 15% B to 95% B 1.00 – 1.30 min: 95 % B Method H UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 MSD signal settings Scan pos & Neg 100 – 1500, Source Votage: Capillary Vol(kV)- 3.50, Cone(V): 50 Source Temp: Desolvation Temp(°C): 350 Source Gas Flow: Desolvation (L/Hr): 750, Cone(L/Hr): 50 Detection signal Diode Array Spectrum Range: 200 – 400 nm; Resolution: 1.2nm Sampling rate 10 point/sec Column AQUITY UPLC BEH C181.7µm, 2.1X50mm Column temperature 35 °C Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow 0.6 mL/min Gradient 0.0 – 0.40 min 97% B 0.40 – 2.50 min 97 % to 2 % B 2.50 – 3.40 min 2 % B 3.40 – 3.50 min 2 % to 97 % B 3.50 – 4.0 min 97 % B GCMS Method U GC Agilent Technologies-7890B GC System with 7693 Auto Sampler and 5977A MSD Injection Temperature 230°C Column Flow 2.0 mL/min Solvent delay 1.5 min Split Ratio 10:01 Column Oven Temperature Program 100°C/1 min, 20°C/min/310°/5min Total run time 16 min Interface Temperature 150°C Ion Source Temperature 230°C Gas He Column & Column dimension ZB-5MS (30m X 0.32mm; 1µm) MSD Scan Range 50-900 Method V GC Agilent Technologies-7890B GC System with 7693 Auto Sampler and 5977A MSD Injection Temperature 230°C Column Flow 2.0 mL/min Solvent delay 1.5 min Split Ratio 10:01 Column Oven Temperature Program 40°C/2 min, 15°C /min/200°/1 min, 25°C/min/310°/0 min, Total run time 18 min Interface Temperature 150°C Ion Source Temperature 230°C Gas He Column & Column dimension ZB-5MS (30m X 0.32mm; 1µm) MSD Scan Range 50-900 Method W GC Agilent Technologies-7890B GC System with 7693 Auto Sampler and 5977A MSD Injection Temperature 230°C Column Flow 2.0 mL/min Solvent delay 1.5 min Split Ratio 10:01 Column Oven Temperature Program 60°C/3 min, 20°C/min/310°/2min Total run time 18 min Interface Temperature 150°C Ion Source Temperature 230°C Gas He Column & Column dimension ZB-5MS (30m X 0.32mm; 1µm) Method SFC-1 Make Waters UPC2-MS Soft Empower3 MS QDa Column CHIRALCEL OX-3(4.6*150MM) 3µm A-Solvent CO2 B-solvent ACN Total Flow 3g/min % of Co-Solvent 15 ABPR 1500psi Colum temp 30°C PDA range 200nm to 400nm Resolution 1.2nm MS Parameters - QDa MS scan range 100Da to 1000Da Cone voltage Positive scan 20V Negative Scan 15V The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center(s) exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist). Synthesis of spiroketone intermediates A Experimental procedure for the synthesis of A-2a To a suspension of 5-chloropentanenitrile (22.9 g, 195 mmol, 1.00 equiv.) in EtOH (136 mL) is added acetyl chloride (111 mL, 1.56 mol, 8.00 equiv.) dropwise at 0 °C. The reaction mixture is allowed to warm to rt and stirred for 12 h. The mixture is concentrated under reduced pressure and washed with Et2O and the crude product A-2a is used as the HCl salt directly in the next step without further purification (HPLC method: A; t_ret = 1.03 min; [M+H]+ = 164). Experimental procedure for the synthesis of A-3a Crude A-2a (HCl salt) (28.0 g, 140 mmol, 1.00 equiv.) and ethylene glycol (7.38 g, 119 mmol, 0.90 equiv.) are dissolved in DCM (300 mL) and stirred at rt for 6 d. The resulting suspension is concentrated under reduced pressure, diluted with Et₂O (200 mL) and filtered. The filtrate is concentrated under reduced pressure, taken up in DCM (200 mL) and treated with a KOH solution (2 M in water, 150 mL). The mixture is stirred at rt overnight keeping the phases intact. The phases are separated, the water phase is extracted with DCM (2x) and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude orthoester A-3a is used for the next step without further purification (HPLC method: A; t = 1.37 min; [M+H + ret ] = 163). Experimental procedure for the synthesis of A-4a Crude A-3a (22.3 g, 107 mmol, 1.00 equiv.), 1-cyclohexenyloxytrimethylsilane (16.4 mL, 82.3 mmol, 0.80 equiv.) and zinc chloride (10.2 g, 74.8 mmol, 0.70 equiv.) are dissolved in DCM (120 mL) and stirred at rt for 5 h. The reaction mixture is treated by addition of saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by NP- chromatography to give the desired compound A-4a (HPLC method: A; t_ret = 1.25 min; [M+Na]+ = 283). Experimental procedure for the synthesis of A-8a A-4a (14.9 g, 57.1 mmol, 1.0 equiv.) and sodium iodide (26.0 g, 171 mmol, 3.0 equiv.) are dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium thiosulfate solution. The organic phase is separated, dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product A-5a is used for the next step without further purification. A-5a (30 g, 85.0 mmol, 1.0 equiv.) is dissolved in THF. The mixture is treated with potassium tert.-butoxide (28.7 g, 256 mmol, 3.0 equiv.) at 0 °C and stirred at rt overnight. The reaction mixture is quenched by addition of water (2 mL), diluted by addition of Et2O and a saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography to give (racemic) compound A-6a (The reaction sequence A-1a à A-6a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem.2004, 19:3962-3967). Enantiomer A-6b can then be obtained after chiral separation via SFC using the following conditions: Column: Lux;Cellulose-4 (250mmX30mmX5µm), 90% CO2, 10% ACN, Flow: 90g/min, Temp: 30°C, enantiomer A-6b (SFC-method: SFC-1, tret=2.99min) as peak 2 after enantiomer elutes. Synthesis of diketones F When multiple HPLC retention times are reported it means that different tautomers are present. Experimental procedure for the synthesis of F-1a 4,6-Dichloropyrimidine-2-carboxylic acid methyl ester E-4a (2.00 g, 9.67 mmol, 1.00 equiv.) is dissolved in dry ACN (5 mL) under nitrogen atmosphere. Magnesium bromide diethyl etherate (2.99 g, 11.6 mmol, 1.20 equiv.), a solution of A-6b (2.38 g, 10.6 mmol, 1.10 equiv.) in ACN (5 mL) and DIPEA (2.67 mL, 14.5 mmol, 1.50 equiv.) is added and the reaction mixture is stirred at 50 °C for 20 h. After complete conversion, the reaction mixture is carefully quenched with 1 M HCl, diluted with water, extracted with DCM, the organic phases are dried, filtered, and concentrated to obtain crude F-1a. The crude compound is purified by NP chromatography. (HPLC method: H, tret = 2.50 min; [M+H] = 399/401). Experimental procedure for the synthesis of F-2a F-1a (10.0 g, 19.4 mmol, 1.00 equiv.) is dissolved in DMSO (10 mL), (1S)-1-[(2S)-1- methylpyrorolidin-2-yl]ethanol (2.76 g, 21.4 mmol, 1.10 equiv.) and DIPEA (6.78 mL, 38.8 mmol, 2.0 equiv.) are added and the solution is stirred at rt overnight. The reaction mixture is diluted with DCM and water. The organic phase is separated, evaporated and the resulting residue is purified by RP chromatography to afford F-2a. (HPLC-method: A, t_ret = 1.58/1.66 min; [M+H] = 492). Synthesis of isoxazole intermediates G Experimental procedure for the synthesis of intermediates G3 and G4 G-3a G-4a F-3a (1.10 g, 1.91 mmol, 1.0 equiv.) is dissolved in 1,4-dioxane (3 mL) and 50 % aq. Hydroxylamine is added (140 µL, 2.29 mmol, 1.2 equiv.). The reaction mixture is stirred overnight at rt. After full conversion of starting material, the reaction is diluted with aq. satd. NaHCO₃ solution and extracted three times with DCM. The organic phases are combined, dried, filtered and concentrated under reduced pressure to give the crude product. The crude mixture of G-1a and G-2a (1.00 g, 1.68 mmol, 1.0 equiv.) is dissolved in 1,4-dioxane (6 mL) and 4 M HCl aq. (2.11 mL, 8.44 mmol, 5.0 equiv.) is added. The reaction mixture is stirred 3 h at rt. After full conversion of starting material is observed, the reaction is diluted with aq. saturated NaHCO₃ solution and extracted three times with DCM. The organic phase is combined, dried, filtered and concentrated under reduced pressure to give the crude product. The crude product is dissolved in ACN and water, filtered, and purified by basic RP chromatography to give the desired product G-3a besides the corresponding isoxazole regioisomer G-4a. The following intermediates G-3 and G-4 (Table 57) are available in an analogous manner from suitable intermediates F. The crude products are purified by chromatography if necessary. Table 57 # structure t [min] [M+ + ret H] HPLC method G-3a 0.67 430 C G-3b 1.57 445 A Experimental procedure for the synthesis of G-9 and G-10 (method IV) G-4b (150 mg, 0.3 mmol, 1.0 equiv.), 2-hydroxythiazole (39.4 mg, 0.39 mmol, 1.30 equiv.) t-BuONa (2 M in THF, 210 µL, 0.42 mmol, 1.4 equiv.) is dissolved in THF (1.5 mL) and stirred at 80 °C for 18 h. After complete conversion, the reaction mixture is extracted 3 times with DCM/H2O. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography to give the desired product G-10a. The following intermediates G-9 and G-10 (Table 58) are available in an analogous manner from G-3b and G-4b. The crude products are purified by chromatography if necessary. Table 58 # structure t [m + ret in] [M+H] HPLC method G-10a 0.92 504 C G-9i 1.04 610 C Experimental procedure for the synthesis of G-9 G-9h (297 mg, 476 µmol, 1.0 equiv.) is dissolved in DCM (0.91 mL) and trifluoracetic acid (0.99 mL, 4.76 mmol, 10.0 equiv.). The reaction is stirred 4 h at rt. After complete conversion, the dissolved is removed under reduced pressure. The residue is dissolved in DCM and extract with aq. saturated Na2CO3. The combined organic phases are dried, filtered, and concentrated under reduced pressure. The residue is purified by RP chromatography to give G-9s. The following intermediates G-9 (Table 59) are available in an analogous manner from G-9h and G-9i. The crude products are purified by chromatography if necessary. Table 59 # structure t + ret [min] [M+H] HPLC method G-9s 1.53 524 A 0.58 G-9t 510 C 0.73 Experimental procedure for the conversion of G-9 to II To a solution of G-9a (75.0 mg, 0.149 mmol, 1.0 equiv.) and mol. sieves (3Å) in anhydrous methanol (4 mL) under an argon atmosphere, are added malononitrile (20.7 mg, 0.297 mmol, 2.0 equiv.), sulfur (7.15 mg, 0.223 mmol, 1.5 equiv.) and ß-alanine (16.7 mg, 0.178 mmol, 1.2 equiv.). The reaction mixture is stirred at 80 °C overnight. After complete conversion, the mixture is cooled to rt, filtered and extracted with DCM and aq. saturated NaHCO₃. The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in in acetonitrile and water and purified by basic RP chromatography to give the desired product II- 1. The following compounds II (Table 60) are available in an analogous manner from the corresponding ketones G-9. The crude products are purified by chromatography if necessary. Table 60 # structure t [min] [M+H + ret ] HPLC method II-1 1.46 585 A # structure t [min] [M + ret +H] HPLC method II-9 1.49 590 A Example 7: Synthesis of compounds according to formula (F) The synthesis of compounds according to formula (F) has been described in WO2021/213800. Example 8: Assessment of Survivin levels in vitro and in vivo – Materials and Methods Cell Titer Glow (CTG) assay Cell Titer Glow Cell Viability Assay (Promega) was performed in two different cell lines (Table 1) using 384-well plates (VIEWPLATE-384 TC, Perkin Elmer, cat no.60007480).11 different KRASG12C and 9 KRASG12D inhibitors were used. Both cell lines were grown according to the ATCC standard protocol, as shown in Table 61. Table 61. Cell culture conditions Cell line name Growth Medium and culture conditions type NCI-H358 adherent RPMI-1640 ATCC-Formulation (Gibco #A10491) + 5% FCS SW1990 adherent Leiboviz´s L-15 (Gibco #11415-049) + 10% FCS + 0% CO₂ NCI-H358 and SW1990 cell lines were seeded in 384-well plates with the density of 500 cells/well in 40 µL total medium in triplicates. The following day the cells were treated with KRASG12D and KRASG12C inhibitors for 120 hours with the starting concentration of 3 µM followed by 1:3 dilutions. On day 5, CTG reagent was added to each well and luminescence was measured at 490 nm with the Enspire spectrophotometer. IC50 value was measured by using the internal BI statistical program MegaLab. Based on the results, compounds with high IC50 (IC50 over 100 nM for G12C inhibitors and IC50 over 300 nM for G12D inhibitors) were excluded. The remaining compounds were subsequently tested with Human Survivin ELISA Kit (Abcam, ab183361). Human Survivin ELISA assay Cells were grown in T175 flasks to a confluency of 90%. H358 cells were treated with 100 nM of G12C inhibitors and SW1990 cells with 300 nM of G12D inhibitors. Exosome-depleted FBS was added to the media (Gibco, A2720801). 72 hours post treatment cell culture supernatant was collected and cells harvested according to the Human Survivin ELISA Kit protocol. Exosome extraction Exosomes were isolated from cell culture media with the exoEasy Maxi Kit (QIAGEN, 76064), as described in the manufacturer´s instructions. Briefly, cell culture supernatant was first filtered with 0.8 µm filter (Sartorius Minisart NML, cat. No. 16592). Then, 1 volume of the filtered cell culture supernatant was mixed with 1 volume of buffer XBP. The mixture was then added on the exoEasy spin column and centrifuged. Columns were subsequently washed, and exosomes eluted in 400 µL of Buffer XE. RNA extraction from tumors Frozen tumors from in vivo studies were cut with a scalpel to size of approximately 5x5 mm. Tumors were then moved into a 2 ml Eppendorf tube containing 1 steel bead.1 mL of Trizol (Quiazol #79306 200ml Qiagen) was added and each sample was homogenized with the tissueLyser II (Qiagen). Tubes were centrifuged, supernatant was transferred to a new tube, gDNA Eliminator Solution and Bromo3chloropropane were added to each sample. Samples were centrifuged again, and subsequent RNA isolation was done by column system RNeasy MiniKit ((250) #74106 Qiagen) following manufacturer's instructions. Briefly, after centrifugation, aqueous phase was mixed with 70% ethanol in ratio 1:1 and added to the supplied column. Columns were centrifuged and washed several times as suggested. RNA was eluted in 40 µl Nuclease free H2O. RNA content was measured with QIAxpert Slide - 40 (25) #990700 - RNeasy modus and RIN values established on Tape Station (Agilent). Isolated RNA was then further processed for sequencing. RNA extraction from exosomes Exosomal RNA was isolated from plasma by exoRNeasy Serum/Plasma Maxi Kit (cat. no. 77064) following the manufacturer’s instructions. Up to 4 ml of plasma per group of mice were pooled, filtered, and bound with XBP buffer in 1:1 ratio. The mixture was then added onto the supplied column, centrifuged, and washed. QIAzol was then subsequently added onto the membrane, tubes were centrifuged, and the collected lysate was transferred into a new tube. Chloroform was added to the mixture, tubes were centrifuged and the upper aqueous phase transferred to a new collection tube. Then 2 volumes of 100% ethanol were added to the tube and pipetted onto an RNeasy MinElute spin column. After centrifugation columns were washed and RNA was eluted in 14 μl Nuclease free H2O. Like for tumors, RNA was measured with QIAxpert Slide and TapeStation and subsequently sequenced. MSD® 96-well S-PLEX Survivin Assay for analysis of plasma samples Plasma samples from mouse in-vivo efficacy and biomarker studies or human plasma samples were centrifuged for 5 minutes at 10000 rcf and were then tested at 2-fold dilution in an MSD® 96-well S-PLEX Assay detecting human Survivin according to manufacturer’s instructions. In short, the assay is (1.) assembled, by washing the plate and incubating with coating solution containing a specific Survivin capture antibody for 1 hour at RT with shaking. After a wash step, blocking solution is added, followed by calibrator and sample solutions. The assay is incubated for 16-18 hours at RT, with shaking. On the next day, the plate is washed and incubated with (2.) TURBO-BOOST solution containing the specific Survivin capture antibody for 1 hour at RT on a shaker. After another wash step, (3.) S-PLEX Enhancement solution is added for 30 minutes at RT with shaking. The plates are then washed again and incubated under shaking for 1 hour at 27°C with (4.) S-PLEX Detection Solution. Finally, the plates are (5.) read on the MSD instrument after a wash step and the addition of MSD GOLD Read Buffer B. (6.) Data analysis is performed with the MSD Discovery software and visualised in GraphPad Prism. MSD® 96-well S-PLEX Survivin Assay for analysis of in-vitro experiments SNU1196 cells were grown in a T175 flasks to a confluency of 90%. SNU1196 cells were treated with 11 different GDPi inhibitors (500 nM). Exosome-depleted FBS was added to the media (Gibco, A2720801).72h post treatment cell culture supernatant was collected, and cells were harvested according to the Abcam Human Survivin ELISA Kit protocol with the cell lysis buffer provided in the kit. Exosomes were isolated from the supernatant according to the exoEasy Maxi Kit (QIAGEN, 76064) and the protein concentration of isolated exosomes and cell lysates was determined by Quick Start™ Bradford Protein Assay (Bio-Rad, 500-0202). Survivin levels were then analyzed using the MSD® 96-well S-PLEX Assay as described above. Human plasma samples Human plasma samples from various indications were analyzed to assess differences in median baseline Survivin level and the inter-subject biological variance. Plasma samples from healthy volunteers were additionally obtained. CRC patient (n=21) plasma samples were either purchased from a commercial vendor (BioIVT) or were from biobanking samples from a former clinical study conducted under a biomarker research proposal (2023-brp-0004). PDAC plasma samples (n=4) were purchased from a commercial vendor (BioIVT). NSCLC serum samples (n=31) were left-over samples from a completed clinical study (1280.16). Example 9: Assessment of Survivin levels in vitro and in vivo - Results Example 9.1: Survivin as biomarker Survivin expression in tumorigenic and healthy cells was analysed and, as shown in Fig. 1A, Survivin was detected in exosomes released by cells from the pancreatic adenocarcinoma epithelial cell line HPAC, but not in exosomes from healthy volunteers. Plasma Survivin levels were additionally measured in healthy controls (n= 30) and cancer patients (CRC (n=21), PDAC (n=4), and NSCLC (n= 31)) using the MSD S-Plex ELISA assay. The results show that the cancer population exhibit an about 2.5-fold higher (median) baseline of Survivin levels compared to healthy volunteers (Fig. 1B). Thus, Survivin is upregulated in cancer patients versus healthy controls. In addition, CRC patients in the placebo group of a Nintedanib trial (biobanking samples from 1199.52) showed stable or increasing Survivin levels, thereby indicating a possible correlation between Survivin and progressive disease (Fig.1C). These findings are in line with earlier published data (Chang et al. 2021), which showed expression of Survivin in tumours and, more importantly, associated high Survivin levels with therapy resistance. To further analyse the expression pattern of Survivin upon treatment with various anti-KRAS drugs, an in-vivo NSCLC CDX model (cell-line derived xenograft model using non-small cell lung cancer HCC461 cell line) was employed. Survivin was found to be significantly downregulated in a dose dependent manner (Fig.2). Thus, the biomarker study in vivo showed a dose-dependent Survivin downregulation after 3 days of daily treatment with the KRASG12D inhibitor compound G12D-cpd#2 (see Table 1). BIRC5-encoded Survivin levels were further tested by ELISA in GP2D and HPAC (G12D mutant) cells treated with increasing doses of a KRASG12D inhibitor for 2 hours (top panel) and 24 hours (bottom panel) (Fig.3). Survivin expression decreased at the IC50 dose (8 nM for GP2D and 46 nM for HPAC) at 24 hours and not at 2 hours, suggesting that Survivin may be a late biomarker of KRAS response. The inventors have further shown that Survivin is downregulated in cell lysates (Fig. 4, 7), media (Fig. 5, 8) and exosomes (Fig, 6, 9), respectively, of NCI-H358 cells (Fig. 4-6) and SW1990 cells (Fig.7-9) following treatment with 100 nM (Fig.4-6) or 300 nM (Fig.7-9) of 11 different KRASG12C (Fig.4-6) or 9 different KRASG12D inhibitors (Fig.7-9) (Figs.4-9). Survivin was also found to be downregulated following treatment of human adenocarcinoma cells of the PC9 YMVA-5 cell line with an HER2 inhibitor (Fig.10). Similar data were obtained using two different GDP-KRAS inhibitors, compounds Cpd#a and Cpd#b (Fig. 11). Further experiments showed Survivin modulation in SNU1196 cells (KRAS-WT amp) treated with various GDP-KRAS inhibitors: SNU1196 cells harboring KRAS-WT amplification were treated with 11 different GDP-KRAS inhibitors (500nM) for 72h. The S-Plex Survivin assay was used to measure Survivin levels in cell lysates and exosomes. As shown in Fig.13 A and B, a strong Survivin downregulation was observed with all the compounds tested in cell lysates and exosomes, thereby confirming the inhibition of the KRAS downstream pathway by these compounds. Lastly, the inventors measured Survivin levels in vivo (Fig. 12). Mice were injected s.c. with SW1990 cells. When tumors reached 200 mm3, mice were treated with the KRASG12D inhibitor G12D-cpd#2 or vehicle for 3 days. Tumors and blood from each animal were collected 3 days post treatment. RNA was isolated from both tumors and plasma (exosomes) and sequenced by RNA-seqencing. Dose-dependent modulation of Survivin was observed in both tumors and exosomes. Example 9.2: Invivo mouse studies demonstrating dose-dependent modulation of Survivin in plasma A Mesoscale Diagnostic (MSD) S-Plex assay was employed to detect Survivin in mouse and human plasma at fg/ml-levels of concentration. Interestingly, using this highly sensitive MSD S-Plex assay a dose-dependent modulation of Survivin in plasma was demonstrated (Fig.14), indicating for the first time that Survivin is a pharmacodynamic (PD) marker of KRAS inhibition. In one example, mice were injected subcutaneously with H358 KRAS G12C mutant cells. When tumors reached approximately 200 mm3, mice were treated either with vehicle or sotorasib (3, 10, 30 and 100mg/kg) once a day for three days. Blood was collected from each mouse, plasma isolated and Survivin analyzed using the S-Plex Survivin assay. As shown in Fig. 14 A and B, Survivin levels in plasma (Fig. 14B) showed the same dose-dependent modulation as in tumors (14A), indicating that Survivin is a PD marker of response to KRAS inhibitors and Survivin plasma levels can be used for dose finding in dose escalation phase and for monitoring treatment efficacy. A similar correlation could be shown for MKN1 tumors (Fig.14C) and mouse plasma (Figure 14D) after treatment with an exemplary GDP-KRAS inhibitor. Again, mice were injected subcutaneously with MKN1 (GI, KRASWTamp) cells. When tumors reached approximately 200 mm3, mice were treated either with vehicle or the GDP-KRAS inhibitor once a day for three days. Blood was collected from each mouse, plasma isolated and Survivin analyzed using the S-Plex Survivin assay. Example 9.3: Survivin downregulation in mouse plasma and correlation of plasma Survivin and tumor volume (TV) in end of efficacy studies in KRAS-WTamp , G12V and G12D cell-line derived xenograft (CDX) models SNU1196 (CRC, KRAS-WT amp; Fig.15 A and B), CAPAN 2 (KRAS-G12V; Fig.15 C-E), and PK59 (KRAS-G12D) cells, respectively, were injected subcutaneously in immunocompromised mice. When tumors reached approximately 200 mm3, mice were treated with either an exemplary GDP inhibitor (same inhibitor as in 9.2) or the G12D inhibitor shown in Table 1 as G12D-cpd#2. At the end of the efficacy study (day 21), blood/plasma was collected from each individual mouse and Survivin levels were analyzed using the S-Plex assay. As shown in Figs.15 (A) and (B), Survivin is downregulated in mouse plasma at the end of the efficacy study with an exemplary GDP-KRAS inhibitor in a KRAS-WT amplified CDX model (day 21; Fig. 15A) and the Survivin levels are directly correlated in vivo with tumor volume (Fig. 15B), showing a strong positive correlation between plasma Survivin levels and tumor volume at end of efficacy studies. Fig.15 (C) and (D) show the downregulation of Survivin in mouse plasma at the end of the efficacy study with an exemplary GDP-KRAS inhibitor in a KRAS-G12V in vivo model in a dose dependent manner (day 21) and shows that Survivin is not detected in untreated mice not bearing tumors. Fig.15 (E) shows that also in this model the Survivin levels are directly correlated in vivo with tumor volume, evidencing a strong positive correlation between plasma Survivin levels and tumor volume at end of efficacy studies. Fig. 15 (F) shows the downregulation of Survivin in mouse plasma at the end of the efficacy study with the KRAS-G12D inhibitor in a KRAS-G12D in vivo model (day 21). Fig. 15 (G) additionally shows median tumor volumes over time for the two different dosages (same experiment as in F) and as compared to a control. Fig.15 (H) shows that also in this model the Survivin levels are directly correlated in vivo with tumor volume, showing a strong positive correlation between plasma Survivin levels and tumor volume at end of efficacy studies. As evidenced by these figures, Survivin levels are directly correlated in vivo with tumor volume, showing a strong positive correlation between plasma Survivin levels and tumor volume at end of efficacy studies. Therefore, Survivin can serve as a surrogate endpoint biomarker of KRAS inhibition and can conveniently be employed as a circulation biomarker in patient blood samples for monitoring treatment efficiency during tumor treatment, thereby reducing the burden on patients associated with invasive tumor biopsies or cumbersome imaging approaches. Example 9.4: Downregulation of Survivin levels in tumors and plasma and correlation between plasma Survivin levels and tumor volume (TV) in end of efficacy studies in CDX models treated with a HER2 inhibitor (HER2-cpd#1). In a first set of experiments, and as shown in Fig. 16, downregulation of Survivin levels was analysed in tumors (16A) as well as in plasma (16B) after treatment with the HER2 inhibitor HER2-cpd#1 in a NSCLC Her2 mutant CDX (PC9 YMVA5). In a second set of experiments, either NC-N87, SKGT-2 or NCI-2170 cells were injected subcutaneously in immunocompromised mice. When the tumors reached approximately 200 mm3, mice were treated with either vehicle or HER2-cpd#1. At the end of the efficacy study (day 21) blood/plasma was collected from each individual mouse and Survivin levels analyzed using the S-Plex assay. As shown in Fig.16C-E, Survivin levels in vivo are directly correlated with tumor volume and show a strong positive correlation between Survivin levels and tumor volume (TV). Thus, Survivin can also serve as a surrogate endpoint biomarker of Her2 inhibition and can conveniently be employed as a circulation biomarker in patient blood samples for monitoring treatment efficiency during tumor treatment, thereby reducing the burden on patients associated with invasive tumor biopsies or cumbersome imaging approaches. Example 9.5: Downregulation of Survivin levels (RNA) by the MDM2 inhibitor MDM2i- cpd#1 in vivo in TP53 WT CDX and PDX models Survivin RNA levels were also analysed in two PDX models treated with the MDM2i-cpd#1. Fig. 17A shows that Survivin RNA is downregulated in a CRC PDX model (Co10748,TP53 WT) and Fig.17B shows downregulation in PDX models of Malignant Peripheral nerve sheath tumors (TP53WT). Briefly, for the CRC PDX (Co10748,TP53 WT), mice were treated with a single dose of 5mg/kg body weight of the MDM2i-cpd#1 and tumors were collected after 24 hours and analyzed. For the PDX models of Malignant Peripheral nerve sheath tumors (TP53WT), mice were treated with a single dose of 1.5mg/kg body weight of the MDM2i-cpd#1 and tumors were again collected after 24 hours and analyzed. The results show that also for treatment with a MDM2 inhibitor, Survivin can serve as a surrogate endpoint biomarker of MDM2 inhibition and can conveniently be employed as a circulation biomarker in patient blood samples for monitoring treatment efficiency during tumor treatment, thereby reducing the burden on patients associated with invasive tumor biopsies or cumbersome imaging approaches. References Aboy M et al. 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Claims

What is claimed is: 1. A method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting KRAS protein or a mutant of a KRAS protein, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample.

2. A method of determining the responsiveness of a cancer patient to a treatment with a compound inhibiting the interaction between MDM2 and p53, the method comprising - measuring the level of Survivin in a first sample obtained from the patient prior to treatment with the compound, - measuring the level of Survivin in a second sample obtained from said patient during or after treatment with the compound, - comparing the level of Survivin in said second sample with the level of Survivin in said first sample, wherein the patient is determined to be responsive to the treatment with said compound when the level of Survivin in the second sample is decreased as compared to the level of Survivin in the first sample.

3. The method of claim 1 or 2, wherein said first and/or said second sample(s) is/are (a) blood, blood plasma, or blood serum sample(s).

4. The method of any one of claims 1 to 3, wherein the step of measuring the level of Survivin in a sample comprises the isolation of exosomes from said sample and measuring the level of Survivin comprised in said exosomes.

5. The method according to any of claims 1 – 4, wherein the level of Survivin is measured using a Survivin-specific assay selected from the group consisting of Western Blot, ELISA, RIA, FACS and the MSD® S-PLEX technology.

6. The method according to any of claims 1 – 5, wherein the cancer is a KRAS dependent cancer, preferably a KRAS dependent cancer selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC).

7. The method according to any of claims 1 and 3 – 6, wherein the compound inhibiting KRAS protein or a mutant of a KRAS protein is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP- KRAS inhibitors or degraders, and HER2 inhibitors or degraders.

8. The method according to any one of claims 1 and 3 – 7, wherein the KRAS(G12C) inhibitor or degrader is selected from the group consisting of: sotorasib (AMG510), adagrasip (MRTX849), G12C-cpd#1, G12C-cpd#2, G12C-cpd#3, G12C-cpd#4, G12C- cpd#5, G12C-cpd#6, G12C-cpd#7, G12C-cpd#8, G12C-cpd#9, G12C-cpd#10, and G12C-cpd#11.

9. The method according to any one of claims 1 and 3– 7, wherein the KRAS(G12D) inhibitor or degrader is selected from the group consisting of MRTX1133, G12D-cpd#2, G12D-cpd#3, G12D-cpd#4, G12D-cpd#5, G12D-cpd#6, G12D-cpd#7, G12D-cpd#8, and G12D-cpd#9.

10. The method according to any one of claims 1 and 3 – 7, wherein the GDP-KRAS inhibitor or degrader is selected from the group consisting of GDP-cpd#1, GDP-cpd#2, GDP-cpd#3, GDP-cpd#4, GDP-cpd#5, GDP-cpd#6, GDP-cpd#7, GDP-cpd#8, GDP- cpd#9, GDP-cpd#10, GDP-cpd#11, GDP-cpd#12, GDP-cpd#13 and GDP-cpd#14.

11. The method according to any one of claims 1 and 3 – 7, wherein the HER2 inhibitor is a compound according to formula F, preferably wherein the compound is HER2-cpd#1.

12. The method according to any one of claims 2 – 6, wherein the compound inhibiting the interaction between MDM2 and p53 is MDM2i-cpd#1.

13. A compound inhibiting KRAS protein or a mutant of a KRAS protein for use in treating a cancer patient, i) wherein the KRAS inhibitor is selected from the group consisting of KRAS(G12C) inhibitors or degraders, KRAS(G12D) inhibitors or degraders, GDP-KRAS inhibitors or degraders, and HER2 inhibitors or degraders; and ii) wherein the patient has been determined to be responsive to the treatment with said compound according to the method of any one of claims 1 to 11.

14. A compound inhibiting the interaction between MDM2 and p53 for use in treating a cancer patient, i) wherein the compound inhibiting the interaction between MDM2 and p53 is MDM2i-cpd#1; and ii) wherein the patient has been determined to be responsive to the treatment with said compound according to the method of claim 12.

15. A method of determining whether a compound inhibiting KRAS protein or a mutant of a KRAS protein, or a compound inhibiting the interaction between MDM2 and p53, is efficacious in the treatment of a cancer, and/or in monitoring a cancer patient´s response to said treatment, said method comprising at least the steps of - providing a first sample from the patient, - measuring the level of Survivin in said first sample from the patient, - administering said compound inhibiting KRAS protein or a mutant of a KRAS protein to the patient, then - providing a second sample from the patient, - measuring the level of Survivin in said second sample, - comparing the levels of Survivin measured in the first and second sample, and - optionally repeating the fourth to sixth step, wherein a decreased level of Survivin in the second sample indicates an effective response.

16. Use of Survivin in a method for determining the ability of a compound to inhibit KRAS protein or a mutant of a KRAS protein, or of a pharmaceutical formulation comprising said compound inhibiting KRAS protein or a mutant of a KRAS protein, to treat cancer.

17. The use according to claim 16, wherein the level of Survivin is determined in a sample obtained from the patient prior to the treatment, and in at least one sample obtained from the patient after treatment with said compound inhibiting KRAS protein or a mutant of a KRAS protein, and wherein a decrease in the level of Survivin after treatment with said compound inhibiting KRAS protein or a mutant of a KRAS protein is indicative of the compound’s ability to treat said cancer.

18. Use of Survivin in a method for determining the ability of a compound to inhibit the interaction between MDM2 and p53, or of a pharmaceutical formulation comprising said compound inhibiting the interaction between MDM2 and p53, to treat cancer.

19. The use according to claim 18, wherein the level of Survivin is determined in a sample obtained from the patient prior to the treatment, and in at least one sample obtained from the patient after treatment with said compound inhibiting the interaction between MDM2 and p53, and wherein a decrease in the level of Survivin after treatment with said compound inhibiting the interaction between MDM2 and p53 is indicative of the compound’s ability to treat said cancer.

20. A kit of parts, comprising the means for determining the level of Survivin in samples provided from a patient suffering from cancer, preferably from a KRAS-dependent cancer, and instructions for how to perform said method according to any one of claims 1 – 12 and 15.