EGFR inhibitor-functionalized albumin-binding platinum compounds for cancer therapy

Abstract

The present invention relates to novel EGFR inhibitor-functionalized albumin-binding platinum compounds of formula (I), including in particular EGFR inhibitor-functionalized albumin-binding oxaliplatin and carboplatin derivatives, as well as their use in therapy, particularly for the treatment or prevention of cancer. (Formula (I))

Description

[0001] New PCT patent application

[0002] Universitat Wien; Medizinische Universitat Wien

[0003] Vossius Ref.: AJ1770 PCT BS

[0004] 1

[0005] EGFR inhibitor-functionalized albumin-binding platinum compounds for cancer therapy

[0006] The present application claims the benefit of priority of European patent application 5 EP24221884.0, filed on December 19, 2024, which is incorporated herein by reference in its entirety.

[0007] The present invention relates to novel EGFR inhibitor-functionalized albumin-binding platinum compounds of formula (I), including in particular EGFR inhibitor-functionalized albumin-binding 0 oxaliplatin and carboplatin derivatives, as well as their use in therapy, particularly for the treatment or prevention of cancer.

[0008] The application of platinum drugs in clinical cancer therapy roots in 1969, when Rosenberg et al. discovered the promising anticancer activity of the platinum(ll) complex cisplatin (Rosenberg, 5 B. et al., Nature, 1969 222(5191):385-6, doi: 10.1038 / 222385a0). The anticancer activity of cisplatin is mainly based on the formation of platinum-DNA adducts, which leads to distortion of the helical DNA structure. This results in DNA strand breaks, inhibition of DNA replication and transcription, and as a final consequence cell cycle arrest and apoptosis. Based on its very strong anticancer activity, cisplatin or its successors carboplatin and oxaliplatin are nowadays 0 an inherent part in every second chemotherapeutic scheme.

[0009] Certain derivatives of such platinum drugs have also been proposed, e.g., in: Abramkin, S. A. et al., J Med Chem, 2010, 53(20):7356-64, doi: 10.1021 / jm100953c; Abramkin, S. et al., Dalton Trans, 2012, 41(10):3001-5, doi: 10.1039 / c2dt12024k; Abramkin, S., “Synthese und 5 Charakterisierung Neuartiger Oxaliplatin Analoga”, University of Vienna, Dissertation, 2012; and WO 2015 / 102922. However, treatment with platinum drugs is always accompanied (besides occurrence of intrinsic or acquired resistance) by (severe) side effects, which include besides nausea and vomiting, also nephrotoxicity or neurotoxicity. Consequently, there is significant interest in the development of new strategies to enhance tumor targeting (and consequently to 0 reduce side effects) of platinum drugs.

[0010] The anticancer activity of platinum(IV) complexes was discovered together with cisplatin in the 1960s. So far, three platinum(IV) drugs have been tested in clinical trials: JM9 (iproplatin), tetraplatin (ormaplatin), and JM-216 (satraplatin). In general, platinum(IV) complexes are 5 kinetically more inert than their platinum(ll) counterparts and have consequently a lower reactivity with biomolecules. Probably due to their reduced cytotoxicity, platinum(IV) drugs have been less extensively studied and developed than platinum(ll) compounds. Nowadays, platinum(IV) complexes are considered as prodrugs, which undergo reduction in the tumor tissue. During this process, the axial ligands are released and the corresponding active square-planar platinum(ll) analogues are formed. Especially these axial ligands are of paramount interest, as they can be used for modulating a range of physicochemical properties such as lipophilicity, stability and reduction potential. Furthermore, the ligands can be designed to target specific tumor sites or to attach additional bioactive components.

[0011] Albumin is the most abundant plasma protein (35-50 g / L in human plasma) with a molecular weight of 66.5 kDa. Albumin has an average half-life of 19 days and is, like most plasma proteins, synthesized in the liver. The physiological functions of albumin are multiple and diverse. For example, it is the major protein responsible for the colloid osmotic pressure of the blood. Most importantly with respect to drug delivery, albumin, a physiological carrier for several molecules such as bilirubin or metal ions, has very potent binding properties and is known to bind several therapeutic drugs (e.g. penicillins). Moreover, it is known that, due to the combination of leaky blood capillary with the absence / defect of lymphatic drainage, albumin accumulates in malignant tissue (also called enhanced permeability and retention (EPR) effect). Consequently, strategies to enhance binding of drugs to serum albumin are an attractive and effective approach for targeted drug delivery into the tumor tissue. Currently, there are several attempts to use the specific tumor accumulation of albumin also for cytotoxic drugs especially paclitaxel, sirolimus and doxorubicin. Thus, Abraxane®, an albumin paclitaxel-containing nanoparticle, has been approved for the treatment of non-small cell lung cancer (NSCLC) as well as non-responding or relapsed breast cancer, and the sirolimus-containing nanoparticle Fyarro was approved for the treatment of malignant perivascular epithelioid cell tumors (PEComa) in 2024. Moreover, the maleimide-containing doxorubicin derivative aldoxorubicin (INNO-206) has successfully finished phase III clinical trials. Consequently, the effectiveness and advantages of albumin as a tumortargeting strategy have already been proven in the clinical situation.

[0012] In a study by Pichler Vet al. (Chem. Commun. 2013; 49(22):2249-51, doi: 10.1039 / c3cc39258a), the first bismaleimide-containing, albumin-binding platinum(IV) drug KP2156 was synthesized together with the respective succinimide derivative KP2157, which was found to possess no reactivity towards albumin. In particular, SEC-ICP-MS measurements using bovine blood serum proved specific binding of KP2156 to the albumin-containing protein fraction, while KP2157 was exclusively detected in the low molecular weight fraction.

[0013]

[0014] KP2299

[0015] To test the impact of albumin binding on the anticancer activity of the new compounds in vivo, the murine CT-26 colon cancer model was used (the use of this syngeneic murine tumor model was necessary due to the importance of the immune system for the anticancer activity of oxaliplatin; Tesniere A et al., Oncogene, 2010, 29(4):482-491, doi: 10.1038 / onc.2009.356; Jungwirth U et al., Mol Pharmacol, 2012, 81(5):719-28, doi: 10.1124 / mol.111.077321). Both platinum complexes were well tolerated with no significant loss of body weight. However, in comparison to KP2157, the bismaleimide-functionalized derivative KP2156 displayed a significantly higher anticancer activity, resulting in a distinctly reduced mean tumor burden based on the induction of apoptotic cell death (Schueffl H. et al., Chem Sci, 2021, 12(38):12587-12599, doi: 10.1039 / d1sc03311e). Subsequently, several monomaleimide platinum(IV) complexes (e.g. KP2299 and KP2551) were developed (Mayr, J. et al., J Biol Inorg Chem, 2017, 22 (4): 591-603, doi: 10.1007 / s00775-017-1450-7; WO 2017 / 097986), which were also highly superior to the approved platinum(ll) therapeutics.

[0016] However, these developments revealed that the compounds had only limited activity against drug-resistant cancer types. One mechanism that frequently leads to drug resistance due to enhanced DNA repair capacities in cancer cells is activation of the epidermal growth factor receptor (EG FR) signaling pathway (Talukdar S. et al., Advances in cancer research, 2020, 147, 161-188, doi: 10.1016 / bs.acr.2020.04.003; Rodemann H. P. et al., Int J Radiat Biol, 2007, 83, 781-791, doi: 10.1080 / 09553000701769970). This hypothesis is supported by the observation that the combination of platinum drugs with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has shown strong synergistic activities not only in preclinical models (Wu J. F. et al., Oncol Rep, 2016, 36, 3251-3258, doi: 10.3892 / or.2016.5156; Xu J. M. et al., Biochem Pharmacol, 2003, 66, 551- 563, doi: 10.1016 / s0006-2952(03)00291-0; Lee J. G. et al., Neoplasia, 2015, 17, 190-200, doi: 10.1016 / j.neo.2014.12.008), but also in clinical studies (e.g. Wu Y. L. et al., Lancet Oncol, 2013, 14, 777-786, doi: 10.1016 / S1470-2045(13)70254-7; Boutsikou E. et al., OncoTargets Ther, 2013, 6, 125-134, doi: 10.2147 / OTT. S42245; Gelibter A. J. et al., Curr Med Res Opin, 2007, 23, 2117-2123, doi: 10.1185 / 030079907X226113).

[0017] Clinically, small-molecular EGFR-TKIs (such as erlotinib, gefitinib or afatinib) were used mainly in lung cancer patients, where the EGFR signaling pathway is frequently constitutively activated by EGFR mutations (e.g. deletion in exon 19 delE746-A750 or the point mutation L858R) (Okabe T. et al., Cancer Research, 2007, 67(5), 2046-53, doi: 10.1158 / 0008-5472. CAN-06-3339). However, despite initial response, rapid occurrence of acquired EGFR-TKI resistance is observed, which is mediated e.g. by the EGFR point mutation T790M. This led to the development of third-generation EGFR inhibitors such as osimertinib, which specifically targets cells with T790M mutation (Ramalingam S. S. et al., J Clin Oncol, 2018, 36(9), 841-849, doi: 10.1200 / JCG.2017.74.7576; WO 2021 / 243596). Notably, the problem of EGFR-TKI resistance development remains and e.g. activation of alternative signaling pathways such as c-MET, or uncoupling of the EGFR-downstream signaling pathway by loss of tumor suppressors such as PTEN are frequently observed (Liu Q. et al., Mol Cancer, 2018, 17(1), 53, doi: 10.1186 / s12943-018-0793-1). Interestingly, osimertinib shows a potent synergism with carboplatin, which led to the approval of this combination in 2024 (Cooper A. J. et al., Nat Rev Clin Oncol, 2022, 19(8), 499-514, doi: 10.1038 / s41571 -022-00639-9; Zalaquett Z. et al., Cancer Treat Rev, 2023, 116, 102557, doi: 10.1016 / j.ctrv.2O23.102557; Zhang J. W. et al., Chin J Cancer, 2014, 33(2), 105-14, doi: 10.5732 / cjc.012.10274; Planchard D. et al., N Engl J Med, 2023, 389(21), 1935-1948, doi: 10.1056 / NEJMoa2306434).

[0018] The present inventors hypothesized that coupling of a third-generation EGFR inhibitor to an albumin-targeted platinum core could improve the therapeutic window of the combination of both clinically approved small molecular therapies (platinum drugs and EGFR inhibitors) and extend their activity to (multi)drug-resistant cancer.

[0019] To address this issue, in the context of the present invention, the first mono-maleimide functionalized platinum(IV) complexes with an EGFR inhibitor as an additional axial ligand were developed and tested for their anticancer activity in vivo. This resulted in several completely unexpected discoveries:

[0020] 1) In contrast to what one might expect from platinum(IV) complexes functionalized with an EGFR inhibitor, the tolerability was noticeably improved when compared to the combination treatment with the respective individual drugs (see Example 2 and Figure 5; animals treated with the combination of the individual drugs suffered from premature death).

[0021] 2) While EGFR inhibitors are potent anticancer drugs, they are susceptible to resistance mechanisms, such as the activation of c-MET pathways or the loss of PTEN tumor suppressors. The novel platinum(l V) complexes of the present invention offer a way of overcoming said EGFR inhibitor-resistance through their distinct mode of action.

[0022] 3) Similarly, oxaliplatin, carboplatin, and related platinum complexes also suffer from acquired drug resistance in tumors. However, the compounds of formula (I) remain active against carboplatin- and osimertinib-resistant models.

[0023] 4) Anticancer drugs are typically effective in some but not in all tumor types. The platinum(IV) complexes of the present invention, however, do not only perform well in the same tumor types as e.g. carboplatin. Rather, they were surprisingly found to be active also in tumor types atypical for carboplatin such as colon cancer.

[0024] These properties render the platinum(IV) complexes of the present invention highly advantageous for therapeutic use, particularly in the treatment or prevention of cancer (including drug-resistant cancer).

[0025] The present invention thus solves the problem of providing novel and improved platinum drugs for the therapeutic intervention in cancer, which show a considerably increased therapeutic effectiveness and a favorable side effect profile, particularly due to an advantageously enhanced tumor targeting.

[0026] Accordingly, the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0027]

[0028] In formula (I), R1and R2are joined together to form a moiety (A1), (A2) or (A3), or R1and R2are each -Cl:

[0029]

[0030] R3and R4are joined together to form a moiety (B1), or R3is a moiety (B2) and R4is -NH3, or R3is -NH3and R4is a moiety (B2), or R3and R4are each -NH3:

[0031]

[0032] (B1) (B2)

[0033] R5is selected from -NH-, -N(C1-8alkyl)-, -O-, and a covalent bond.

[0034] R6is -(C0-3 alkylene)-(CH2-0-CH2)y-(Co-3 alkylene)- or C1-10 alkylene, wherein y is an integer of 1 to 10, wherein one or more -CH2- units comprised in said C1-10 alkylene are each optionally replaced by a group independently selected from -O-, -CO-, -C(=O)O-, -O-C(=O)-, -NH-, -N(Ci-s alkyl)-, -NH-CO-, -N(C1-8alkyl)-CO-, -CO-NH-, -CO-N(C1-8alkyl)-, carbocyclylene and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more groups R61.

[0035] R7is a moiety (D1), (D2), (D3) or (D4):

[0036] 00

[0037]

[0038]

[0039] (D3) (D4)

[0040] Each R71is independently selected from hydrogen, halogen, C1-5 alkyl and C1-5 haloalkyl.

[0041] R72is selected from a covalent bond, C1-5 alkylene, -O-, -NH- and -N(Ci-s alkyl)-. Each R73is independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-s alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0042] R74is selected from a covalent bond, C1-5 alkylene, C2-5 alkenylene, -(C0-3 alkylene)-0-(Co-3 alkylene)-, -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-NH-(Co-3 alkylene)-, and -(C0-3 alkylene)-N(Ci-s alkyl)-(Co-3 alkylene)-, wherein the carbocyclylene moiety in said -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)- and the heterocyclylene moiety in said -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)- are each optionally substituted with one or more groups R78.

[0043] R75and R76are each independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, and C1-5 haloalkyl.

[0044] R77is selected from C1-5 haloalkyl, C2-5 alkenyl, and C2-5 alkynyl.

[0045] R8is a moiety (E1) or (E2):

[0046] T>12 1?

[0047] ,RR

[0048] * N / NZ

[0049] R11R11

[0050] I I N O

[0051] R

[0052]

[0053] 13 / 'R14 XR14

[0054] (E1) (E2)

[0055] R11is C1-5 alkylene, wherein one-CH2- unit comprised in said C1-5 alkylene is optionally replaced by a group -CHR111-, wherein R111, if present, is joined with either R12or R13, if present, to form together a C1-5 alkylene.

[0056] R12is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R121. R13, if present, is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R131.

[0057]

[0058] X is C(-R145) or N.

[0059] R141is selected from hydrogen, C1-8alkyl, halogen, C1-8 haloalkyl, -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-8 alkyl), -(C0-3 alkylene)-CO-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-cycloalkyl, and -(C0-3 alkylene)-CO-O-heterocycloalkyl.

[0060] R142is selected from hydrogen, C1-8alkyl, C2-8alkenyl, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl; or R142and a group R147are joined together to form a C3-5 alkylene, wherein said R147is attached to the carbon ring atom directly adjacent to the nitrogen ring atom carrying R142.

[0061] R143, R144and R145are each independently selected from hydrogen, C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(Ci-8 haloalkyl), and -(C0-3 alkylene)-CN.

[0062] R146is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C1-8 haloalkyl, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl. Each R147is independently selected from C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(Co-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(Co-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-s haloalkyl), -(C0-3 alkylene)-O-(Ci-s haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0063] Each R61, R78, R9, R10, R121, and R131is independently selected from Ci-s alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-8 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-8 alkyl), -(C0-3 alkylene)-SO2-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0064] m is an integer of 0 to 6.

[0065] n is an integer of 0 to 8.

[0066] p is an integer of 0 to 4.

[0067] q is an integer of 0 to 5.

[0068] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient. Accordingly, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use as a medicament.

[0069] The invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer. Moreover, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment or prevention of cancer.

[0070] The invention likewise relates to a method of treating or preventing cancer, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or of a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, to a subject (preferably a human) in need thereof.

[0071] The cancer to be treated or prevented in accordance with the present invention is preferably selected from gastrointestinal cancer, colorectal cancer (e.g., colorectal carcinoma), colon cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer, biliary tract cancer, hepatobiliary cancer, stomach cancer, genitourinary cancer, urothelial cancer (e.g., urothelial carcinoma; including bladder cancer), testicular cancer, anal cancer (e.g., anal squamous cell carcinoma), cervical cancer, malignant mesothelioma, osteogenic sarcoma, esophageal and / or esophagogastric cancer, laryngeal cancer, prostate cancer (e.g., hormone-refractory prostate cancer), lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer, or breast cancer having a BRCA1 and / or BRCA2 gene mutation), hematological cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia), lymphoma (e.g., Hodgkin lymphoma or non-Hodgkin lymphoma, such as, e.g., follicular lymphoma or diffuse large B-cell lymphoma), multiple myeloma, gynecological cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian carcinoma), uterine cancer, brain cancer, glioblastoma, astrocytoma, neuroblastoma, bone cancer (e.g., osteosarcoma), fibrosarcoma, Ewing’s sarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma, Merkel-cell cancer, head and / or neck cancer (e.g., head and neck squamous cell carcinoma), squamous cell cancer, thymoma, neuroendocrine cancer, goblet cell cancer, and mouth cancer. The cancer to be treated or prevented may also include brain metastases (e.g., brain metastases of any one of the aforementioned types of cancer). Moreover, the cancer to be treated or prevented (including any one of the aforementioned specific types of cancer) may be growth factor receptor-overexpressing (including c-Met, VEGFR, FGFR, Her2 or EGFR, either in wild-type or mutant form), KRAS wild-type or mutant, may harbor PTEN loss, or may be a (multi-)drug resistant cancer, particularly an EGFR inhibitor-resistant (e.g., osimertinib-resistant or erlotinib-resistant) and / or platinum compound-resistant (e.g., carboplatin-resistant or oxaliplatin-resistant) cancer. Said EGFR inhibitor-resistant cancer may, e.g., have an EGFR activating mutation (see, e.g., Leonetti A. et al., Br J Cancer, 2019, 121(9), 725-737, doi: 10.1038 / s41416-019-0573-8; Xu C. et al., Transl Oncol, 2020, 13(9), 100791, doi: 10.1016 / j.tranon.2020.100791), particularly an EGFR L858R mutation, an EGFR T790M mutation, an EGFR C797S mutation, an EGFR C797X mutation (wherein X is any amino acid other than C, i.e. other than cysteine), an EGFR L792X mutation (wherein X is any amino acid other than L, i.e. other than leucine), an EGFR G796X mutation (wherein X is any amino acid other than G, i.e. other than glycine), an EGFR L718Q mutation, an EGFR G724S mutation, an EGFR S768I mutation, an EGFR exon 19 deletion mutation (including, e.g., classical E19del orC-helix E19del), and / or an EGFR exon 20 insertion mutation.

[0072] More preferably, the cancer to be treated or prevented is selected from colorectal cancer, colon cancer, pancreatic cancer, lung cancer (particularly non-small cell lung cancer or small-cell lung cancer), ovarian cancer (particularly ovarian carcinoma), urothelial cancer (particularly bladder cancer), cervical cancer, malignant mesothelioma, melanoma, head and / or neck cancer (particularly head and neck squamous cell carcinoma), or testicular cancer. As explained above, the cancer (including each one of the aforementioned specific types of cancer) may be an EGFR wild-type cancer or an EGFR-mutant cancer (particularly a cancer having an EGFR-activating mutation, such as, e.g., an EGFR L858R mutation, an EGFR exon 19 deletion mutation or a resistance-mediating EGFR T790M mutation). Even more preferably, the cancer to be treated or prevented in accordance with the present invention is colorectal cancer, colon cancer, pancreatic cancer, lung cancer (particularly non-small cell lung cancer or small-cell lung cancer), ovarian cancer (particularly ovarian carcinoma), cervical cancer, melanoma, or head and / or neck cancer (particularly head and neck squamous cell carcinoma). Accordingly, the cancer to be treated or prevented may thus be, for example, lung cancer (particularly non-small cell lung cancer) or colorectal cancer.

[0073] The present invention is also described by the appended figures:

[0074] Figure 1: Superior anticancer activity of KP3038 against H1650 NSCLC cells in vivo. KP3038 is compared against osimertinib, carboplatin and solvent controls in female H1650 xenograftbearing (less osimertinib-responsive due to PTEN loss) mice. H1650-bearing C. B.17 SCID female mice were treated twice a week for two weeks i.v. with 72.5 mg / kg KP3038 i.v. (dose equimolar to 30 mg / kg osimertinib mesylate), once a week with 60 mg / kg carboplatin i.v. (maximum tolerated dose, MTD) or 5 days a week for two weeks with 30 mg / kg osimertinib mesylate p.o. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2. Figure 2: Superior anticancer activity of KP3038 against HCC827 / erlo cells in vivo. KP3038 is compared against osimertinib and solvent controls in male HCC827 / erlo-bearing xenograft (osimertinib-resistant due to C-Met expression) mice. (A) Prior to inoculation, resistance of HCC827 / erlo cells to osimertinib was confirmed in cell culture. Cell viability after 72 h treatment was measured by MTT assay. Values given in the graph are the mean ± SD of triplicates from one representative experiment out of three. (B) HCC827 / erlo-bearing male C. B.17 SCID mice were treated twice a week for two weeks with 72.5 mg / kg KP3038 i.v. (dose equimolar to 30 mg / kg osimertinib mesylate), or 5 days a week for two weeks with 30 mg / kg osimertinib mesylate p.o. Impact on tumor growth is presented as means ± SEM. (C) The overall survival is depicted via a Kaplan-Meier curve. See Example 2.

[0075] Figure 3: Superior anticancer activity of KP3038 against CT26 murine colorectal carcinoma cells in vivo. KP3038 is compared against osimertinib and solvent-treated control in male CT26-bearing allograft (carboplatin-resistant) mice. Mice were treated twice a week for two weeks with 72.5 mg / kg KP3038 i.v. (dose equimolar to 30 mg / kg osimertinib mesylate) or 5 days a week for two weeks with 30 mg / kg osimertinib mesylate p.o. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2.

[0076] Figure 4: Anticancer activity of KP3037, KP3038, oxaliplatin, carboplatin and osimertinib against H1975 xenografts (T790M mutation in EGFR) in vivo. Male H1975-bearing C. B.17 SCID mice were treated twice a week for two weeks with 78.2 mg / kg KP3038 i.v. or 76.6 mg / kg KP3037 i.v. (in both cases dose was equimolar to 30 mg / kg osimertinib mesylate), or twice a week with 60 mg / kg carboplatin i.v. or 6 mg / kg oxaliplatin (in both cases the MTD), or 5 days a week for two weeks with 30 mg / kg osimertinib mesylate p.o. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2.

[0077] Figure 5: Anticancer activity and tolerability of osimertinib alone and in combination with either oxaliplatin or carboplatin against H1975 xenografts (T790M mutation in EGFR) in vivo with a control group receiving 0.5% HPMC perorally (p.o.) as comparison. Similar growth and survival rates across all treatment groups were seen, albeit with excessive toxicity for both combination treatments. H1975-bearing male C. B.17 SCID mice were treated twice a week for two weeks with 30 mg / kg osimertinib mesylate p.o. either alone or in combination with 6 mg / kg oxaliplatin or 60 mg / kg carboplatin, respectively. Both platinum drugs were given intravenously (i.v). Noteworthy, both combination therapy groups had to be stopped and all animals sacrificed (on day 19) after 2 drug applications due to signs of toxicity and death of one animal. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2.

[0078] Figure 6: Prodrug nature of of KP3038 compared to osimertinib in H1975 NSCLC cells in vitro (A) shows the cell viability of H1975 cells treated with either KP3038 or osimertinib measured by MTT assay after 72 h. In contrast to osimertinib, KP3038 has no impact on cell number in vitro after 3 days. Values given in the graph are the mean ± SD of triplicates from one representative experiment out of three. (B) shows the clonogenic survival of H1975 cells treated with either KP3038 or osimertinib after 9 days of incubation. Cell colonies were visualized by crystal violet staining. Crystal violet staining intensity was evaluated by fluorescence measurement. After 9 days, KP3038 had activity comparable to osimertinib. Values are given as means ± SD of one representative experiment performed in duplicates. The shown figure is a representative of three independently performed experiments. See Example 2.

[0079] Figure 7: Pharmacological evaluation of KP3038 vs. carboplatin in CT-26-bearing Balb / c mice. Male animals were treated once i.v. with 72.5 mg / kg KP3038 or 60 mg / kg carboplatin. Of note, carboplatin was given at 3.2-fold higher molar concentration. Blood samples were collected via the facial vein after 5 min, 30 min, 300 min and 1440 min; Tumor and organ samples were collected after 5 h and 24 h. Platinum levels of all samples were measured via ICP-MS. See Example 2.

[0080] Figure 8: Superior anticancer activity of KP3038 against HCC827 / mix tumors in vivo. HCC827 / mix is a 1: 1: 1 mix of HCC827 subclones with different resistance phenotypes (parental HCC827 - sensitive to EGFR inhibition, HCC827 / erlo - resistant to EGFR inhibition due to c-met overexpression, HCC827 / EPR - resistant to first generation EGFR inhibitors due to a T750M mutation of the EGFR). KP3038 is compared against osimertinib and solvent controls in male mice. HCC827 / mix-bearing male C. B.17 SCID mice were treated twice a week for two weeks with 56.46 mg / kg KP3038 i.v. or 5 days a week for two weeks with 30 mg / kg osimertinib mesylate p.o. Impact on tumor growth is presented as means ± SEM. See Example 2.

[0081] Figure 9: Superior anticancer activity of KP3037 against CT26 murine colorectal carcinoma cells in vivo. KP3037 is compared against oxaliplatin and solvent-treated control in male CT26-bearing allograft (carboplatin-resistant) mice. Mice were treated twice a week for two weeks with 54.65 mg / kg KP3037 i.v. or with 3 mg / kg oxaliplatin i.v. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2. Figure 10: Anticancer activity of KP3037, KP3038, osimertinib, and a combination of carboplatin and osimertinib against H1975 xenografts (T790M mutation in EGFR) in vivo. Male H1975-bearing C. B.17 SCID mice were treated twice a week for two weeks with 71.6 mg / kg KP3038 i.v. or 54.6 mg / kg KP3037 i.v., or 29.8 mg / kg osimertinib mesylate p.o., or a combination of 30 mg / kg carboplatin i.v. with 29.8 mg / kg osimertinib p.o. (A) Impact on tumor growth; data are presented as means ± SEM. (B) The overall survival is depicted via a Kaplan-Meier curve. See Example 2.

[0082] Figure 11: EGFR-inhibitory activity of KP3037, KP3038, oxaliplatin, carboplatin, and osimertinib in H1975 xenografts (T790M mutation in EGFR) in vivo. Male H1975-bearing C. B.17 SCID mice were treated once with 78.2 mg / kg KP3038 i.v. or with 76.6 mg / kg KP3037 i.v. (in both cases dose was equimolar to 30 mg / kg osimertinib mesylate), or with 60 mg / kg carboplatin i.v. or with 9 mg / kg oxaliplatin (in both cases the MTD), or with 30 mg / kg osimertinib mesylate p.o. After 24 h, tumors were harvested, formalin-fixed and paraffin-embedded. From these samples, slices were stained for phosphorylated EGFR by routine histological methods. (A) Example pictures.

[0083] (B) Intensity of pEGFR staining was quantified over the whole slide using HALO software. Data shown are mean + / - SD. See Example 2.

[0084] The compounds of formula (I) will be described in more detail in the following:

[0085]

[0086] or a pharmaceutically acceptable salt or solvate thereof.

[0087] In formula (I), R1and R2are joined together to form a moiety (A1), (A2) or (A3), or R1and R2are each -Cl: O > / z°

[0088] -|-0— / 4-0~ \x\ 4"0—

[0089] 4”^ —1~ l”O — v ~ l”O — '

[0090]

[0091] 0 0 O (A1) (A2) (A3);

[0092] It will be understood that if the groups R1and R2are joined together to form a moiety (A3), they can form the moiety (A3) in either one of the two possible orientations, i.e., the methyleneoxy group (-O-CH2-) comprised in (A3) can be attached as R1and the carbonyloxy group (-0-C0-) comprised in (A3) can be attached as R2, or alternatively, the methyleneoxy group (-O-CH2-) comprised in (A3) can be attached as R2and the carbonyloxy group (-0-C0-) comprised in (A3) can be attached as R1.

[0093] Preferably, R1and R2are joined together to form a moiety (A1) or (A2). More preferably, R1and R2are joined together to form a moiety (A1), or R1and R2are joined together to form a moiety (A2) and m is 0.

[0094] R3and R4are joined together to form a moiety (B1), or R3is a moiety (B2) and R4is -NH3, or R3is -NH3and R4is a moiety (B2), or R3and R4are each -NH3:

[0095]

[0096] (B1) (B2);

[0097] Preferably, R3and R4are joined together to form a moiety (B1), or R3and R4are each -NH3. More preferably, R3and R4are joined together to form a moiety (B1) and n is 0, or R3and R4are each -NH3.

[0098] In accordance with the above definitions of R1, R2, R3and R4, it is particularly preferred that: - R1and R2are joined together to form a moiety (A1), and R3and R4are joined together to form a moiety (B1);

[0099] - R1and R2are joined together to form a moiety (A2), and R3and R4are each -NH3;

[0100] - R1and R2are joined together to form a moiety (A2) and R3and R4are joined together to form a moiety (B1); - R1and R2are joined together to form a moiety (A3), wherein the carbonyloxy group comprised in (A3) is attached as R2, and R3and R4are each -NH3;

[0101] - R1and R2are joined together to form a moiety (A3), wherein the carbonyloxy group comprised in (A3) is attached as R1, and R3and R4are each -NH3;

[0102] - R1and R2are each -Cl, and R3and R4are each -NH3;

[0103] - R1and R2are each -Cl, and R3and R4are joined together to form a moiety (B1);

[0104] - R1and R2are each -Cl, R3is a moiety (B2), and R4is -NH3; or

[0105] - R1and R2are each -Cl, R3is -NH3, and R4is a moiety (B2).

[0106] Even more preferably, R1and R2are joined together to form a moiety (A1) and R3and R4are joined together to form a moiety (B1), or R1and R2are joined together to form a moiety (A2), and R3and R4are each -NH3.

[0107] If R3and R4are joined together to form a moiety (B1), then it is furthermore preferred that the two asymmetric carbon atoms of the cyclohexyl ring comprised in moiety (B1) both have the R-configuration, i.e. that the cyclohexane-1,2-diamine group in moiety (B1) is present as (1R,2R)-cyclohexane-1,2-diamine, as illustrated in the following:

[0108] H2

[0109] . N— 1

[0110]

[0111] (R8)„H2

[0112] R5is selected from -NH-, -N(Ci-s alkyl)-, -O-, and a covalent bond.

[0113] Preferably, R5is -NH- or -N(Ci-s alkyl)-. More preferably, R5is selected from -NH-, -N(-CH3)-, and -N(-CH2CH3)-. Even more preferably, R5is -NH-.

[0114] R6is -(C0-3 alkylene)-(CH2-0-CH2)y-(Co-3 alkylene)- or C1-10 alkylene, wherein y is an integer of 1 to 10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), wherein one or more (e.g., one, two or three) -CH2- units comprised in said C1-10 alkylene are each optionally replaced by a group independently selected from -O-, -CO-, -C(=O)O-, -O-C(=O)-, -NH-, -N(C1-8alkyl)-, -NH-CO-, -N(C1-8alkyl)-CO-, -CO-NH-, -CO-N(C1-8alkyl)-, carbocyclylene and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more (e.g., one, two or three) groups R61.

[0115] Preferably, R6is -(C0-3 alkylene)-(CH2-0-CH2)y-(Co-3 alkylene)- or C1-10 alkylene, wherein one or more (e.g., one or two) -CH2- units comprised in said C1-10 alkylene are each optionally replaced by a group independently selected from -O-, -CO-, -NH-, -N(Ci-s alkyl)-, carbocyclylene and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more (e.g., one, two or three) groups R61, and wherein y is an integer of 1 to 10. More preferably, R6is -(C0-3 alkylene)-(CH2-0-CH2)y-(Co-3 alkylene)- or C1-10 alkylene, wherein one -CH2- unit comprised in said C1-10 alkylene is optionally replaced by a group selected from cycloalkylene (e.g., a monocyclic 5- or 6-membered cycloalkylene) and heterocycloalkylene (e.g., a monocyclic 5- or 6-membered heterocycloalkylene, such as piperazinylene, particularly piperazin-1, 4-diyl), wherein said cycloalkylene and said heterocycloalkylene are each optionally substituted with one or more (e.g., one, two or three) groups R61, wherein one -CH2- unit comprised in said C1-10 alkylene is optionally replaced by -O-, and wherein y is an integer of 2 to 8. Even more preferably, R6is -(CH2)x-(CH2-O-CH2)y-(CH2)z-, -(CH2)x-(piperazin-1,4-diyl)-(CH2)a-, -(CH2)x-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-, or C1-10 alkylene, wherein x is independently an integer of 0 to 3 (i.e., 0, 1, 2 or 3), wherein y is an integer of 2 to 6 (i.e., 2, 3, 4, 5 or 6), wherein z is an integer of 0 to 3 (i.e., 0, 1, 2 or 3), and wherein a is an integer of 2 to 6 (i.e., 2, 3, 4, 5 or 6). Yet even more preferably, R6is -CH2-(CH2-O-CH2)y-CH2-, -(CH2)x-(piperazin-1,4-diyl)-(CH2)a- or -(CH2)x-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-, wherein x is an integer of 1 to 3 (e.g., 2), wherein y is an integer of 2 to 6 (particularly 3 or 4), and wherein a is an integer of 2 to 5 (particularly 4 or 5). Particularly preferred examples of R6include -CH2-(CH2-O-CH2)3-CH2-, -CH2-(CH2-O-CH2)4-CH2-, -CH2CH2-(piperazin-1,4-diyl)-CH2CH2-, -CH2CH2-(piperazin-1,4-diyl)-CH2CH2CH2CH2-, -CH2CH2-(piperazin-1,4-diyl)-CH2CH2CH2CH2CH2-, or -CH2CH2-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-.

[0116] Each R61is independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-8 alkyl), -(C0-3 alkylene)-SO2-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0117] Preferably, each R61is independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -OH, -(C1.3 alkylene)-OH, -O-(Ci-8 alkyl), -(C1.3 alkylene)-O-(Ci-8 alkyl), -SH, -S(Ci-8 alkyl), -NH2, -NH(CI-8 alkyl), -N(Ci-s alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O- (Ci-8haloalkyl), -CN, -CHO, -CO-(Ci-8alkyl), -COOH, -CO-O-(Ci-8alkyl), -O-CO-(Ci-8alkyl), -CO-NH2, -CO-NH(CI-8alkyl), -CO-N(CI-8alkyl)(Ci-8alkyl), -NH-CO-(CI-8alkyl), -N(C1-8alkyl)-CO-(Ci-8alkyl), -SO2-NH2, -SO2-NH(CI-8alkyl), -SO2-N(CI-8alkyl)(Ci-8alkyl), -NH-SO2-(CI-8alkyl), -N(C1-8alkyl)-SC>2-(Ci-8alkyl), cycloalkyl, and heterocycloalkyl. More preferably, each R61is independently selected from Ci-8alkyl, C2-8alkenyl, C2-8alkynyl, -OH, -O- (Ci-8alkyl), -SH, -S(Ci-8alkyl), -NH2, -NH(CI-8alkyl), -N(CI-8alkyl)(Ci-8alkyl), halogen, Ci-8haloalkyl, -O-(Ci-8haloalkyl), and -CN. Even more preferably, each R61is independently selected from Ci-8alkyl (e.g., methyl or ethyl), -OH, and -NH2.

[0118] R7is a moiety (D1), (D2), (D3), or (D4):

[0119] 0

[0120]

[0121] (D1) (D2) (D3) (D4).

[0122] Corresponding preferred examples of R7include, in particular, any one of the following groups:

[0123]

[0124] More preferably, R7is a moiety (D1) or (D2):

[0125]

[0126] Even more preferably, R7is selected from

[0127]

[0128] Yet even more preferably,

[0129]

[0130] R7is 0. Still more preferably,

[0131]

[0132] R7is

[0133] Each R71is independently selected from hydrogen, halogen, C1-5 alkyl, and C1-5 haloalkyl.

[0134] Preferably, each R71is independently selected from hydrogen, halogen (e.g., -Br) and C1-5 haloalkyl (e.g., -CF3). More preferably, each R71is hydrogen or halogen. Even more preferably, each R71is hydrogen.

[0135] R72is selected from a covalent bond, C1-5 alkylene, -O-, -NH-, and -N(Ci-s alkyl)-.

[0136] Preferably, R72is selected from -O- and -NH-. More preferably, R72is -O-.

[0137] Each R73is independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-s alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0138] Preferably, each R73is independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl. More preferably, each R73is independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -NO2, cycloalkyl, and heterocycloalkyl. Even more preferably, each R73is independently selected from halogen, C1-5 alkyl, -CF3, -NO2, and cyclopropyl.

[0139] R74is selected from a covalent bond, C1-5 alkylene, C2-5 alkenylene, -(C0-3 alkylene)-0-(Co-3 alkylene)-, -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-NH-(Co-3 alkylene)-, and -(C0-3 alkylene)-N(Ci-s alkyl)-(Co-3 alkylene)-, wherein the carbocyclylene moiety in said -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)- and the heterocyclylene moiety in said -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)- are each optionally substituted with one or more (e.g., one, two or three) groups R78.

[0140] Preferably, R74is selected from a covalent bond, C1-5 alkylene, -(C0-3 alkylene)-0-(Co-3 alkylene)-, -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)- (e.g., -(C0-3 alkylene)-arylene-(Co-3 alkylene)-), -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)- (e.g., -(C0-3 alkylene)-heteroarylene-(Co-3 alkylene)-), and -(C0-3 alkylene)-N(Ci-s alkyl)-(Co-3 alkylene)-, wherein the carbocyclylene moiety in said -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)- and the heterocyclylene moiety in said -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)- are each optionally substituted with one or more (e.g., one, two or three) groups R78. More preferably, R74is selected from -(C0-3 alkylene)-heteroarylene-(Co-3 alkylene)- and -(C0-3 alkylene)-N(Ci-s alkyl)-(Co-3 alkylene)-, wherein the heteroarylene moiety in said -(C0-3 alkylene)-heteroarylene-(Co-3 alkylene)- is optionally substituted with one or more (e.g., one, two or three) groups R78. Even more preferably R74is heteroarylene or -N(Ci-s alkyl)- (e.g., -N(-CH3)-). Still more preferably R74is heteroarylene, particularly 1,3,4-oxadiazol-2,5-diyl.

[0141] R75and R76are each independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, and C1-5 haloalkyl.

[0142] Preferably, R75is selected from C1-5 alkyl (e.g., methyl or ethyl) and C2-5 alkenyl (e.g., ethenyl). More preferably, R75is methyl or ethenyl. Even more preferably, R75is methyl.

[0143] Preferably, R76is selected from C1-5 alkyl (e.g., methyl or ethyl) and C2-5 alkenyl (e.g., ethenyl). More preferably, R76is ethenyl.

[0144] R77is selected from C1-5 haloalkyl, C2-5 alkenyl, and C2-5 alkynyl.

[0145] Preferably, R77is C1-5 haloalkyl or C2-5 alkenyl. More preferably, R77is -CH2-halogen or ethenyl. Even more preferably, R77is selected from chloromethyl, bromomethyl, and iodomethyl. Each R78is independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-8 alkyl), -(C0-3 alkylene)-SO2-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0146] Preferably, each R78is independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -OH, -(C1.3 alkylene)-OH, -O-(Ci-8 alkyl), -(C1.3 alkylene)-O-(Ci-8 alkyl), -SH, -S(Ci-8 alkyl), -NH2, -NH(CI-8 alkyl), -N(Ci-s alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(C1-8 haloalkyl), -CN, -CHO, -CO-(Ci-8alkyl), -COOH, -CO-O-(Ci-8alkyl), -O-CO-(Ci-8alkyl), -CO-NH2, -CO-NH(CI-8alkyl), -CO-N(CI-8alkyl)(Ci-8alkyl), -NH-CO-(CI-8alkyl), -N(C1-8alkyl)-CO-(Ci-8alkyl), -SO2-NH2, -SO2-NH(CI-8alkyl), -SO2-N(CI-8alkyl)(Ci-8alkyl), -NH-SO2-(CI-8 alkyl), -N(Ci-s alkyl)-SO2-(Ci-8 alkyl), cycloalkyl, and heterocycloalkyl. More preferably, each R78is independently selected from C1-8alkyl, -OH, -O-(Ci-8 alkyl), -SH, -S(Ci-8 alkyl), -NH2, -NH(CI-8 alkyl), -N(Ci-s alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(C1-8 haloalkyl), -CN, cycloalkyl, and heterocycloalkyl. Even more preferably, each R78is independently selected from C1-5 alkyl (e.g., methyl or ethyl), halogen, C1-5 haloalkyl (e.g., -CF3), -CN, and cycloalkyl.

[0147] In accordance with the above, particularly preferred examples of -R6-R7include -CH2-(CH2-O-CH2)3-CH2-(D1a), -CH2-(CH2-O-CH2)3-CH2-(D2a), -CH2-(CH2-O-CH2)4-CH2-(D1a), -CH2-(CH2-O-CH2)4-CH2-(D2a), -CH2CH2-(piperazin-1,4-diyl)-CH2CH2-(D2a), -CH2CH2-(piperazin-1,4-diyl)-CH2CH2CH2CH2-(D1a), -CH2CH2-(piperazin-1,4-diyl)-CH2CH2CH2CH2-(D2a), -CH2CH2-(piperazin-1,4-diyl)-CH2CH2CH2CH2CH2-(D1a), -CH2CH2-(piperazin-1,4-diyl)- CH2CH2CH2CH2CH2-(D2a), -CH2CH2-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-(D1a), or -CH2CH2-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-(D2a),

[0148] wherein (D

[0149]

[0150] 1a) is0, and wherein

[0151]

[0152] (D2a) is R8is a moiety (E1) or (E2):

[0153] , R12. R12

[0154] / N'

[0155] < A

[0156] R

[0157]

[0158] 13 / 'R14 XR14

[0159] (E1) (E2).

[0160] R11is C1-5 alkylene, wherein one-CH2- unit comprised in said C1-5 alkylene is optionally replaced by a group -CHR111-, wherein R111, if present, is joined with either R12or R13, if present, to form together a C1-5 alkylene.

[0161] Preferably, R11is a C2-4 alkylene (e.g., ethylene), wherein one -CH2- unit comprised in said C2-4 alkylene is optionally replaced by a group -CHR111-, wherein R111is joined with R13to form together a C1-3 alkylene. More preferably, R11is -CH2CH2-or -CHR111-CH2-, wherein the carbon atom carrying R111(i.e., the -CHR111- in said group -CHR111-CH2-) is directly adjacent to the nitrogen atom carrying R12, and wherein R111is joined with R13to form together a group -CH2CH2-. Even more preferably, R11is -CH2CH2-.

[0162] R12is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (e.g., one, two or three) groups R121.

[0163] Preferably, R12is hydrogen or C1-8alkyl. More preferably, R12is hydrogen or C1-5 alkyl (e.g., methyl or ethyl). Even more preferably, R12is methyl.

[0164] R13, if present, is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (e.g., one, two or three) groups R131.

[0165] Preferably, R13is hydrogen or C1-8alkyl. More preferably, R13is hydrogen or C1-5 alkyl (e.g., methyl or ethyl). Even more preferably, R13is methyl.

[0166] R121and R131are each independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O- (Ci-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-8 alkyl), -(C0-3 alkylene)-CO-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SC>2-NH(Ci-8 alkyl), -(C0-3 alkylene)-SC>2-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-SC>2-(Ci.8 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0167] Preferably, R121and R131are each independently selected from C1-8alkyl, -OH, -(C1-3 alkylene)-OH, -O-(Ci-8alkyl), -(C1.3 alkylene)-O-(Ci-8alkyl), -SH, -S(Ci-8alkyl), -NH2, -NH(CI-8alkyl), -N(CI-8 alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(Ci-8 haloalkyl), -CN, -CHO, -CO-(Ci-8 alkyl), -COOH, -CO-O-(Ci-8alkyl), -O-CO-(Ci-8alkyl), -CO-NH2, -CO-NH(CI-8alkyl), -CO-N(CI-8alkyl)(Ci-8alkyl), -NH-CO-(CI-8alkyl), -N(C1-8alkyl)-CO-(Ci-8alkyl), -SO2-NH2, -SO2-NH(CI-8alkyl), -SO2-N(CI-8alkyl)(Ci-8alkyl), -NH-SO2-(CI-8alkyl), -N(C1-8alkyl)-SO2-(Ci-8alkyl), cycloalkyl, and heterocycloalkyl. More preferably, R121and R131are each independently selected from C1-8alkyl, -OH, -O-(Ci-8alkyl), -SH, -S(Ci-8alkyl), -NH2, -NH(CI-8alkyl), -N(CI-8alkyl)(Ci-8alkyl), halogen, C1-8 haloalkyl, -O-(Ci-8 haloalkyl), -CN, cycloalkyl, and heterocycloalkyl. Even more preferably, R121and R131are each independently selected from C1-5 alkyl (e.g., methyl or ethyl), halogen, C1-5 haloalkyl (e.g., -CF3), -CN, and cycloalkyl.

[0168] In accordance with the above, it is particularly preferred that R8is

[0169] I

[0170] (CH2)2.4

[0171] 14

[0172] Even more preferably, R8is

[0173] (CH2)2

[0174] N

[0175] R13 / \R14

[0176]

[0177] Still more preferably, R8is -N(-CH3)-CH2CH2-N(-CH3)-R14or -N(-CH3)-CH2CH2-O-R14. R14is a group

[0178]

[0179] The ring atom X is C(-R145) or N.

[0180] Preferably, X is C(-R145).

[0181] R141is selected from hydrogen, C1-8alkyl, halogen, C1-8 haloalkyl, -(Co-3 alkylene)- CN, -(Co-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO- (Ci-8 alkyl), -(Co-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-8 alkyl), -(Co-3 alkylene)-CO- N(CI-8 alkyl)(Ci-8 alkyl), -(Co-3alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(Co-3 alkylene)-CO-O-cycloalkyl, and -(Co-3 alkylene)-CO-O-heterocycloalkyl.

[0182] Preferably, R141is selected from hydrogen, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(Co-3 alkylene)-CO-NH(Ci-8 alkyl), -(Co-3 alkylene)-CO-N(Ci-8 alkyl)(Ci-8 alkyl), and -(Co-3 alkylene)-CO-O-cycloalkyl. More preferably, R141is hydrogen or -(Co-3 alkylene)-CO-O-(Ci-8 alkyl). Even more preferably, R141is hydrogen or -CO-O-(Ci-s alkyl). Still more preferably, R141is hydrogen or -CO-O-isopropyl.

[0183] R142is selected from hydrogen, C1-8alkyl, C2-8alkenyl, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl; or R142and a group R147are joined together to form a C3-5 alkylene, wherein said R147is attached to the carbon ring atom directly adjacent to the nitrogen ring atom carrying R142.

[0184] Preferably, R142is selected from hydrogen, C1-8alkyl, C1-8 haloalkyl and -(C0-3 alkylene)- cycloalkyl, or R142and a group R147are joined together to form a group -CH2CH2CH2CH2-, wherein said R147is attached to the carbon ring atom directly adjacent to the nitrogen ring atom carrying R142. More preferably, R142is selected from hydrogen, C1-5 alkyl (e.g., methyl or ethyl), C1-5 haloalkyl (e.g., -CF3 or-CH2CF3) and cycloalkyl. Even more preferably, R142is selected from hydrogen, methyl, -CH2CF3 and cyclopropyl. Yet even more preferably, R142is selected from methyl, -CH2CF3 and cyclopropyl.

[0185] It will be understood that if q is 1 (i.e., there is one group R147), if the group R147is attached to the carbon ring atom directly adjacent to the nitrogen ring atom carrying R142, and if R142and R147are joined together to form a group -CH2CH2CH2CH2-, then the resulting cycgroup has the following structure:

[0186]

[0187] R143, R144and R145are each independently selected from hydrogen, C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(Ci-8 haloalkyl), and -(C0-3 alkylene)-CN.

[0188] Preferably, R143, R144and R145are each independently selected from hydrogen, C1-8alkyl, -OH, -O-(Ci-8 alkyl), -NH2, -NH(Ci-s alkyl), -N(Ci-s alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(Ci-8 haloalkyl), and -CN. More preferably, R143, R144and R145are each independently selected from hydrogen, methyl, ethyl, halogen, -CF3, and -CN. Even more preferably, R143, R144, and R145are each hydrogen.

[0189] R146is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C1-8 haloalkyl, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0190] Preferably, R146is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C1-8 haloalkyl, -CO-(Ci-8 alkyl), -CO-NH2, -CO-NH(CI-8alkyl), -CO-N(CI-8alkyl)(Ci-8alkyl), cycloalkyl, and heterocycloalkyl. More preferably, R146is selected from hydrogen, C1-8alkyl, and C1-8 haloalkyl. Even more preferably, R146is C1-4alkyl orCi-4 haloalkyl. Yet even more preferably, R146is methyl, -CF3 or -CH2CF3. Still more preferably, R146is methyl. Each R147is independently selected from C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-s haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0191] Preferably, each R147is independently selected from C1-8alkyl, -OH, -O-(Ci-8 alkyl), -NH2, -NH(CI-8 alkyl), -N(Ci-s alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(C1-8 haloalkyl), -CN, cycloalkyl, and heterocycloalkyl. More preferably, each R147is independently selected from C1-8alkyl, halogen, C1-8 haloalkyl, -CN, and -(C0-3 alkylene)-cycloalkyl. Even more preferably, each R147is independently selected from methyl, ethyl, halogen, -CF3, and -CN.

[0192] In accordance with the above, it is particularly preferred that R14is any one of the following groups:

[0193]

[0194]

[0195] Even more preferably, R14is any one of the following groups:

[0196]

[0197] Yet even more preferably, R14is any one of the following groups:

[0198]

[0199]

[0200] In accordance with the above definitions of (E1), (E2) and R14, it is particularly preferred that the group R8is any one of the following groups:

[0201] (

[0202]

[0203] v)

[0204]

[0205] The above-depicted groups correspond to the active moieties of specific EGFR inhibitors. In particular, the above-depicted group (i) corresponds to osimertinib, groups (ii) to (v) correspond to osimertinib derivatives, group (vi) corresponds to the indole-N-demethylated metabolite of osimertinib (also known as AZ5104), group (vii) corresponds to rezivertinib, group (viii) corresponds to mobocertinib, group (ix) corresponds to almonertinib (also known as aumolertinib), group (x) corresponds to befotertinib, group (xi) corresponds to alflutinib (also known as furmonertinib), and group (xii) corresponds to oritinib.

[0206] Even more preferably, R8is any one of the following groups:

[0207]

[0208]

[0209] R9and R10are each independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-8 alkyl), -(C0-3 alkylene)-SO2-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl.

[0210] Preferably, R9and R10are each independently selected from C1-8alkyl, -OH, -(C1-3 alkylene)-OH, -O-(Ci-8alkyl), -(C1.3 alkylene)-O-(Ci-8alkyl), -SH, -S(Ci-8alkyl), -NH2, -NH(CI-8alkyl), -N(CI-8 alkyl)(Ci-s alkyl), halogen, C1-8 haloalkyl, -O-(Ci-8 haloalkyl), -CN, -CHO, -CO-(Ci-8 alkyl), -COOH, -CO-O-(Ci-8alkyl), -O-CO-(Ci-8alkyl), -CO-NH2, -CO-NH(CI-8alkyl), -CO-N(CI-8alkyl)(Ci-8alkyl), -NH-CO-(CI-8alkyl), -N(C1-8alkyl)-CO-(Ci-8alkyl), -SO2-NH2, -SO2-NH(CI-8alkyl), -SO2-N(CI-8alkyl)(Ci-8alkyl), -NH-SO2-(CI-8alkyl), -N(C1-8alkyl)-SO2-(Ci-8alkyl), cycloalkyl, and heterocycloalkyl. More preferably, R9and R10are each independently selected from C1-8alkyl, -OH, -(C1-3 alkylene)-OH, -O-(Ci-8 alkyl), -(C1-3 alkylene)-O-(Ci-8 alkyl), -SH, -S(Ci-8alkyl), -NH2, -NH(CI-8alkyl), -N(CI-8alkyl)(Ci-8alkyl), halogen, C1-8 haloalkyl, -O-(Ci-8 haloalkyl), -CN, cycloalkyl, and heterocycloalkyl. Even more preferably, R9and R10are each independently selected from C1-5 alkyl (e.g., methyl or ethyl), -OH, -O-(Ci-s alkyl) (e.g., methoxy), -NH2, -NH(CI-5alkyl) (e.g., -NHMe), -N(CI-5alkyl)(Ci-5alkyl) (e.g., -NMe2), halogen (e.g., -F), C1-5 haloalkyl (e.g., -CF3), -O-(Ci-s haloalkyl) (e.g., -OCF3), and cycloalkyl (e.g., cyclopropyl). For example, the moiety (B1) may carry one methyl substituent (i.e., n is 1, and R10is methyl), particularly in the 4-position of the cyclohexyl ring, as shown in the following:

[0211]

[0212] Any substituent R10, if present, may have the R-configuration or the S-configuration. For example, if the moiety (B1) carries one methyl substituent, particularly in the 4-position of the cyclohexyl ring (as described above), this methyl substituent may have the R-configuration or the S-configuration. Thus, moiety (B1) may be, e.g., a (1R,2R,4R)-4-methyl-cyclohexane-1,2-diamine moiety or a (1R,2R,4S)-4-methyl-cyclohexane-1,2-diamine moiety.

[0213] m is an integer of 0 to 6.

[0214] Preferably, m is 0, 1, 2, 3, or 4. More preferably, m is 0, 1 or 2. Even more preferably, m is 0 or 1. Yet even more preferably, m is 0.

[0215] It is to be understood that m indicates the number of substituents R9that are bound to the cyclobutyl ring comprised in moiety (A2). If m is 0, then this cyclobutyl ring is unsubstituted, i.e. it is substituted with hydrogen instead of R9.

[0216] n is an integer of 0 to 8.

[0217] Preferably, n is an integer of 0 to 6. More preferably, n is 0, 1, 2, 3, or 4. Even more preferably, n is 0, 1 or 2. Yet even more preferably, n is 0 or 1. Still more preferably, n is 0.

[0218] It is to be understood that n indicates the number of substituents R10that are bound to the corresponding cyclohexyl ring, e.g., the cyclohexyl ring comprised in moiety (B1) or (B2) or in formula (Ic) or (Id). If n is 0, then this cyclohexyl ring is not substituted with any group R10, i.e. it is substituted with hydrogen instead of R10.

[0219] p is an integer of 0 to 4.

[0220] Preferably, p is 0, 1 or 2. More preferably, p is 0 or 1. Even more preferably, p is 0. It is to be understood that p indicates the number of substituents R73that are bound to the phenyl ring comprised in moiety (D2). If p is 0, then this phenyl ring is not substituted with any group R73, i.e. it is substituted with hydrogen instead of R73.

[0221] q is an integer of 0 to 5.

[0222] Preferably, q is 0, 1, 2, 3, or 4. More preferably, q is 0, 1 or 2. Even more preferably, q is 0 or 1. Yet even more preferably, q is 0.

[0223] It is to be understood that q indicates the number of substituents R147that are bound to the 1H-indole ring comprised in the group R14. The corresponding substituent(s) R147can be attached at any ring atom of the 1H-indole ring that would otherwise carry a hydrogen atom, i.e., at the phenyl ring and / or at the pyrrole ring comprised in the bicyclic 1 H-indole ring. If q is 0, then the 1 H-indole ring is not substituted with any group R147, i.e. it is substituted with hydrogen instead of R147.

[0224] Examples of the compounds of formula (I) include, in particular, the following compounds KP3037, KP3038, MalPEG-Carbo-Rezivertinib, MalPEG-Carbo-Mobocertinib (also referred to as KP4070), MalPEG-Carbo-Almonertinib, MalPEG-Carbo-KP2840, MalPEG-Carbo-KP2839, MalPip-Carbo-KP2839, OxaPEG-Carbo-KP2839, OxaPip-Carbo-KP2839, MalPEG-Carbo-KP4012, MalPip-Carbo-KP4012, OxaPEG-Carbo-KP4012, OxaPip-Carbo-KP4012, MalPip-Carbo-Rezivertinib, MalPip-Carbo-Mobocertinib, MalPip-Carbo-Almonertinib, OxaPip-Carbo-Rezivertinib, OxaPip-Carbo-Mobocertinib, OxaPip-Carbo-Almonertinib, MalPip-Oxali-KP2839, MalPip-Oxali-KP4012, MalPip-Oxali-Rezivertinib, MalPip-Oxali-Mobocertinib, MalPip-Oxali-Almonertinib, OxaPip-Oxali-KP2839, OxaPip-Oxali-KP4012, OxaPip-Oxali-Rezivertinib, OxaPip-Oxali-Mobocertinib, OxaPip-Oxali-Almonertinib, KP4060, KP4061, KP4062, and KP4072, as well as pharmaceutically acceptable salts and solvates of any of these compounds:

[0225]

[0226] MalPEG-Carbo-Rezivertinib MalPEG-Carbo-Mobocertinib (also referred to as KP4070)

[0227]

[0228] MalPEG-Carbo-KP2839 MalPip-Carbo-KP2839

[0229]

[0230] MalPEG-Carbo-KP4012 MalPip-Carbo-KP4012

[0231]

[0232] MalPip-Carbo-Rezivertinib MalPip-Carbo-Mobocertinib MalPip-Carbo-Almonertinib

[0233]

[0234] OxaPip-Carbo-Rezivertinib OxaPip-Carbo-Mobocertinib OxaPip-Carbo-Almonertinib

[0235]

[0236] MalPip-Oxali-KP2839 O

[0237]

[0238] MalPip-Oxali-KP4012

[0239]

[0240] OxaPip-Oxali-KP2839 OxaPip-Oxali-Rezivertinib

[0241]

[0242] OxaRp-Oxali-Mobocertinib OxaPip-Oxali-AImonertinib

[0243]

[0244] KP4061 KP4062 o

[0245]

[0246] KP4072

[0247] In a 1stspecific embodiment, the compound of formula (I) is a compound of the following formula (la) or a pharmaceutically acceptable salt or solvate thereof:

[0248]

[0249] wherein the groups and variables in formula (la), including in particular R5, R6, R7, R8, R9and m, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0250] In a 2ndspecific embodiment, the compound of formula (I) is a compound of the following formula (lb) or a pharmaceutically acceptable salt or solvate thereof:

[0251]

[0252] (lb)

[0253] wherein R7is a group

[0254]

[0255] 0 and wherein the further groups and variables in formula (lb), including in particular R5, R6, R8, R9and m, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0256] In a 3rdspecific embodiment, the compound of formula (I) is a compound of the following formula (Ic) or a pharmaceutically acceptable salt or solvate thereof:

[0257]

[0258] wherein the groups and variables in formula (Ic), including in particular R6, R8, R9and m, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I). In a 4thspecific embodiment, the compound of formula (I) is a compound of the following formula (Id) or a pharmaceutically acceptable salt or solvate thereof:

[0259]

[0260] wherein R7is a group

[0261]

[0262] and wherein the further groups and variables in formula (Id), including in particular R5, R6, R8, R9and m, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0263] In a 5thspecific embodiment, the compound of formula (I) is a compound of the following formula (le) or a pharmaceutically acceptable salt or solvate thereof:

[0264]

[0265]

[0266] and wherein the further groups and variables in formula (le), including in particular R5, R6, R8, R9and m, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0267] In a 6thspecific embodiment, the compound of formula (I) is a compound of the following formula (If) or a pharmaceutically acceptable salt or solvate thereof:

[0268]

[0269] wherein the groups and variables in formula (If), including in particular R5, R6, R7, R8, R10and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0270] In a 7thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ig) or a pharmaceutically acceptable salt or solvate thereof:

[0271]

[0272] -H I

[0273] r

[0274]

[0275] r^R

[0276] wherein R7is a group O71

[0277] , and wherein the further groups and variables in formula (Ig), including in particular R5, R6, R8, R10and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0278] In an 8thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ih) or a pharmaceutically acceptable salt or solvate thereof:

[0279]

[0280] wherein the groups and variables in formula (Ih), including in particular R6, R8, R10and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0281] In a 9thspecific embodiment, the compound of formula (I) is a compound of the following formula (li) or a pharmaceutically acceptable salt or solvate thereof:

[0282]

[0283] wherein R7is a group

[0284]

[0285] and wherein the further groups and variables in formula (li), including in particular R5, R6, R8, R10and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0286] In a 10thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ij) or a pharmaceutically acceptable salt or solvate thereof:

[0287] (U)

[0288]

[0289] and wherein the further groups and variables in formula (Ij), including in particular R5, R6, R8, R10and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0290] In an 11thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ik) or a pharmaceutically acceptable salt or solvate thereof:

[0291] O^R5-R6

[0292] 'R7

[0293]

[0294] wherein R1and R2are joined together to form a moiety (A3), wherein R3and R4are each -NH3, and wherein the further groups and variables in formula (Ik) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0295] In a 12thspecific embodiment, the compound of formula (I) is a compound of the following formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0296]

[0297] wherein R1and R2are joined together to form a moiety (A3), wherein R3and R4are each -NH3,

[0298] wherein R7is a group

[0299]

[0300] 0 (preferably a group 0

[0301]

[0302] ), and wherein the further groups and variables in formula (II) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0303] In a 13thspecific embodiment, the compound of formula (I) is a compound of the following formula (Im) or a pharmaceutically acceptable salt or solvate thereof:

[0304] O^R5-R6

[0305] SR7

[0306]

[0307] (Im)

[0308] wherein R1and R2are joined together to form a moiety (A3), wherein R3and R4are each -NH3,

[0309] R7is a group

[0310]

[0311] (preferably a group

[0312]

[0313] ), and wherein the further groups and variables in formula (Im) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0314] In a 14thspecific embodiment, the compound of formula (I) is a compound of the following formula (In) or a pharmaceutically acceptable salt or solvate thereof:

[0315]

[0316] wherein R1and R2are each -Cl, wherein R3and R4are each -NH3, and wherein the further groups and variables in formula (In) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0317] In a 15thspecific embodiment, the compound of formula (I) is a compound of the following formula (Io) or a pharmaceutically acceptable salt or solvate thereof:

[0318]

[0319] wherein R1and R2are each -Cl, wherein R3and R4are each -NH3, wherein R7is a group

[0320]

[0321] (preferably a group ), and wherein the further groups and variables in formula (Io) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I). In a 16thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ip) or a pharmaceutically acceptable salt or solvate thereof:

[0322]

[0323] wherein R1and R2are each -Cl, wherein R3and R4are each -NH3, wherein R7is a group

[0324]

[0325] wherein the further groups and variables in formula (Ip) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0326] In a 17thspecific embodiment, the compound of formula (I) is a compound of the following formula (Iq) or a pharmaceutically acceptable salt or solvate thereof:

[0327]

[0328] wherein R1and R2are each -Cl, wherein R3and R4are joined together to form a moiety (B1), and wherein the further groups and variables in formula (Iq) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0329] In an 18thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ir) or a pharmaceutically acceptable salt or solvate thereof:

[0330]

[0331] wherein R1and R2are each -Cl, wherein R3and R4are joined together to form a moiety (B1),

[0332] wherein R7is a group

[0333]

[0334] 0 (preferably a group

[0335]

[0336] and wherein the further groups and variables in formula (Ir) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0337] In a 19thspecific embodiment, the compound of formula (I) is a compound of the following formula (Is) or a pharmaceutically acceptable salt or solvate thereof:

[0338]

[0339] wherein R1and R2are each -Cl, wherein R3and R4are joined together to form a moiety (B1),

[0340] wherein R7is a group

[0341]

[0342] (preferably a group

[0343]

[0344] ), and wherein the further groups and variables in formula (Is) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0345] In a 20thspecific embodiment, the compound of formula (I) is a compound of the following formula (It) or a pharmaceutically acceptable salt or solvate thereof:

[0346]

[0347] wherein R1and R2are each -Cl, wherein R3is a moiety (B2), wherein R4is -NH3, and wherein the further groups and variables in formula (It) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0348] In a 21stspecific embodiment, the compound of formula (I) is a compound of the following formula (Iu) or a pharmaceutically acceptable salt or solvate thereof:

[0349] O^R5-R6

[0350] 'R7

[0351]

[0352] wherein R1and R2are each -Cl, wherein R3is a moiety (B2), wherein R4is -NH3, wherein R7is

[0353] a group

[0354]

[0355] 0 (preferably a group

[0356]

[0357] ), and wherein the further groups and variables in formula (Iu) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0358] In a 22ndspecific embodiment, the compound of formula (I) is a compound of the following formula (Iv) or a pharmaceutically acceptable salt or solvate thereof:

[0359]

[0360] wherein R1and R2are each -Cl, wherein R3is a moiety (B2), wherein R4is -NH3, wherein R7is

[0361] a group

[0362]

[0363] (preferably a group

[0364]

[0365] ), and wherein the further groups and variables in formula (Iv) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0366] In a 23rdspecific embodiment, the compound of formula (I) is a compound of the following formula (Iw) or a pharmaceutically acceptable salt or solvate thereof:

[0367]

[0368] wherein R1and R2are each -Cl, wherein R3is -NH3, wherein R4is a moiety (B2), and wherein the further groups and variables in formula (Iw) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0369] In a 24thspecific embodiment, the compound of formula (I) is a compound of the following formula (Ix) or a pharmaceutically acceptable salt or solvate thereof:

[0370] O^R5-R6

[0371] 'R7

[0372]

[0373] wherein R1and R2are each -Cl, wherein R3is -NH3, wherein R4is a moiety (B2), wherein R7is

[0374] a group

[0375]

[0376] 0 (preferably a group

[0377]

[0378] ), and wherein the further groups and variables in formula (Ix) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0379] In a 25thspecific embodiment, the compound of formula (I) is a compound of the following formula (Iy) or a pharmaceutically acceptable salt or solvate thereof: O^R5-R6

[0380] 'R7

[0381]

[0382] wherein R1and R2are each -Cl, wherein R3is -NH3, wherein R4is a moiety (B2), wherein R7is

[0383] 72

[0384] < 11

[0385]

[0386] group (preferably group

[0387]

[0388] ), and wherein the further groups and variables in formula (Iy) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0389] In a 26thspecific embodiment, the compound of formula (I) is a compound of the following formula (Iz) or a pharmaceutically acceptable salt or solvate thereof:

[0390] °\^R8

[0391] ' l O

[0392] O

[0393] / X -Nfy | O

[0394] ^J-" NH2XJ,0

[0395] 10)» X

[0396]

[0397] wherein the groups and variables in formula (Iz), including in particular R5, R6, R7, R8, R9, R10, m and n, have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0398] In a 27thspecific embodiment, the compound of formula (I) is a compound of the following formula (Iza) or a pharmaceutically acceptable salt or solvate thereof:

[0399] ' l o

[0400] o

[0401] NH2I o

[0402] ■ NHO^0

[0403]

[0404] wherein R7is a group

[0405]

[0406] 0 (preferably a group 0

[0407]

[0408] ), and wherein the further groups and variables in formula (Iza) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0409] In a 28thspecific embodiment, the compound of formula (I) is a compound of the following formula (Izb) or a pharmaceutically acceptable salt or solvate thereof:

[0410] °\^R8

[0411] ' l O

[0412] O

[0413] / X -Nfy | O

[0414] I '" K

[0415] ^J-" NH2XJ,0

[0416] 10)» X

[0417]

[0418] o

[0419] °xx / 0

[0420] /

[0421] .0S-R-

[0422] wherein R7is a group

[0423]

[0424] N'N(preferably a group o0

[0425] 0s- 0

[0426] N-N

[0427]

[0428] ), and wherein the further groups and variables in formula (Izb) have the same meanings, including the same preferred meanings, as described and defined herein above for the compound of formula (I).

[0429] For a person skilled in the field of synthetic chemistry, various ways for the preparation of the compounds of formula (I) will be readily apparent. For example, the compounds of formula (I) can be prepared as described in the following and, in particular, they can be prepared in accordance with or in analogy to the synthetic routes described in Example 1.

[0430] Preparation of the platinum(ll) precursors:

[0431] The platinum(ll) precursors (P2) can be synthesized out of potassium tetrachloridoplatinate (P1) in aqueous solution, either using the corresponding ammine ligands (B1) according to Kidani, Y; Inagaki, K. J. Med. Chem. 1978, 21(12), 1315–1318 or using ammonia (R3and R4are each: -NH3) according to Dhara, S. Ch. Indian J. Chem. 1970, 8(2), 193-194. (P2) precursors, where R3is a (B2) moiety and R4is -NH3 (or R3is -NH3 and R4is a (B2) moiety) can be synthesized out of (P2), where R3and R4are each -NH3, according to Giandomenico, C. M. et al. Inorg. Chem. 1995, 34, 1015-1021.

[0432] The platinum(ll) precursors (P3) can be synthesized out of the precursors (P2) in aqueous solution using AgNO₃ or Ag₂SO₄ and the corresponding ligands R1and R2, wherein R1and R2are joined together to form a moiety (A1), (A2) or (A3) (Kidani, Y; Inagaki, K. J. Med. Chem.

[0433] 1978, 27(12), 1315-1318 or Rochon, F. D.; Gruia, L. M. Inorg. Chim. Acta 2000, 306, 193-204).

[0434] [Reaction scheme image - see imgf000060_0003]

[0435]

[0436] (P1) (P3)

[0437] Preparation of the platinum(IV) precursors: The platinum(IV) precursors (P4) can be synthesized out of the platinum(ll) precursors (P3). (P4) can be prepared by oxidation of (P3) with H2O2in aqueous solution. Optionally, this oxidation reaction can also be performed with precursors (P2), leading to precursors (P4) wherein R1and R2are -Cl.

[0438] OH

[0439] R3R1 H2O2R3X XR1

[0440] Xpf - „. PL o

[0441] R< " R2 H2O R4R2

[0442]

[0443] OH

[0444] (P3) (P4)

[0445] Preparation of the activated platinum(IV) precursors:

[0446] The activated platinum(IV) precursors (P5) and (P6) can be synthesized from the platinum(IV) precursors (P4) using an appropriate activating agent like A / , / '-disuccinimidyl carbonate (DSC) (Babu et al. Inorg. Chem. 2020, 59, 5182-5193) or bis(4-nitrophenyl) carbonate in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base). Whether the reaction yields di-activated (P5) or mono-activated (P6) can be controlled by the molar equivalents of the activating agent (e.g. DSC) added to the platinum(IV) precursors (P4). For example, the addition of 2 or more equivalents DSC results primarily in the formation of di-activated (P5) whereas the addition of up to 1.5 equivalents DSC results primarily in the formation of mono-activated (P6).

[0447]

[0448] (P6) Preparation of protected maleimide compounds:

[0449] To a solution of the corresponding maleimide-containing compounds (P7) in an organic solvent like acetonitrile, THF, DMF, 1,4-dioxane or EtOAc, a diene like dimethylfuran or furan (2.0-10.0 eq.) is added. The mixture is heated at temperatures between room temperature (r.t.) up to +90°C, depending on the diene (with or without a Lewis acid like ZnCl2; Vermeeren et al. Angew. Chem. 2020, 59, 6201-6206) and concentrated after stirring for 2-24 h. The crude product can be used without further purification, provided that no Lewis acid was added, otherwise an extraction with water and an organic solvent like EtOAc or DCM can be performed. The exo / endo ratio of the Diels-Alder products (P8) can vary but can generally be controlled by temperature and stirring time (Discekici et al. 2018, 140, 5009-5013).

[0450]

[0451] (P7) (P8)

[0452] Preparation of compounds of formula (P11):

[0453] The compounds (P11) can be synthesized from the activated platinum(IV) precursors (P5) using maleimide-containing amines (P8) and EGFR-inhibitor amines (P9) in consecutive order in an organic solvent like DMF or DMSO (in case of salts a base is added for neutralization). The first amine is typically added in a slight deficit (0.9-1.0 eq.) and optionally stirred for 0.1- 4 h at r.t., whereas the second amine is added in a slight excess (1.0-1.5 eq.) and stirred at r.t. for 2-24 h.

[0454]

[0455] (P11)

[0456] Alternatively, compounds (P11) can be synthesized from the activated platinum(IV) precursors (P6) using maleimide-containing amines (P8) in an organic solvent like DMF or DMSO to generate the compounds (P10) (in case of salts a base is added for neutralization). Subsequently, the remaining axial OH ligand is again reacted with an activating agent like / V, / V'- disuccinimidyl carbonate (DSC, ~1.3 eq.) or bis(4-nitrophenyl) carbonate in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h. Then (P9) is added (-1.6 eq.) and stirring is continued for 2-24 h at room temperature. Optionally, also the EGFR-inhibitor amines (P9) can be reacted first with the activated platinum(IV) precursors (P6) with subsequent activation and addition of the maleimide-containing amines (P8).

[0457] For (P8) also alcohol-functionalized compounds can be used instead of amines (Yempala, T. et al., Angew Chem Int Ed Engl, 2019, 58(50), 18218-18223).

[0458] o

[0459]

[0460] (P6) (P10) <P9> (P11)

[0461] Alternatively, also the respective amines (P8) and (P9) can be reacted with an activating agent like N, / V'-disuccinimidyl carbonate (DSC, -1.3 eq.) or bis(4-nitrophenyl) carbonate in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h and subsequently reacted with (P4).

[0462] The compounds of formula (I) can be synthesized out of the platinum(IV) precursors (P4) using the respective isocyanates (R-N=C=O) of R11NH2 or R6NH2 in an organic solvent like DMF or DMSO. 1) Such isocyanates can be prepared from the respective amines using e.g. phosgene or triphosgene (Kocz, R. et al., J. Org. Chem., 1994, 59(10), 2913-2914, doi: 10.1021 / jo00089a046). 2) Such isocyanates can be prepared from the respective carboxylic acids (R11COOH instead of R11NH2 or R6COOH instead of R6NH2) according to a procedure like: To a solution of the corresponding carboxylic acid in an organic solvent like acetone and 1.0-1.2 eq. of a base like triethylamine (at about -5°C), an alkyl chloroformate like ethyl chloroformate (1.0-1.2 eq.) in an organic solvent like acetone is added. Subsequently, NaNs (1 eq.) is added and stirring is continued without cooling for 20-60 min. The reaction mixture is poured into water and extracted with toluene. The combined organic layers are dried over MgSO4and heated to reflux at 120-140°C for 50-100 min. After removal of the solvent under reduced pressure, the crude product can be used without further purification.

[0463] Alternatively, the following procedure can be used: to a solution of the corresponding carboxylic acid in an organic solvent like anhydrous toluene and 1.0-1.2 eq. of a base like triethylamine diphenylphosphoryl azide (1 eq.) is added and the reaction mixture is stirred at room temperature for 3-10 h. A saturated NaHCO3(or 5% K2CO3) solution is added and the phases are separated. The organic layer is washed with sat. NaHCO3(or 5% K2CO3) solution and brine, dried over MgSO4filtered and subsequently refluxed for 15-24 h. After removal of the solvent under reduced pressure, the crude product can be used without further purification.

[0464] Compounds of formula (I) having other groups R8can be prepared in an analogous manner, i.e., following any of the synthetic procedures described herein above but using the corresponding precursor (of R8) in place of compound (P9).

[0465] Preparation of compounds of formula (P12):

[0466] The compounds of formula (P12) can be synthesized from compounds (P11) by stirring at high temperature (90-130 °C) in an aprotic organic solvent like DMF, DMSO or toluene (with or without strong organic acids like TFA or methanesulfonic acid) for 2-24 h.

[0467] o o

[0468]

[0469] (P11) (P12)

[0470] Preparation of compounds of formula (P15):

[0471] The compounds (P15) can be synthesized from the activated platinum(IV) precursors (P5) using oxadiazole-containing amines (P13) and EGFR-inhibitor amines (P9) in consecutive order in an organic solvent like DMF or DMSO (in case of salts a base is added for neutralization). The first amine is typically added in a slight deficit (0.9-1.0 eq.) and optionally stirred for 0.1- 4 h at r.t., whereas the second amine is added in a slight excess (1.0-1.5 eq.) and stirred at r.t. for 2-24 h.

[0472]

[0473] (P15) Alternatively, compounds (P15) can be synthesized from the activated platinum(IV) precursors (P6) using oxadiazole-containing amines (P13) in an organic solvent like DMF or DMSO to generate the compounds (P14) (in case of salts a base is added for neutralization). Subsequently, the remaining axial OH ligand is again reacted with an activating agent like / V, / V'-disuccinimidyl carbonate (DSC, ~1.3 eq.) or bis(4-nitrophenyl) carbonate in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h. Then (P9) is added (-1.6 eq.) and stirring is continued for 2-24 h at room temperature. Optionally, also the EGFR-inhibitor amines (P9) can be reacted first with the activated platinum(IV) precursors (P6) with subsequent activation and addition of the oxadiazole-containing amines (P13).

[0474] For (P13), also alcohol-functionalized compounds can be used instead of amines (Yempala, T. et al., Angew Chem Int Ed Engl, 2019, 58(50), 18218-18223).

[0475] (P14)

[0476]

[0477] (P15)

[0478] Compounds (P16) and (P17), where the albumin-binding unit R7is attached via a carboxylic acid (R7R6R5COOH) can be synthesized out of the platinum(IV) precursors (P4), R7R6R5COOH and any peptide-coupling reagent like DCC ( / V, / V'-dicyclohexylcarbodiimide) or TBTLI (N, N, N', N -tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoro bo rate) etc. (Zhang, J. Z. et al., Chem. Eur. J., 2013, 19, 1672-1676, doi: 10.1002 / chem.201203159). Alternatively, before coupling to (P4) the carboxylic acid R7R6R5COOH can be converted to an isocyanate, symmetric or asymmetric anhydride or acyl chloride.

[0479] General procedure for the preparation of isocyanates:

[0480] To a solution of the corresponding carboxylic acid in an organic solvent like acetone and 1.0-1.2 eq. of a base like triethylamine (at about -5°C), an alkyl chloroformate like ethyl chloroformate (1.0-1.2 eq.) in an organic solvent like acetone is added. Subsequently, NaNs (1 eq.) is added and stirring is continued without cooling for 20-60 min. The reaction mixture is poured into water and extracted with toluene. The combined organic layers are dried over MgSO4and heated to reflux at 120-140°C for 50-100 min. After removal of the solvent under reduced pressure, the crude product can be used without further purification.

[0481] Alternatively, the following procedure can be used: to a solution of the corresponding carboxylic acid in an organic solvent like anhydrous toluene and 1.0-1.2 eq. of a base like triethylamine diphenylphosphoryl azide (1 eq.) is added and the reaction mixture is stirred at room temperature for 3-10 h. A saturated NaHCO3(or 5% K2CO3) solution is added and the phases are separated. The organic layer is washed with sat. NaHCO3(or 5% K2CO3) solution and brine, dried over MgSO4filtered and subsequently refluxed for 15-24 h. After removal of the solvent under reduced pressure, the crude product can be used without further purification.

[0482] General procedure for the preparation of anhydrides:

[0483] Symmetric anhydrides can be prepared using triphosgene (Kocz, R. et al. J. Org. Chem., 1994, 59(10), 2913-2914, doi: 10.1021 / jo00089a046). Asymmetric anhydrides can be synthesized either using acetic anhydride (Hofer, D et al., J. Inorg. Biochem., 2015, 153, 259-271, doi: 10.1016 / j.jinorgbio.2015.08.018), acyl chlorides (Kim, S. et al., J Org. Chem., 1985, 50, 560-565, doi: 10.1021 / jo00205a004) or alkylchloroformates.

[0484] General procedure for the preparation of acyl chlorides:

[0485] Acyl chlorides can be prepared from the carboxylic acids using for example oxalyl chloride and dimethylformamide as a catalyst (Mantovani, G. et al., J. Am. Chem. Soc., 2005, 127, 2966-2973, doi: 10.1021 / ja0430999).

[0486] Preparation of compounds of formula (P19):

[0487] The compounds (P19) can be synthesized from the activated platinum(IV) precursors (P5) using maleimide-containing amines (P8) and EGFR-inhibitor amines (P18) in consecutive order in an organic solvent like DMF or DMSO (in case (P8) and / or (P18) are used in salt form, e.g. as HCI salt(s), a base is added for neutralization). The first amine is typically added in a slight deficit (0.9-1.0 eq.) and optionally stirred for 0.1- 4 h at r.t., whereas the second amine is added in a slight excess (1.0-1.5 eq.) and stirred at r.t. for 2-24 h.

[0488]

[0489] (P5) (P19) Alternatively, compounds (P19) can be synthesized from the activated platinum(IV) precursors (P6) using maleimide-containing amines (P8) in an organic solvent like DMF or DMSO to generate the compounds (P10) (in case (P8) is used in salt form, e.g. as an HCI salt, a base is added for neutralization). Subsequently, the remaining axial OH ligand is again reacted with an activating agent like / , / V'-disuccinimidyl carbonate or bis(4-nitrophenyl) carbonate (1.0-1.5 eq.; e.g., ~1.3 eq.) in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h. Then (P18) is added (1.0-2.0 eq.; e.g., -1.6 eq.) and stirring is continued for 2-24 h at room temperature. Optionally, also the EGFR-inhibitor amines (P18) can be reacted first with the activated platinum(IV) precursors (P6) with subsequent activation and addition of the maleimide-containing amines (P8).

[0490] For (P8) also alcohol-functionalized compounds can be used instead of amines (Yempala, T. et al., Angew Chem Int Ed Engl, 2019, 58(50), 18218-18223).

[0491] o

[0492]

[0493] (P6) (P10) (P18) (P19)

[0494] Alternatively, also the respective amines (P8) and (P18) can be reacted with an activating agent like / V, / V'-disuccinimidyl carbonate or bis(4-nitrophenyl) carbonate (-1.3 eq.) in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h and subsequently be reacted with (P4).

[0495] Preparation of compounds of formula (P20):

[0496] The compounds of formula (P20) can be synthesized from compounds (P19) by stirring at high temperature (90-130 °C) in an aprotic organic solvent like DMF, DMSO or toluene (with or without strong organic acids like TFA or methanesulfonic acid) for 2-24 h.

[0497] o

[0498]

[0499] (P19) Preparation of compounds of formula (P21):

[0500] The compounds (P21) can be synthesized from the activated platinum(IV) precursors (P5) using oxadiazole-containing amines (P13) and EGFR-inhibitor amines (P18) in consecutive order in an organic solvent like DMF or DMSO (in case (P13) and / or (P18) are used in salt form, e.g. as HCI salt(s), a base is added for neutralization). The first amine is typically added in a slight deficit (0.9-1.0 eq.) and optionally stirred for 0.1- 4 h at r.t., whereas the second amine is added in a slight excess (1.0-1.5 eq.) and stirred at r.t. for 2-24 h.

[0501] (P18)

[0502]

[0503] Alternatively, compounds (P21) can be synthesized from the activated platinum(IV) precursors (P6) using oxadiazole-containing amines (P13) in an organic solvent like DMF or DMSO to generate the compounds (P14) (in case (P13) is used in salt form, e.g. as an HCI salt, a base is added for neutralization). Subsequently, the remaining axial OH ligand is again reacted with an activating agent like A / . / V'-disuccinimidyl carbonate or bis(4-nitrophenyl) carbonate (~1.3 eq.) in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h. Then (P18) is added (-1.6 eq.) and stirring is continued for 2-24 h at room temperature. Optionally, also the EGFR-inhibitor amines (P18) can be reacted first with the activated platinum(IV) precursors (P6) with subsequent activation and addition of the oxadiazole-containing amines (P13).

[0504] For (P13), also alcohol-functionalized compounds can be used instead of amines (Yempala, T. et al., Angew Chem Int Ed Engl, 2019, 58(50), 18218-18223). (P14)

[0505]

[0506] (P21)

[0507] Preparation of compounds (P16) and (P17):

[0508] Compounds (P16) can be synthesized out of the platinum(IV) precursors (P4) and R7R6R5COOH using any peptide-coupling reagent like DCC ( / V, / V'-dicyclohexylcarbodiimide) or TBTLI (N, N, N', N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate) etc. in an organic solvent, with or without a base (Zhang, J. Z. et al., Chem. Eur. J., 2013, 19, 1672-1676, doi: 10.1002 / chem.201203159). Alternatively, the carboxylic acid R7R6R5COOH can be converted to a symmetric or asymmetric anhydride or acyl chloride and attached to (P4) in an organic solvent like DMF or acetone (with or without a base).

[0509] Alternatively, R7R6R5COOH can be converted to the respective isocyanate, in an organic solvent like toluene, acetone or DMF to form the corresponding compounds (P17).

[0510] O

[0511] OH

[0512] R3R1

[0513] ^Pt

[0514] R4R2

[0515] OH

[0516] (P4)

[0517] OH

[0518]

[0519] (P17) Subsequently, the remaining axial OH ligand in (P16) and (P17) is reacted with an activating agent like / V, / V'-disuccinimidyl carbonate or bis(4-nitrophenyl) carbonate (~1.3 eq.) in an aprotic organic solvent like DMF, DMSO, THF or acetonitrile (with or without base) at room temperature for 2-6 h. Then an EGFR-inhibitor amine (P9) or (P18) is added (-1.6 eq.) and stirring is continued for 2-24 h at room temperature to form the corresponding compound of formula (I). Optionally, also the EGFR-inhibitor amines (P9) or (P18) can be reacted first with the activated platinum(IV) precursors (P6) with subsequent attachment of R7R6R5COOH using any peptide-coupling reagent like DCC ( / V, / V'-dicyclohexylcarbodiimide) or TBTLI (N, N, N', N'-tetramethyl-O-(benzotriazol-l-yl)uronium tetrafluoroborate). Alternatively, before coupling of the carboxylic acid (R7R6R5COOH) it can be converted to an isocyanate, symmetric or asymmetric anhydride or acyl chloride.

[0520] Compounds having other groups R8can be prepared analogously, using the corresponding EGFR-inhibitor precursor instead of (P9) or (P18).

[0521] The following definitions apply throughout the present specification, unless specifically indicated otherwise.

[0522] As used herein, the term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0523] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-8alkyl” denotes an alkyl group having 1 to 8 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0524] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-8alkenyl” denotes an alkenyl group having 2 to 8 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4alkenyl. As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more carbon-to-carbon double bonds. The term “C2-8 alkynyl” denotes an alkynyl group having 2 to 8 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2-4 alkynyl.

[0525] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group, which may be linear or branched. A “C1-8alkylene” denotes an alkylene group having 1 to 8 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C1-4alkylene (including, in particular, linear C14 alkylene), more preferably to methylene or ethylene.

[0526] As used herein, the term “alkenylene” refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A “C2-5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkenylene” preferably refers to C2-4alkenylene (including, in particular, linear C2-4alkenylene).

[0527] As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. A “carbocyclyl” may, for example, have 3 to 14 ring atoms. Unless defined otherwise, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0528] As used herein, the term “carbocyclylene” refers to a carbocyclyl group, as defined herein above, but having two points of attachment (i.e., a divalent carbocyclyl group). Unless defined otherwise, “carbocyclylene” preferably refers to arylene, cycloalkylene or cycloalkenylene.

[0529] As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. A “heterocyclyl” may, for example, have 3 to 14 ring atoms. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl. “Heterocyclyl” may, for example, refer to an oxadiazolyl or a piperazinyl group.

[0530] As used herein, the term “heterocyclylene” refers to a heterocyclyl group, as defined herein above, but having two points of attachment (i.e., a divalent heterocyclyl group). Unless defined otherwise, “heterocyclylene” preferably refers to heteroarylene, heterocycloalkylene or heterocycloalkenylene. “Heterocyclylene” may, for example, refer to a 1,3,4-oxadiazol-2,5-diyl group or a piperazin-1, 4-diyl group.

[0531] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0532] As used herein, the term “arylene” refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Arylene” may, e.g., refer to phenylene (e.g., phen-1,2-diyl, phen-1,3-diyl, or phen-1,4-diyl), naphthylene (e.g., naphthalen-1,2-diyl, naphthalen-1,3-diyl, naphthalen-1,4-diyl, naphthalen-1,5-diyl, naphthalen-1,6-diyl, naphthalen-1,7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2,7-diyl, or naphthalen-2,8-diyl), 1,2-dihydronaphthylene, 1,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless defined otherwise, an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen-1, 4-diyl).

[0533] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatomcontaining ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl), or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1.2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1,2,3-triazolyl, 2H- 1,2,3-triazolyl, 1 H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, the term “heteroaryl” particularly preferably refers to pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.

[0534] As used herein, the term “heteroarylene” refers to a heteroaryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatomcontaining ring. “Heteroarylene” may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, p-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g., 1,2,4-oxadiazol-3,5-diyl, 1,2,5-oxadiazol-3,4-diyl, or 1,3,4-oxadiazol-2,5-diyl), thiadiazolylene (e.g., 1,2,4-thiadiazol-3,5-diyl, 1,2,5-thiadiazol-3,4-diyl, or 1,3,4-thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1,5-a]pyrimidinylene, 1,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1,2,3-triazolylene, 2H-1,2,3-triazolylene, 1H-1,2,4-triazolylene, or 4H-1,2,4-triazolylene), benzotriazolylene, 1H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1,2,3-triazinylene, 1,2,4-triazinylene, or 1,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene, 1,3-benzodioxolylene, benzodioxanylene (e.g., 1,3-benzodioxanylene or 1,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, the term “heteroarylene” preferably refers to a divalent 5- to 14-membered (more preferably 5-to 10-membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroarylene” refers to a divalent 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. A “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene. Moreover, unless defined otherwise, the term “heteroarylene” particularly preferably refers to pyridinylene, imidazolylene, thiazolylene, 1H-tetrazolylene, 2H-tetrazolylene, thienylene (i.e., thiophenylene), or pyrimidinylene.

[0535] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Moreover, unless defined otherwise, the term “cycloalkyl” even more preferably refers to cyclohexyl or cyclopropyl, and yet even more preferably refers to cyclohexyl.

[0536] As used herein, the term “cycloalkylene” refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkylene” may, e.g., refer to cyclopropylene (e.g., cyclopropan-1,1-diyl or cyclopropan-1,2-diyl), cyclobutylene (e.g., cyclobutan-1,1-diyl, cyclobutan-1,2-diyl, or cyclobutan-1,3-diyl), cyclopentylene (e.g., cyclopentan- 1, 1-diyl, cyclopentan- 1, 2-diyl, or cyclopentan- 1, 3-diyl), cyclohexylene (e.g., cyclohexan-1, 1-diyl, cyclohexan-1, 2-diyl, cyclohexan-1,3-diyl, or cyclohexan-1, 4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless defined otherwise, “cycloalkylene” preferably refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene. A particularly preferred “cycloalkylene” is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Moreover, unless defined otherwise, particularly preferred examples of a “cycloalkylene” include cyclohexylene or cyclopropylene, particularly cyclohexylene.

[0537] As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3- to 11-membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5- to 7-membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, “heterocycloalkyl” even more preferably refers to tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.

[0538] As used herein, the term “heterocycloalkylene” refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkylene” may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1,3-dithiolanylene, thianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless defined otherwise, “heterocycloalkylene” preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a “heterocycloalkylene” include tetrahydropyranylene, piperidinylene, piperazinylene, morpholinylene, pyrrolidinylene, or tetrahydrofuranylene.

[0539] As used herein, the term “cycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. “Cycloalkenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, “cycloalkenyl” preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0540] As used herein, the term “cycloalkenylene” refers to a cycloalkenyl group, as defined herein above, but having two points of attachment, i.e. a divalent unsaturated alicyclic (i.e., non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. “Cycloalkenylene” may, e.g., refer to cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cyclohexadienylene, cycloheptenylene, or cycloheptadienylene. Unless defined otherwise, “cycloalkenylene” preferably refers to a C3-11 cycloalkenylene, and more preferably refers to a C3-7 cycloalkenylene. A particularly preferred “cycloalkenylene” is a divalent monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0541] As used herein, the term “heterocycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1, 2, 3, 4, 4a, 5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, “heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0542] As used herein, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined herein above, but having two points of attachment, i.e. a divalent unsaturated alicyclic (i.e., non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatomcontaining ring comprised in said unsaturated alicyclic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenylene” may, e.g., refer to imidazolinylene, tetrahydropyridinylene, dihydropyridinylene, pyranylene, thiopyranylene, dihydropyranylene, dihydrofuranylene, dihydropyrazolylene, dihydropyrazinylene, dihydroisoindolylene, octahydroquinolinylene, or octahydroisoquinolinylene. Unless defined otherwise, “heterocycloalkenylene” preferably refers to a divalent 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenylene” refers to a divalent 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0543] As used herein, the term “halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

[0544] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3.

[0545] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0546] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0547] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0548] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

[0549] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated.

[0550] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, including the upper and lower endpoints of each numerical range, as well as each subrange encompassed by a numerical range disclosed herein.

[0551] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia", i.e., “containing, among further optional elements,...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of” and “consisting of”. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0552] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair, which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. If the compound of formula (I) is in the form of a pharmaceutically acceptable salt, it is preferably in the form of a hydrochloride salt. More preferably, however, the compound of formula (I), including any one of the specific compounds of formula (I) described herein (such as KP3038), is not in the form of a salt.

[0553] Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol or acetonitrile (i.e., as a methanolate, ethanolate or acetonitrilate), or in any crystalline form (i.e., as any polymorph), or in amorphous form. It is to be understood that such solvates of the compounds of the formula (I) also include solvates of pharmaceutically acceptable salts of the compounds of the formula (I).

[0554] Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. In particular, if one or both of the ligand pairs R1 / R2and R3 / R4is / are asymmetric, e.g., due to their substitution pattern or the presence of moiety (A3) and / or moiety (B2), the platinum(IV) atom in the corresponding compound of formula (I) will form a stereocenter, resulting in stereoisomers that differ with respect to the orientation of the two axial ligands (i.e., the axial ligand comprising R5, R6and R7as well as the axial ligand comprising R8); any such stereoisomers of the compounds of formula (I) are likewise encompassed by the present invention. The present invention further encompasses any tautomers of the compounds provided herein.

[0555] The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0556] The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,11C,13N,15O,76Br,77Br,120l and / or124l. Such compounds can be used as tracers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

[0557] The compounds provided herein may be administered as compounds per se or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0558] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0559] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, or intraperitoneal (especially in form of hyperthermic chemoperfusion) administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders, and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.

[0560] The compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, or ophthalmic (including intravitreal or intracameral) administration.

[0561] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution, which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0562] Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0563] Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. Liposomes containing a compound of the present invention can be prepared by methods known in the art.

[0564] Said compounds or pharmaceutical compositions may also be administered by the pulmonary route or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0565] It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification / spray drying process.

[0566] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; or ophthalmic route, including by intravitreal, or intracameral route. Particularly preferred routes of administration are parenteral administrations like, e.g., intravenous and intraperitoneal (during hyperthermic chemoperfusion).

[0567] Typically, a physician will determine the actual dosage, which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0568] A proposed, yet non-limiting dose of the compounds according to the invention for intravenous administration to a human (of approximately 70 kg body weight) may be 10 to 1000 mg, preferably 40 to 120 mg, of the active ingredient (such as KP3038) per unit dose. The unit dose may be administered, e.g., once every two weeks. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0569] The compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can be administered in monotherapy (e.g., without concomitant administration of any further therapeutic agents or, in particular, without concomitant administration of any further anticancer drugs). However, the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can also be administered in combination with one or more further therapeutic agents. If the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition (e.g., a further anticancer drug), the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compound of formula (I) with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compound of formula (I) and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compound of formula (I) and the further therapeutic agent(s). If administration is sequential, either the compound of formula (I) according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or they may be administered in one or more different (separate) pharmaceutical formulations.

[0570] Preferably, the one or more further therapeutic agents to be administered in combination with a compound of the present invention are anticancer drugs. The anticancer drug(s) to be administered in combination with a compound of formula (I) according to the invention may, e.g., be selected from: an angiogenesis inhibitor (e.g., a protease inhibitor, a fibroblast growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytostatic drug (e.g., an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (e.g., a microtubule-stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (e.g., a nitrogen mustard or a nitrosourea); an endocrine agent (e.g., an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, an anti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analog); or a compound that targets an enzyme or receptor that is overexpressed and / or otherwise involved in a specific metabolic pathway that is misregulated / deregulated in the tumor cell (e.g., ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors, e.g., Abelson protein tyrosine kinase inhibitors) and the various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors, PI3K inhibitors and platelet-derived growth factor receptor kinase inhibitors)); methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase- 1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), poly ADP ribose polymerase inhibitors (PARP inhibitors), mammalian target of rapamycin inhibitors (mTOR inhibitors) and epidermal growth factor receptor (EGFR) inhibitors / antagonists. In addition, this also includes combination with an immunooncology therapeutic agent e.g. targeting CTLA-4, PD-1 / PD-L1 but also other immune-stimulatory strategies.

[0571] An alkylating agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N, N'N'-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazine (such as temozolomide).

[0572] A cytotoxic drug, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analogue antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogue antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or6-thioguanine), and pyrimidine analogue antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

[0573] An antimitotic agent, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel, or nab-paclitaxel (e.g., Abraxane®)), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analogue (such as ixabepilone / azaepothilone B).

[0574] An anti-tumor antibiotic, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).

[0575] A tyrosine kinase inhibitor, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, or vandetanib.

[0576] A topoisomerase inhibitor, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).

[0577] A PARP inhibitor, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, BMN-673, olaparib, rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide.

[0578] An mTOR inhibitor, which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, temsirolimus, everolimus, sirolimus, or Fyarro (sirolimus protein bound).

[0579] Further anticancer drugs may also be used in combination with a compound of the present invention. The anticancer drugs may comprise biological or chemical molecules, like TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sitimagene, ceradenovec, tegafur, testolactone, tiazofurine, tipifarnib, vorinostat, or iniparib.

[0580] Also, biological drugs, like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), antibody conjugates (such as antibody-drug conjugates), and / or modified antibodies (like CDR-grafted antibodies, humanized antibodies, “full humanized” antibodies, etc.) directed against cancer or tumor markers / factors / cytokines involved in proliferative diseases can be employed in co-therapy approaches with the compounds of the invention. Examples of such biological molecules are anti-HER2 antibodies (e.g. trastuzumab, Herceptin®), anti-CD20 antibodies (e.g. Rituximab, Rituxan®, MabThera®, Reditux®), anti-CD19 / CD3 constructs (see, e.g., EP1071752) and anti-TNF antibodies (see, e.g., Taylor PC. Antibody therapy for rheumatoid arthritis. Curr Opin Pharmacol. 2003. 3(3): 323-328). Further antibodies, antibody fragments, antibody constructs and / or modified antibodies to be used in cotherapy approaches with the compounds of the invention can be found, e.g., in: Taylor PC. Curr Opin Pharmacol. 2003. 3(3):323-328; or Roxana A. Maedica. 2006. 1 (1):63-65. Examples of antibody-drug conjugates to be used in combination with a compound of the present invention include, in particular, gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, loncastuximab tesirine, tisotumab vedotin, or mirvetuximab soravtansine.

[0581] An anticancer drug, which can be used in combination with a compound of the present invention may, in particular, be an immunooncology therapeutic (such as an antibody (e.g., a monoclonal antibody or a polyclonal antibody), an antibody fragment, an antibody construct (e.g., a singlechain construct), an antibody conjugate (e.g., an antibody-drug conjugate), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a “full humanized” antibody) targeting any one of CTLA-4, PD-1, PD-L1, TIM3, LAG3, 0X4, CSF1R, IDO, CD40, TIGIT, VISTA, BTLA, CD47, or CCR8. Such immunooncology therapeutics include, e.g., an anti-CTLA-4 antibody (particularly an antagonistic or pathway-blocking anti-CTLA-4 antibody; e.g., ipilimumab or tremelimumab), an anti-PD-1 antibody (particularly an antagonistic or pathwayblocking anti-PD-1 antibody; e.g., nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab (CT-011), cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, APE02058, or JTX-4014), an anti-PD-L1 antibody (particularly a pathway-blocking anti-PD-L1 antibody; e.g., atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, bintrafusp alfa, CK-301, BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, or MEDI6469), an anti-TIM3 antibody (particularly a pathway-blocking anti-TIM3 antibody; e.g., sabatolimab, cobolimab, lomvastomig, BGB-A425, INCAGN02390, LY3321367, LY3415244, or Sym023), an anti-LAG3 antibody (particularly an antagonistic or pathway-blocking anti-LAG3 antibody; e.g., relatlimab (BMS-986016), ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, or IMP731), an anti-0X4 antibody (particularly an agonistic anti-0X4 antibody; e.g., MEDI0562), an anti-CSF1R antibody (particularly a pathway-blocking anti-CSF1R antibody; e.g., IMC-CS4 or RG7155), an anti-IDO antibody (particularly a pathway-blocking anti-IDO antibody), an anti-CD40 antibody (particularly an agonistic anti-CD40 antibody; e.g., CP-870,893 or Chi Lob 7 / 4), an anti-TIGIT antibody (e.g., tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, or M6223), an anti-VISTA antibody (e.g., onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, orAPX-201), an anti-BTLA antibody (e.g., tifcemalimab, icatolimab, ANB032, or HFB200603), an anti-CD47 antibody (e.g., magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, or TI-061), or an anti-CCR8 antibody (e.g., BMS-986340, S-531011, BAY-3375968, GS-1811 (or JTX-1811), FPA157, SRF114, HBM1022, or LM-108). Further immunooncology therapeutics are known in the art and are described, e.g., in: Kyi C et al., FEBS Lett, 2014, 588(2):368-76; Intlekofer AM et al., J Leukoc Biol, 2013, 94(1):25-39; Callahan MK et al., J Leukoc Biol, 2013, 94(1):41-53; Ngiow SF et al., Cancer Res, 2011, 71(21):6567-71; and Blattman JN et al., Science, 2004, 305(5681 ):200-5.

[0582] It is particularly preferred that the compounds of formula (I), such as KP3038, are to be administered in combination with folinic acid or a pharmaceutically acceptable salt thereof (e.g., leucovorin calcium or leucovorin sodium) and 5-fluorouracil.

[0583] A further example of a combination therapy may comprise the administration of a compound of formula (I) in combination with a taxane (such as, e.g., paclitaxel / taxol, nab-paclitaxel (e.g., Abraxane®), docetaxel, larotaxel, ortataxel, or tesetaxel; preferably paclitaxel or nab-paclitaxel; more preferably paclitaxel) and an anti-PD-1 antibody (particularly an antagonistic anti-PD-1 antibody; such as, e.g., nivolumab, pembrolizumab, pidilizumab, AMP-224, or APE02058; preferably nivolumab). It is preferred that said compound of formula (I) is to be administered in combination with paclitaxel and nivolumab.

[0584] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously / concomitantly in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof) or the further therapeutic agent(s) may be administered first. When administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation.

[0585] The compounds of formula (I) can also be administered in combination with physical therapy, such as radiotherapy. Radiotherapy may commence before, after, or simultaneously with administration of the compounds of the invention. For example, radiotherapy may commence 1-10 minutes, 1-10 hours or 24-72 hours after administration of the compounds. Yet, these time frames are not to be construed as limiting. The subject is exposed to radiation, preferably gamma radiation, whereby the radiation may be provided in a single dose or in multiple doses that are administered over several hours, days and / or weeks. Gamma radiation may be delivered according to standard radiotherapeutic protocols using standard dosages and regimens. The present invention thus relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more anticancer drugs and / or in combination with radiotherapy and / or immunotherapy.

[0586] Yet, the compounds of formula (I) can also be used in monotherapy, particularly in the monotherapeutic treatment or prevention of cancer (i.e., without administering any other anticancer agents until the treatment with the compound(s) of formula (I) is terminated). Accordingly, the invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the monotherapeutic treatment or prevention of cancer.

[0587] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, or a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate or a simian (e.g., a monkey or an ape, such as a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, or a gibbon), or a human. In accordance with the present invention, it is envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, a cattle, or a pig). Most preferably, the subject / patient is a human (e.g., a female human or a male human).

[0588] The term “treatment” of a disorder or disease as used herein (e.g., “treatment” of cancer) is well known in the art. “Treatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).

[0589] The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0590] The term “prevention” of a disorder or disease as used herein (e.g., “prevention” of cancer) is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term “prevention” comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0591] It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables comprised in formula (I). In this specification, a number of documents including patent applications, scientific literature and manufacturers’ manuals are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0592] The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0593] The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0594] EXAMPLES

[0595]

[0596] Synthesis of functionalized platinum compounds

[0597]

[0598] Scheme 1: Reaction scheme for the synthesis of ligands for the platinum complexes.

[0599]

[0600] Scheme 2: Reaction scheme for the synthesis of Mal-PEG(4)-NH2.

[0601]

[0602] Scheme 3: Reaction scheme for the synthesis of Oxadiazole-PEG(4)-NH2.

[0603]

[0604] Scheme 4: Reaction scheme for the synthesis of Oxadiazole-Pip-NH2. H3NV

[0605] H2O

[0606]

[0607] Scheme 5: Reaction scheme for the synthesis of the platinum complex precursors OxPt-4 / -5 and CarboPt-4.

[0608]

[0609] Scheme 6: Reaction scheme for the synthesis of the platinum complexes KP3037 (Method 1 and 2) and KP3038.

[0610]

[0611] Scheme 7: Reaction scheme for the synthesis of the platinum complexes OxaPEG-Carbo-KP2839 and OxaPip-Carbo-KP2839.

[0612]

[0613] Scheme 8: Reaction scheme for the synthesis of ligands for the platinum complexes. sequential addition, in DMF, r.t.

[0614] CarboPt-4 OxaliPt-4

[0615] Mal-PEG(4)-NH2

[0616] KP4060: Pt = oxaliplatin; R1= C(=O)OCH(CH3)2R2= CH3KP4061: Pt = oxaliplatin; R1= H, R2= cyclopropyl KP4062: Pt = oxaliplatin; R1= H, R2= H KP4070: Pt = carboplatin; R1= C(=O)OCH(CH3)2R2= CH3

[0617]

[0618] Scheme 9: Reaction scheme for the synthesis of the platinum complexes KP4060, KP4061, KP4062, KP4070 (also referred to as MalPEG-Carbo-Mobocertinib) and KP4072. Materials and Methods:

[0619] Milli-Q water (18.2 MQ cm, Merck Milli Q Advantage, Darmstadt, Germany) was used for synthesis as well as analytical and preparative RP-HPLC. Potassium tetrachloridoplatinate (K2[PtCl4]) was purchased from Johnson Matthey (Switzerland). Anhydrous solvents (DCM, DMF, DMSO, EtOH, THF and toluene) were purchased from CARLO ERBA Reagents or Acros Organics. All other chemicals and solvents were purchased from commercial suppliers (Aaron Chemicals, Alfa Aesar, Ambeed, BLDpharm, Acros Organics / Fisher Scientific, Fluka, Sigma Aldrich, TCI, VWR) and used without purification. Solvents for NMR measurements were purchased from Eurisotop. Silica gel (particle size 40-63 pm) for column chromatography was purchased from MACHEREY-NAGEL. Low-resolution ESI-MS spectra were measured on a Bruker amazon speed ETD mass spectrometer in postitive and negative mode. High-resolution mass spectra of final compounds were measured on either a Bruker timsTOF flex mass spectrometer or a Thermo Scientific Orbitrap Exploris™ 120 Mass Spectrometer with an ESI ion source in positive mode. All mass spectra were measured by direct infusion at the Mass Spectrometry Centre of the University of Vienna.1H NMR spectra of intermediate compounds were recorded at 25°C using a Bruker BioSpin AV NEO 500 spectrometer at 500.10 MHz. For the characterization of final compounds KP3037 and KP3038, one- and two-dimensional NMR spectra were recorded at 80°C using a Bruker BioSpin AV NEO 500 spectrometer.1H NMR spectra were measured at 500.32 MHz and13C NMR spectra at 125.81 MHz.1H NMR spectra of final compounds OxaPEG-Carbo-KP2839 and OxaPip-Carbo-KP2839 were measured at 25°C on a Bruker BioSpin AV NEO 600 spectrometer at 600.18 MHz. All NMR spectra were measured in deuterated dimethyl sulfoxide (DMSO-d6) or methanol (MeOD-ck). Chemical shifts (ppm) were referenced internally to the residual solvent peaks. For the description of the spin multiplicities the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, bs = broad singlet, dd = doublet of doublets, m = multiplet. Purification by preparative reverse-phase (RP) HPLC was performed on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) on an Agilent 1260 Infinity II system. Flow rates of 17 mL / min were constant for each run at 20°C. Elemental analysis measurements were performed on a Eurovector EA 3000 CHNS-0 Elemental Analyser at the Microanalytical Laboratory of the University of Vienna and are within ±0.4%, confirming >95% purity.

[0620] Procedure for the synthesis of ligand KP2839 (see Scheme 1):

[0621] Tert-butyl methyl(2-(methylamino)ethyl)carbamate (858 mg, 4.42 mmol), / V-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1 / 7-indol-3-yl)pyrimidin-2-amine (1160 mg, 2.95 mmol) and K2CO3(807 mg, 5.90 mmol) were dissolved in 20 mL DMF and heated at 100°C for 17 h. After cooling to room temperature (r.t.) the mixture was poured into 50 mL cold H2O, the precipitate filtered off and dried in vacuo at 50°C for 3.5 h. KP2839-1 was obtained as a bright orange solid (1604 mg, 97%).1H NMR(500 MHz, DMSO-d6): 6 = 8.68 (d, J= 21.7 Hz, 1H), 8.37 (d, J= 7.8 Hz, 1H), 8.33 (s, 1H), 8.32 (d, J= 5.4 Hz, 1H), 8.10 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.25 (t, J= 8.0 Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 43.1 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.41 (t, J = 6.0 Hz, 2H), 3.32-3.26 (m, 2H, overlap with water signal), 2.87 (d, J = 5.6 Hz, 3H), 2.77 (d, J= 5.6 Hz, 3H), 1.35 (d, J= 13.3 Hz, 9H) ppm. MS (m / z): calcd. C29H35N7O5 (M + H)+= 562.28; found, 562.47.

[0622] KP2839-1 (1640 mg, 2.92 mmol) was suspended in 60 mL EtOH and 20 mL H2O before Fe (988 mg, 17.52 mmol) and NH4CI (118 mg, 2.19 mmol) were added. The mixture was heated at 100°C for 16 h, cooled to r.t. and all volatiles were removed. The residue was taken up in 40 mL DCM, filtered and the filter washed with another 40 mL DCM. The filtrate was dried over Na2SO4 and filtered again. The filtrate was then reduced in vacuo to give 1560 mg crude product, which was purified by silica column chromatography using 2.5% MeOH in DCM as the eluent. After solvent removal, KP2839-2 was obtained as a light-yellow foam (1402 mg, 89%).1H NMR (500 MHz, DMSO-d6): 6 = 8.42 (d, J = 8.0 Hz, 1 H), 8.31 (s, 1 H), 8.27 (d, J = 5.3 Hz, 1 H), 7.79 (s, 1H), 7.54-7.47 (m, 2H), 7.24 (t, J= 7.2 Hz, 1H), 7.19-7.12 (m, 2H), 6.77 (s, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H), 2.79 (d, J = 19.5 Hz, 3H), 2.66-2.59 (m, 3H), 1.39 (s, 9H) ppm. 2H below the water signal. MS (m / z): calcd. C29H37N7O3 (M + H)+= 532.30; found, 532.42.

[0623] KP2839-2 (1400 mg, 2.61 mmol) and DIPEA (920 pL, 5.21 mmol) were dissolved in 30 mL dry DCM and cooled to ca. -80°C using liquid IXh / acetone. A solution of acryloyl chloride (219 pL, 2.61 mmol) in 8 mL dry DCM was added under Ar atmosphere at a flow rate of 40 pL / min. After the addition, the mixture was warmed up very slowly by allowing the cold bath to reach -10°C. Stirring was then continued in cold water for 5 min, then at r.t. for 50 min. The reaction mixture was diluted with DCM to a total volume of 70 mL and washed 1x with 70 mL saturated NaHCO₃ solution. The organic phase was dried over Na2SC>4 and filtered. The filtrate was reduced in vacuo to give 1684 mg crude product, which was purified by silica column chromatography using 10% acetone in DCM as the eluent. KP2839-3 was obtained as a light-yellow foam (1345 mg, 86%).1H NMR (500 MHz, DMSO-d6): 5 = 9.14 (d, J = 31.8 Hz, 1H), 8.95 (s, 1H), 8.61 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.27-7.20 (m, 2H), 7.16 (t, J= 7.5 Hz, 1H), 6.98 (s, 1H), 6.67 (dd, J= 16.5, 10.1 Hz, 1H), 6.26 (d, J = 16.7 Hz, 1H), 5.75 (dd, J= 10.0, 1.6 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.04-2.93 (m, 2H), 2.76 (d, J = 20.0 Hz, 3H), 2.71 (bs, 3H), 1.36 (s, 9H) ppm. 2H below the water signal. MS (m / z): calcd. C32H39N7O4 (M + H)+= 586.31; found, 586.41.

[0624] KP2839-3 (1277 mg, 2.14 mmol) was dissolved in 27 mL DCM and TFA (6.0 mL, 77.10 mmol) was added. The mixture was stirred for 1 h at r.t. and the solvent was removed in vacuo on the Schlenk like. The dry residue was re-dissolved in DCM and the volatiles again removed in vacuo, on the rotovap. The residue was then dissolved in H2O and lyophilized. KP2839 was obtained as a bright-yellow, solid TFA salt hydrate (1667 mg).1H NMR (500 MHz, DMSO-d6): 5 = 9.38 (s, 1H), 8.68 (s, 1H), 8.62 (bs, 1H), 8.54-8.38 (m, 2H), 8.37-8.10 (m, 2H), 7.57 (d, J= 8.2 Hz, 1H), 7.32 (d, J= 6.0 Hz, 1H), 7.27 (t, J= 7.6 Hz, 1H), 7.16 (t, J= 7.0 Hz, 1H), 7.03 (s, 1H), 6.69 (dd, J= 16.9, 10.2 Hz, 1H), 6.28 (dd, J = 17.0, 1.6 Hz, 1H), 5.80 (d, J= 11.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.24 (t, J = 5.6 Hz, 2H), 3.15 (quint, J= 5.6 Hz, 2H), 2.66-2.60 (m, 6H) ppm. MS (m / z): calcd. C27H31N7O2 (M + H)+= 486.26; found, 486.37.

[0625] Procedure for the synthesis of ligand KP2840 (see Scheme 1):

[0626] Tert-butyl (2-(methylamino)ethyl)carbamate (416 mg, 2.37 mmol), / V-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1 / 7-indol-3-yl)pyrimidin-2-amine (620 mg, 1.58 mmol) and K2CO3(440 mg, 3.15 mmol) were dissolved in 18 mL DMF and heated at 100°C for 9 h. After cooling to r.t. the mixture was poured into 100 mL cold H2O, the precipitate filtered off and dried in vacuo at 40°C over night. KP2840-1 was obtained as a red solid (880 mg, quant. Yield).1H NMR (500 MHz, DMSO-d6): 6 = 8.66 (s, 1 H), 8.36 (d, J = 7.6 Hz, 1 H), 8.33 (s, 1 H), 8.31 (d, J = 5.4 Hz, 1H), 8.09 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.21 (d, J= 5.4 Hz, 1H), 7.12 (t, J= 7.4 Hz, 1H), 6.86 (s, 1H), 6.84 (t, J= 5.2 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.25-3.15 (m, 4H), 2.84 (s, 3H), 1.33 (s, 9H) ppm. MS (m / z): calcd. C28H33N7O5 (M + H)+= 548.26; found, 548.30.

[0627] KP2840-1 (870 mg, 1.56 mmol) was suspended in 33 mL EtOH and 11 mL H2O before Fe (527 mg, 9.35 mmol) and NH4CI (63 mg, 1.17 mmol) were added. The mixture was heated at 100°C for 3.5 h, cooled to r.t. and all volatiles were removed. The residue was taken up in 60 mL DCM containing 10% MeOH, filtered and the filter washed with another 60 mL DCM containing 10% MeOH. The filtrate was washed 2x with 60 mL brine, dried over Na2SO4 and filtered again. The filtrate was then reduced in vacuo to give 854 mg crude product, which was purified by silica column chromatography using 2% MeOH in DCM as the eluent. After solvent removal, KP2840-2 was obtained as a light-yellow foam (763 mg, 92%).1H NMR (500 MHz, DMSO-d6): 5 = 8.42 (d, J = 8.0 Hz, 1 H), 8.31 (s, 1 H), 8.26 (d, J = 5.3 Hz, 1 H), 7.79 (s, 1H), 7.51 (d, J= 8.2 Hz, 1H), 7.49 (s, 1H), 7.24 (t, J= 7.6 Hz, 1H), 7.19-7.13 (m, 2H), 6.89 (t, J= 5.7 Hz, 1H), 6.74 (s, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.08 (q, J= 6.3 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H), 1.38 (s, 9H) ppm. MS (m / z): calcd. C28H35N7O3 (M + H)+= 518.29; found, 518.32.

[0628] KP2840-2 (691 mg, 1.29 mmol) and DIPEA (457 pL, 2.59 mmol) were dissolved in 15 mL dry DCM and cooled to ca. -80°C using liquid N2 / acetone. A solution of acryloyl chloride (109 pL, 1.29 mmol) in 4.2 mL dry DCM was added under Ar atmosphere at a flow rate of 40 pL / min. After the addition, the mixture was warmed up very slowly by allowing the cold bath to reach -15°C. Stirring was then continued in an ice bath for 10 min, then at r.t. for 40 min. The reaction mixture was diluted with 70 mL DCM containing 10% MeOH and washed 3x with 70 mL saturated NaHCO3solution. The organic phase was dried over Na2SC>4 and filtered. The filtrate was reduced in vacuo to give 800 mg crude product, which was purified by silica column chromatography using 10% acetone in DCM as the eluent. KP2840-3 was obtained as a lightyellow foam (678 mg, 87%).1H NMR (500 MHz, DMSO-d6): 6 = 9.23 (s, 1H), 9.02 (s, 1H), 8.63 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.91 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.26-7.21 (m, 2H), 7.15 (t, J= 7.5 Hz, 1H), 7.04 (t, J = 5.3 Hz, 1H), 6.98 (s, 1H), 6.72 (dd, J = 16.9, 10.2 Hz, 1H), 6.27 (dd, J= 16.8, 1.1 Hz, 1H), 5.75 (dd, J= 10.5, 1.6 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.10 (q, J = 6.0 Hz, 2H), 2.90 (t, J = 6.2 Hz, 2H), 2.64 (s, 3H), 1.37 (s, 9H) ppm.

[0629] MS (m / z): calcd. C31H37N7O4 (M + H)+= 572.30; found, 572.35.

[0630] KP2840-3 (668 mg, 1.11 mmol) was dissolved in 20 mL DCM and TFA (4.547 mL, 58.42 mmol) was added. The mixture was stirred for 40 min at r.t. and the solvent was removed in vacuo on the Schlenk like. The dry residue was re-dissolved in DCM and the volatiles again removed in vacuo, on the rotovap. The residue was then dissolved in H2O, lyophilized and dried in vacuo at 40°C for 24 h. KP2840 was obtained as a bright-yellow, solid TFA salt hydrate (831 mg).

[0631] 1H NMR (500 MHz, DMSO-d6): 5 = 9.33 (s, 1H), 9.03-8.03 (bs, 1H) 8.68 (s, 2H), 8.27 (s, 2H), 7.82 (s, 3H), 7.56 (d, J = 8.2 Hz, 1H), 7.31 (d, J= 5.9 Hz, 1H), 7.27 (t, J= 7.6 Hz, 1H), 7.16 (t, J = 7.1 Hz, 1H), 7.01 (s, 1H), 6.69 (dd, J= 17.0, 10.3 Hz, 1H), 6.27 (dd, J= 17.0, 1.8 Hz, 1H), 5.79 (dd, J= 10.3, 1.6 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.20 (t, J= 5.7 Hz, 2H), 3.08-3.01 (m, 2H), 2.61 (s, 3H) ppm. MS (m / z): calcd. C26H29N7O2 (M + H)+= 472.25; found, 472.28.

[0632] Procedure for the synthesis of ligand KP2890 (see Scheme 1):

[0633] / V, / V'-Dimethylpropane-1,3-diamine (1.8 mL, 14.33 mmol) was dissolved in 40 mL dry DCM and a solution of di-terf-butyl dicarbonate (1071 mg, 4.81 mmol) in 20 mL dry DCM was added under Ar atmosphere with an automated syringe pump at a flow rate of 50 pL / min at 0°C. The mixture was warmed to r.t. and stirred for another 45 min. The mixture was washed with 70 mL H2O and the aqueous phase extracted 3x with EtOAc. The combined aqueous phases were washed 2x with brine, dried over MgSCL, filtered and the filtrate reduced in vacuo. KP2890-1 was obtained as a clear oil (870 mg, 89%).1H NMR (500 MHz, DMSO-d6) 5 = 3.17 (t, J = 7.1 Hz, 2H), 3.15-3.07 (m, 1H), 2.75 (bs, 3H), 2.40 (t, J= 6.7 Hz, 2H), 2.25 (s, 3H), 1.57 (quint, J = 6.8 Hz, 2H), 1.38 (s, 9H) ppm. MS (m / z): calcd. C10H22N2O2 (M + H)+= 203.18; found, 203.12. KP2890-1 (456 mg, 2.25 mmol), A / -(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1 / 7-indol-3-yl)pyrimidin-2-amine (591 mg, 1.50 mmol) and K2CO3(420 mg, 3.01 mmol) were dissolved in 9 mL DMF and heated at 100°C for 9 h. After cooling to r.t. the mixture was poured into 100 mL cold H2O, the precipitate filtered off and dried in vacuo at 40°C over night. KP2890-2 was obtained as a bright orange solid (844 mg, 98%).1H NMR (500 MHz, DMSO-d6): 5 = 8.66 (s, 1H), 8.42-8.28 (m, 3H), 8.10 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.24 (t, J= 7.8 Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 6.80 (s, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.22-3.09 (m, 4H), 2.82 (s, 3H), 2.75 (s, 3H), 1.78 (quint, J = 6.9 Hz, 2H), 1.37 (s, 9H) ppm. MS (m / z): calcd. C30H37N7O5 (M + Na)+= 598.27; found, 598.33.

[0634] KP2890-2 (842 mg, 1.46 mmol) was suspended in 30 mL EtOH and 10 mL H2O before Fe (495 mg, 8.78 mmol) and NH4CI (59 mg, 1.10 mmol) were added. The mixture was heated at 100°C for 5 h, cooled to r.t. and all volatiles were removed. The residue was taken up in 65 mL DCM, filtered and the filter washed with another 65 mL DCM. The filtrate was washed 1x with 60 mL brine, dried over Na2SO4 and filtered again. The filtrate was then reduced in vacuo to give 788 mg crude product, which was purified by silica column chromatography using 2% MeOH in DCM as the eluent. After solvent removal, KP2890-3 was obtained as a light-yellow foam (715 mg, 89%).1H NMR (500 MHz, DMSO-d6): 5 = 8.42 (d, J= 8.0 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J= 5.3 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.51 (d, J= 8.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.18-7.13 (m, 2H), 6.74 (s, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.22 (t, J= 7.1 Hz, 2H), 2.82 (t, J= 5.9 Hz, 2H), 2.75 (bs, 3H), 2.57 (s, 3H), 1.65 (bs, 2H), 1.38 (s, 9H) ppm. MS (m / z): calcd. C30H39N7O3 (M + H)+= 546.32; found, 546.36.

[0635] KP2890-3 (713 mg, 1.31 mmol) and DIPEA (461 pL, 2.61 mmol) were dissolved in 14.5 mL dry DCM and cooled to ca. -80°C using liquid N2 / acetone. A solution of acryloyl chloride (115 pL, 1.37 mmol) in 4.3 mL dry DCM was added under Ar atmosphere at a flow rate of 45 pL / min. After the addition, the mixture was warmed up very slowly by allowing the cold bath to reach -15°C. Stirring was then continued in an ice bath for 10 min, then at r.t. for 45 min. The reaction mixture was diluted with 60 mL of DCM containing 10% MeOH and washed 3x with 60 mL saturated NaHCO₃ solution. The organic phase was dried over Na2SO4 and filtered. The filtrate was reduced in vacuo to give 849 mg crude product, which was purified by silica column chromatography using a 10-15% acetone gradient in DCM as the eluent. KP2890-4 was obtained as a light-yellow foam (715 mg containing 8% DCM residue, 83%).1H NMR (500 MHz, DMSO-d6): 5 = 9.51-9.11 (m, 1H), 9.03-8.85 (m, 1H), 8.65-8.55 (m, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.89 (s, 1H), 7.52 (d, J= 8.2, 1H), 7.26-7.21 (m, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.93 (s, 1H), 6.87-6.64 (m, 1H), 6.26 (d, J= 17.0 Hz, 1H), 5.73 (d, J= 10.6 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.21 (bs, 2H), 2.85 (t, J= 6.5 Hz, 2H), 2.78-2.70 (m, 3H), 2.67-2.55 (m, 3H), 1.64 (bs, 2H), 1.43-1.34 (m, 9H) ppm. MS (m / z): calcd. C33H41N7O4 (M + H)+= 600.33 found, 600.37.

[0636] KP2890-4 (710 mg, 1.08 mmol) was dissolved in 18 mL DCM and TFA (2.934 mL, 37.71 mmol) was added. The mixture was stirred for 50 min at r.t. and the solvent was removed in vacuo on the Schlenk like. The dry residue was re-dissolved in DCM and the volatiles again removed in vacuo, on the rotovap. The residue was then dissolved in H2O, lyophilized and dried in vacuo at 40°C for 23 h. KP2890 was obtained as a bright-yellow, solid TFA salt hydrate (1016 mg).

[0637] 1H NMR (500 MHz, DMSO-d6): 6 = 9.24 (s, 1H), 8.90-8.55 (bs, 1H), 8.67 (s, 1H), 8.58-8.01 (bs, 1H), 8.28 (s, 4H), 7.56 (d, J= 8.1 Hz, 1H), 7.33-7.24 (m, 2H), 7.18 (t, J= 7.1 Hz, 1H), 6.98 (s, 1H), 6.71 (dd, J= 16.9, 10.2 Hz, 1H), 6.25 (dd, J= 17.0, 1.3 Hz, 1H), 5.76 (d, J= 11.2 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.00-2.88 (m, 4H), 2.68 (s, 3H), 2.54 (t, J= 5.6 Hz, 3H, overlap with DMSO signal), 1.76 (quint, J= 7.0 Hz, 2H) ppm. MS (m / z): calcd. C28H33N7O2 (M + H)+= 500.28; found, 500.33.

[0638] Procedure for the synthesis of albumin-binding unit Mal-PEG(4)-NH2 (see Scheme 2):

[0639] Tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (515 mg, 1.45 mmol) was dissolved in 9 mL CHCI3 and the solution was cooled in an ice bath at 0°C for 10 min. Methyl 2,5-dioxo-2,5-dihydro-1 / 7-pyrrole-1-carboxylate (342 mg, 2.91 mmol), tetrabutylammonium hydrogen sulfate (444 mg, 1.31 mmol) and NEts (265 pL, 1.89 mmol) were added in this order and the mixture was stirred in the cold for 10 min. 18 mL of saturated NaHCO3solution were added and the mixture was stirred vigorously to give the impression of an emulsion. The flask was taken out of the ice bath and stirred over night for 18 h at r.t. The aqueous phase was extracted 3x with 40 mL CHCI3, then the organic layer was washed once with brine, dried over Na2SO4 and filtered. The filtrate was reduced in vacuo to give 800 mg crude product, which was purified by silica column chromatography using 3% MeOH in DCM as the eluent. Mal-1 was obtained as a clear oil (533 mg, 87%).1H NMR(500 MHz, DMSO-d6): 6 = 7.03 (s, 2H), 6.76 (t, J= 5.4 Hz, 1H), 3.58-3.54 (m, 2H), 3.53-3.43 (m, 16H), 3.05 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H) ppm. MS (m / z): calcd. C19H32N2O8 (M + Na)+= 439.21; found, 439.24.

[0640] Mal-1 (507 mg, 1.21 mmol) was dissolved in 20 mL MeCN and 2,5-dimethylfurane (1.3 mL, 12.05 mmol) was added. The mixture was stirred at 64°C oil bath temperature over night for 18 h, then all volatiles were removed in vacuo. The residue was dried in high vacuum. Mal-2 was obtained as a light-yellow oil (611 mg, 94%). The molar ratio of exo / endo was 1.00: 0.32, according to NMR.1H NMR (500 MHz, DMSO-d6): 5 = 6.76 (t, J = 5.4 Hz, 1H), 6.37 (s, 1.42H, C / 7mai-exo), 6.22 (s, 0.45H, C / 7mai-endo), 3.52-3.43 (m, 16H), 3.38-3.35 (m, 2H, overlap with water signal), 3.27 (s, 0.52H, CHendo), 3.05 (q, J= 6.0 Hz, 2H), 2.89 (s, 1.39H, CHexo), 1.63 (s, 1.39H, C / 73,endo), 1.53 (s, 4.27H, C / 73,exo), 1.37 (s, 9H) ppm. Ca. 5% of deprotected maleimide species could be observed at 7.03 ppm. MS (m / z): calcd. C25H40N2O9 (M + Na)+= 535.26; found, 535.31. Mal-2 (607 mg, 1.12 mmol) was dissolved in a solution of HCI in EtOH (5.0 mL, 6.25 mmol) and stirred at r.t. for 2.5 h, then at 45 °C for 1 h. All volatiles were removed in vacuo and the residue was taken up again in DCM, which was removed once more. The residue was dried in high vacuum to give the product as a dark-orange oil as an HCI-salt (568 mg). The oil was dissolved in 6 mL EtOAc and NEt3(180 pL, 1.29 mmol) was added. The mixture was stirred for 20 min at r.t., then the formed solid (triethylammonium chloride) was filtered off. The filtrate was washed once with 25 mL brine and the aqueous phase again once with EtOAc and DCM in this order. The combined organic phases were dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Mal-PEG(4)-NH2 was obtained as an orange oil (417 mg, 85%). The molar ratio of exo / endowas 1.00: 0.28, according to NMR.1H NMR (500 MHz, DMSO-d6): 6 = 6.37 (s, 1.65H, C / 7mai-exo), 6.22 (s, 0.46H, C / 7mai-endo), 3.53-3.42 (m, 18H), 3.39-3.35 (m, 2H, overlap with water signal), 3.28 (s, 0.62H, C / 7endo, overlap with water signal), 2.89 (s, 1.71H, C / 7exo), 2.68 (t, J = 5.7 Hz, 2H), 1.63 (s, 1.39H, CH3,endo), 1.53 (s, 5.08H, CH3,exo) ppm. MS (m / z): calcd. C20H32N2O7(M + H)+= 413.23; found, 413.25.

[0641] Procedure for the synthesis of albumin-binding unit Oxadiazole-PEG(4)-NH2 (see Scheme 3):

[0642] Ethylparabene (2501 mg, 14.90 mmol) was dissolved in 24.5 mL EtOH, hydrazine monohydrate (8850 pL, 178.79 mmol, 12.0 eq.) was added and the mixture was stirred at reflux for 17 h. While cooling to 0°C, a white solid precipitated that was filtered off and washed with cold EtOH. The filtrate was concentrated in vacuo on the Schlenk line and a second fraction was obtained by trituration of the residue in EtOH. Oxa-1 was obtained as a white solid (2079 mg, 89%).1H NMR (500 MHz, DMSO-d6): 5 = 9.48 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 4.35 (s, 2H) ppm. MS (m / z): calcd. C7H8N2O2 (M + H)+= 153.07; found, 153.22.

[0643] Oxa-1 (2069 mg, 13.19 mmol) was suspended in 24 mL dry EtOH and 12 mL dry DMF and KOH (822 mg, 13.19 mmol, 1.0 eq.) was added. The mixture was stirred for 10 min at r.t. until a clear solution was obtained, then CS2 (3132 pL, 51.84 mmol) was added. The mixture was stirred at r.t. for 25 min before stirring at reflux for 17 h. The volume was then reduced to ca. 2 / 3 in vacuo on the Schlenk line, 20 mL cold H2O were added and the pH was adjusted to 1 with ca. 18 mL 1 M HOI. The product was extracted into 60 mL EtOAc, the organic phase washed 2x with 45 mL H2O, Ixwith 60 mL brine and dried over Na2SO4. After filtration, the filtrate was reduced in vacuo and triturated in a mixture of Et2O / Hexane 1:1 (v / v). The filtrate was concentrated and a second fraction was obtained likewise. Oxa-2 was obtained as an off-white solid (2108 mg containing 7% DMF residue, 76%).1H NMR (500 MHz, DMSO-d6): 5 = 14.54 (bs, 1H), 10.39 (s, 1H), 7.71 (d, J= 8.8 Hz, 2H), 6.93 (d, J= 8.8 Hz, 2H) ppm. MS (m / z): calcd. C8H6N2O2S (M - H)"= 193.01; found, 192.79.

[0644] Oxa-2 (2098 mg, 9.94 mmol) was dissolved in 40 mL dry THF and NEt3(1670 pL, 11.93 mmol) was added. The mixture was cooled to 0°C and CH3I (688 pL, 10.93 mmol, 1.1 eq.) was added dropwise over 15 min. The mixture was allowed to warm to r.t. and stirred for 2 h. 60 mL H2O were added, the product extracted with 3x 60 mL EtOAc and the organic layer dried over Na2SO4. After filtration, the filtrate was reduced in vacuo and triturated in Et20. The filtrate was concentrated and a second fraction was obtained likewise. Oxa-3 was obtained as a sand-colored solid (2099 mg, 96%).1H NMR (500 MHz, DMSO-d6): 6 = 10.30 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 6.93 (d, J= 8.8 Hz, 2H), 2.74 (s, 3H) ppm. MS (m / z): calcd. C9H8N2O2S (M + H)+= 209.04; found, 209.08.

[0645] Oxa-3 (2098 mg, 9.57 mmol) was suspended in 67 mL dry EtOH and cooled to 0°C before m-CPBA (7375 mg, 29.92 mmol) was added in portions over 20 min. The mixture was warmed to r.t. and stirred for 5 h, then for a second time m-CPBA (7375 mg, 29.92 mmol) was added in portions over 20 min, but at r.t. Stirring was continued for 17 h at r.t., then 200 mL H2O and 200 mL saturated NaHCO3solution were added. The product was extracted with 3x 150 mL EtOAc, the organic layer washed 1x with brine and dried over Na2SO4. After filtration, the filtrate was reduced in vacuo and triturated in 30 mL EtOAc / Hexane 1:1 (v / v). The solid was filtered off and washed 1x with 20 mL EtOAc / Hexane 1:1 (v / v). Oxa-4 was obtained as a white solid (1262 mg, 55%).1H NMR (500 MHz, DMSO-d6): 5 = 10.59 (bs, 1H), 7.94 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.68 (s, 3H) ppm. MS (m / z): calcd. C9H8N2O4S (M - H)_= 239.01; found, 238.81. Ph3P on polymer (1932 mg, 3.09 mmol; 1.6 mmol / g loading on styrol crosslinked with 1% DVB) was suspended in 11.5 mL dry THF and 11.5 mL dry toluene and diisopropylazodicarboxylate (DIAD; 621 pL, 3.09 mmol) was added at r.t. The mixture was stirred vigorously until a homogenous suspension was obtained, then it was cooled to below 0°C with NaCI / ice. A suspension of Oxa-4 (500 mg, 2.06 mmol), tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (935 mg, 3.09 mmol) and neopentyl alcohol (92 mg, 1.03 mmol) in 5.3 mL dry THF, 5.3 mL dry toluene and 0.8 mL dry DMF was added over 30 min under Ar atmosphere. After the addition, the mixture was stirred in the cold for another 5 min, then warmed to r.t. and stirred for 72 h. The polymer was filtered off and washed 1x with THF and 3x with DCM in this order. The filtrate was reduced in vacuo to give 1982 mg crude product, which was purified by silica column chromatography using an 80-85% EtOAc gradient in n-Hexane as the eluent. After solvent removal, Oxa-PEG-1 was obtained as a waxy white solid (535 mg, 50%).1H NMR (500 MHz, DMSO-d6): 5 = 8.03 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H), 6.75 (t, J= 5.4 Hz, 1H), 4.25-4.20 (m, 2H), 3.82-3.75 (m, 2H), 3.70 (s, 3H), 3.62-3.57 (m, 2H), 3.57-3.53 (m, 2H), 3.53-3.47 (m, 4H), 3.37 (t, J= 6.1 Hz, 2H), 3.05 (q, J= 5.9 Hz, 2H), 1.36 (s, 9H) ppm. MS (m / z): calcd. C22H33N3O9S (M + Na)+= 538.18; found, 538.24.

[0646] Oxa-PEG-1 (533 mg, 1.03 mmol) was dissolved in 16 mL dry DCM and TFA (2816 pL, 36.18 mmol) was added under Ar atmosphere. The mixture was stirred for 35 min, then all volatiles were removed in vacuo on the Schlenk line. The residue was re-dissolved in DCM and the volatiles again removed in vacuo, on the rotovap. The residue was then taken up in H2O and lyophilized. Oxadiazole-PEG(4)-NH2was obtained as a white, solid TFA salt (531 mg, 97%).

[0647] 1H NMR (500 MHz, DMSO-d6): 5 = 8.04 (d, J = 8.8 Hz, 2H), 7.84 (bs, 3H), 7.21 (d, J = 8.9 Hz, 2H), 4.26-4.20 (m, 2H), 3.82-3.75 (m, 2H), 3.70 (s, 3H), 3.63-3.54 (m, 10H, overlap with water signal), 3.02-2.92 (m, 2H) ppm. MS (m / z): calcd. C17H25N3O7S (M + H)+= 416.15; found, 416.19.

[0648] Procedure for the synthesis of albumin-binding unit Oxadiazole-Pip-NHz (see Scheme 4):

[0649] Piperazineethanol (259 mg, 1.97 mmol) was dissolved in 5 mL DMF and K2CO3(1375 mg, 9.85 mmol) was added. A solution of ferf-butyl (2-bromoethyl)carbamate in 5 mL DMF was added dropwise, then the mixture was heated to 54°C oil bath temperature and stirred for 6 h. The solvent was removed in vacuo, the residue taken up in DCM and the mixture filtered. The filtrate was concentrated in vacuo to give 641 mg crude product, which was purified by silica column chromatography using a 20-30% MeOH gradient in DCM as the eluent. After solvent removal, Oxa-Pip-1 was obtained as a clear oil (451 mg, 80%).1H NMR (500 MHz, DMSO-d6) 5 = 6.61 (t, J = 5.2 Hz, 1H), 4.36 (bs, 1H), 3.47 (q, J = 5.8 Hz, 2H), 3.01 (q, J = 6.5 Hz, 2H), 2.61-2.11 (m, 10H), 2.28 (t, J = 6.7 Hz, 2H), 1.37 (s, 9H) ppm.

[0650] PhsP on polymer (764 mg, 1.22 mmol; 1.6 mmol / g loading on styrol crosslinked with 1% DVB) was suspended in 4.5 mL dry THF and 4.5 mL dry toluene and diisopropylazodicarboxylate (DIAD; 245 pL, 1.22 mmol) was added at r.t. The mixture was stirred vigorously until a homogenous suspension was obtained, then it was cooled to 0°C with NaCI / ice. A suspension of Oxa-4 (196 mg, 0.81 mmol), Oxa-Pip-1 (347 mg, 1.21 mmol) and neopentyl alcohol (36 mg, 0.41 mmol) in 2.0 mL dry THF, 2.0 mL dry toluene and 0.32 mL dry DMF was added over ca.

[0651] 5 min under Ar atmosphere. After the addition, the mixture was stirred in the cold for another 10 min, then warmed to r.t. and stirred for 45 h. The polymer was filtered off and washed 3x with a mixture of 20% MeOH in DCM. The filtrate was reduced in vacuo to give 934 mg crude product, which was purified by silica column chromatography using a mixture of 80% EtOAc and 20% MeOH as the eluent. After solvent removal, Oxa-Pip-2 was obtained as a waxy white solid (317 mg containing 5% EtOAc, 72%).1H NMR (500 MHz, DMSO-d6): 5 = 8.02 (d, J= 8.9 Hz, 2H), 7.20 (d, J= 8.9 Hz, 2H), 6.61 (t, J= 5.3, 1H), 4.19 (t, J= 5.7 Hz, 2H), 3.70 (s, 3H), 3.01 (q, J = 6.5 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.39 (bs, 4H), 2.29 (t, J = 6.8 Hz, 2H), 1.37 (s, 9H) ppm.

[0652] 4H below the DMSO signal. MS (m / z): calcd. C22H33N5O6S (M + H)+= 496.22; found, 496.25. Oxa-Pip-2 (310 mg, 0.58 mmol) was dissolved in 30 mL DCM and TFA (1.6 mL, 20.80 mmol) was added. The mixture was stirred for 3 h at 30°C, then all volatiles were removed in vacuo. The residue was dissolved in MQ-H₂O, frozen and lyophilized. In order to remove excess TFA, this process was repeated twice. Oxadiazole-Pip-NH2 was obtained as a white, solid TFA salt hydrate (447 mg).1H NMR (500 MHz, DMSO-d6): 5 = 8.09 (d, J = 8.9 Hz, 2H), 7.70 (bs, 3H), 7.25 (d, J = 8.9 Hz, 2H), 4.47 (t, J = 4.2 Hz, 2H), 3.71 (s, 3H), 3.58 (bs, 4H, overlap with water signal), 3.25-2.84 (m, 8H), 2.61 (bs, 2H, overlap with DMSO signal) ppm. MS (m / z): calcd. C17H25N5O4S (M + H)+= 396.17; found, 396.20. Procedure for the synthesis of platinum complex precursor oxaliplatin (see Scheme 5):

[0653] K2[PtCI4] (3652 mg, 8.80 mmol) was dissolved in 36 mL MQ-H₂O and a solution of (1?,2?)-cyclohexane-1,2-diamine (1028 mg, 8.82 mmol) in 2 mL MQ-H₂O was added. The mixture was stirred for 4 h at r.t. with a glass stirring bar under light exclusion. The formed yellow precipitate was filtered off. A second and third fraction were obtained after stirring the filtrate for another 2.5 h and 17 h after that. The product was dried over P2O5 in an evacuated desiccator. OxPt-1 was obtained as a yellow solid (3237 mg, 97%).1H NMR (500 MHz, DMSO-d6) 6 = 5.57 (d, J = 8.5 Hz, 2H), 5.04 (t, J= 9.3 Hz, 2H), 2.11-2.02 (m, 2H), 1.83 (d, J= 12.7 Hz, 2H), 1.43 (d, J= 8.6 Hz, 2H), 1.25-1.15 (m, 2H), 0.95 (t, J = 9.9 Hz, 2H) ppm. MS (m / z): calcd. C6H14Cl2N2Pt (M + Na)+= 403.01; found, 403.05.

[0654] OxPt-1 (3132 mg, 8.24 mmol) was suspended in 40 mL MQ-H₂O and AgNO₃ (2733 mg, 16.06 mmol) was added. The mixture was stirred at r.t. with a glass stirring bar for 7 h under light exclusion. The mixture was filtered using a glass paper inlay and the filtrate treated with K₂C₂O₄ · H₂O (1480 mg, 7.99 mmol). The mixture was stirred over night for 14.5 h and then put in the refrigerator (4°C) for 1.5 h. The product was filtered and washed 1x with cold (4°C) MQ-H₂O. The filtrate was reduced by rotary evaporation and again cooled in the refrigerator to obtain a second and likewise a third fraction. OxPt-2 was obtained as a white solid (2906 mg, 91%).

[0655] 1H NMR (500 MHz, DMSO-d6) 5 = 6.11 (d, J = 8.6 Hz, 2H), 5.37 (t, J = 9.6 Hz, 2H), 2.07-1.94 (m, 2H), 1.82 (d, J= 12.9 Hz, 2H), 1.45 (d, J = 8.7 Hz, 2H), 1.28-1.14 (m, 2H), 1.01 (t, J= 9.9 Hz, 2H) ppm. MS (m / z): calcd. C8H14N2O4Pt (M + Na)+= 420.05; found, 420.09.

[0656] OxPt-2 (1361 mg, 3.43 mmol) was suspended in 20 mL MQ-H₂O and H2O2(4 mL, 70.39 mmol) was added. The mixture was stirred over night for 22 h with a glass stirring bar, then the water was removed by rotary evaporation. The residue was taken up in EtOH and reduced again and this step was repeated 1x. The resulting solid was dried in vacuo for 20 h at 40°C. OxPt-3 was obtained as a white solid (1504 mg, quant, yield).1H NMR (500 MHz, DMSO-d6) 5 = 10.22 (s, 2H), 7.73-7.50 (m, 2H), 6.94-6.70 (m, 2H), 1.99 (d, J= 11.2 Hz, 2H), 1.49 (d, 8.2 Hz, 2H), 1.46-1.36 (m, 2H), 1.25 (bs, 1H), 1.07 (t, J = 10.2 Hz, 2H), 0.79 (bs, 1H) ppm. MS (m / z): calcd. C8H16N2O6Pt (M + Na)+= 454.05; found, 454.11.

[0657] OxPt-3 (200 mg, 0.46 mmol) was suspended in 19 mL DMF and A / . / V'-disuccinimidyl carbonate (424 mg, 1.39 mmol) was added. The mixture was stirred over night for 17 h, then the solvent was removed in vacuo. The residue was taken up in 30 mL MeCN and 50 mL Et2O were added. The precipitate was filtered off, washed 3x with Et2O and dried in vacuo over night. OxPt-4 was obtained as a white solid (300 mg, 86%).1H NMR (500 MHz, DMSO-d6) 5 = 8.62 (d, J = 8.2 Hz, 2H), 8.07 (t, J= 8.6 Hz, 2H), 2.73 (s, 8H), 2.08 (d, J= 11.7 Hz, 2H), 1.61-1.48 (m, 4H), 1.14 (t, J = 9.4 Hz, 2H) ppm. 2H below the DMSO signal. OxPt-3 (300 mg, 0.70 mmol) was suspended in 5 mL dry DMSO and a solution of / V, / V'-disuccinimidyl carbonate (188 mg, 0.70 mmol) in 5 mL dry DMSO was added with an automated syringe pump at a flow rate of 300 pL / h under Ar at r.t. The mixture was stirred for another 2 h, then a solution of Mal-PEG(4)-NH2 (302 mg, 0.70 mmol) in 1.2 mL dry DMSO was added and stirring was continued for 1.5 h. The mixture was filtered and the solvent removed in vacuo. The residue was purified via preparative HPLC on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) using a mixture of 20% AcN and 80% MQ-H₂O with 0.1% FA as the eluent. The product fractions were combined and lyophilized to give OxPt-5 as a white solid (216 mg, 36%).

[0658] 1H NMR (500 MHz, DMSO-d6) 6 = 9.93-9.40 (m, 1H), 8.28 (bs, 1H), 7.80-7.53 (m, 1H), 7.08 (bs, 1H), 6.36 (s, 2H), 6.31 (t, J= 5.0 Hz, 1H), 3.52-3.44 (m, 18H), 3.10-2.98 (m, 2H), 2.89 (s, 2H), 2.60-2.52 (m, 2H, overlap with DMSO signal), 2.14-2.00 (m, 2H), 1.53 (s, 6H), 1.51-1.47 (m, 2H), 1.47-1.25 (m, 2H), 1.18-1.03 (m, 2H) ppm. OH proton signal not visible. MS (m / z): calcd. C29H46N4O14Pt (M + Na)+= 892.26; found, 892.28.

[0659] Procedure for the synthesis of platinum complex precursor carboplatin (see Scheme 5):

[0660] K2[PtCl4] (25 g, 60.23 mmol) was dissolved in 400 mL tridistilled H2O and KI (200 g, 1204.59 mmol) was added. The mixture was stirred at r.t. with a glass stirring bar under light exclusion for 45 min, then a 29% aqueous solution of NH4OH (22 mL, 165.63 mmol) was added and stirring was continued for 90 min at r.t. The precipitate was filtered off, washed with EtOH and Et20 and dried over P2O5 for 72 h. CarboPt-1 was obtained as a yellow solid (27.96 g, 96%), which was directly used in the next step.

[0661] CarboPt-1 (27.935 g, 57.84 mmol) was suspended in 1.500 L tridistilled H2O and Ag₂SO₄ (17.676 g, 56.69 mmol) was added. The mixture was stirred at r.t. with a glass stirring bar for 4 h under light exclusion. The mixture was filtered to remove Agl and the filtrate treated with Ba(OH)₂ · 8H₂O (17.886 g, 56.69 mmol) and 1,1 -cyclobutanedicarboxylic acid (8.171 g, 56.69 mmol). The mixture was stirred at r.t. with a glass stirring bar for 20 h under light exclusion, filtered over a plug of celite and the filtrate was lyophilized. CarboPt-2 was obtained as a white solid (18.98 g, 88%), which was directly used in the next step.

[0662] CarboPt-2 (700 mg, 1.89 mmol) was suspended in 10.5 mL MQ-H₂O and H2O2(1.07 mL, 18.85 mmol) was added. The mixture was stirred at r.t. with a glass stirring bar for 6 h under light exclusion, then 35 mL EtOH were added and the solid was filtered off. The filter was washed 3x with Et20 and dried in vacuo over night. CarboPt-3 was obtained as a white solid (641 mg, 84%), which was directly used in the next step.

[0663] CarboPt-3 (400 mg, 0.99 mmol) was suspended in 6 mL DMSO and N, / V'-disuccinimidyl carbonate (798 mg, 2.96 mmol) was added. The mixture was stirred at r.t. for 3 h, then 40 mL of a mixture of Et2O / EtOAc 1:1 (v / v) was added. The formed precipitate was filtered off, washed 3x with EtOAc and 3x with Et2O in this order and dried in vacuo over night at r.t. CarboPt-4 was obtained as a white solid (653 mg with 17% DMSO residue, 78%).1H NMR (500 MHz, DMSO-d6) 5 = 6.78-6.16 (m, 6H), 2.71 (s, 8H), 1.80 (quint, J= 8.0 Hz, 2H) ppm. 4H below the DMSO signal. MS (m / z): calcd. C16H20N4O14Pt (M + Na)+= 710.05; found, 710.07.

[0664] Procedure for the synthesis of final platinum complexes (see Schemes 6 and 7):

[0665] KP2839 (704 mg, 0.90 mmol) was dissolved in 20 mL MQ-H₂O and 1M NaOH was added until a white precipitate formed and the solution decolorized. The solid was filtered off and dried in vacuo at 50°C for 5 h. KP2839-fb was obtained as an off-white solid (434 mg, 97%)

[0666] 1. Synthesis of KP3037 (see Scheme 6):

[0667] OxPt-5 (135 mg, 0.16 mmol) was dissolved in 3.5 mL dry DMF and N, / V'-disuccinimidyl carbonate (51 mg, 0.19 mmol) was added. The mixture was stirred under Ar at r.t. for 2 h before NEta (65 pL, 0.46 mmol) and KP2839-fb (112 mg, 0.23 mmol) were added. The mixture was stirred for 5 h, then all volatiles were removed in vacuo and the residue was purified by silica column chromatography using a 5-9% MeOH gradient in DCM as the eluent. After solvent removal, KP3037-1 was obtained as a yellow solid (153 mg, 70%). The molar ratio of exo / endo was 1.00: 0.06, according to NMR.1H NMR (500 MHz, DMSO-d6) 6 = 9.81-9.26 (m, 2H), 9.15 (d, J= 18.7 Hz, 1H), 8.88 (d, J= 13.2 Hz, 1H), 8.59 (s, 1H), 8.50 (d, J= 52.5 Hz, 2H), 8.32 (d, J = 5.3 Hz, 1H), 8.27 (d, J= 7.7 Hz, 1H), 7.88 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.26-7.20 (m, 2H), 7.17 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 43.7 Hz, 1H), 6.78 (t, J = 5.5 Hz, 1H), 6.71 (dd, J = 16.3, 10.7, 1H), 6.36 (s, 1.90H, CHma|.exo), 6.25 (d, J = 17.0 Hz, 1H), 6.22 (s, 0.11 H, CHma|.endo), 5.74 (d, J = 11.7 Hz, 1H), 3.94-3.84 (m, 6H), 3.53-3.42 (m, 16H), 3.38-3.34 (m, 2H, overlap with water signal), 3.32-3.25 (m, 2H, overlap with water signal), 3.27 (s, 0.16H, C / 7eno), 3.16-3.02 (m, 2H), 3.01-2.82 (m, 2H), 2.89 (s, 1.90H, CHexo), 2.78-2.67 (m, 3H), 2.62-2.55 (m, 3H), 2.14 (bs, 2H), 1.62 (s, 0.40H, C / 73,endo), 1.53 (s, 5.59H, CW3,exo), 1.49 (bs, 2H), 1.38 (bs, 2H), 1.15 (bs, 2H) ppm. 2H below the DMSO signal. MS (m / z): calcd. C57H75N11O17Pt (M + H)+= 1381.51; found, 1381.46.

[0668] KP3037-1 (143 mg, 0.10 mmol) was dissolved in 4.5 mL DMSO and TFA (24 pL, 0.31 mmol) was added. The solution was heated to 94°C oil bath temperature and stirred for 3 h, then all volatiles were removed in vacuo. The residue was purified via preparative HPLC on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) using a mixture of 34% AcN and 66% MQ-H₂O with 0.1% TFA as the eluent. The product fractions were combined and lyophilized 2x. The solid was then dried in vacuo at 40°C for 24 h to give KP3037 as a yellow, solid TFA-salt (103 mg, 69%).1H NMR (500 MHz, DMSO-d6) 5 = 9.57-9.23 (m, 2H, H16), 8.98 (s, 1H, H32), 8.77 (s, 1H, H27), 8.63 (s, 1 H, H48), 8.47 (bs, 1H, H36), 8.40 (d, J = 5.3 Hz, 1H, H16), 8.35-8.29 (m, 1H, H16), 8.28 (d, J= 5.8 Hz, 1H, H38), 8.24 (d, J= 8.0 Hz, 1H, H43), 7.54 (d, J= 8.2 Hz, 1H, H46), 7.31-7.25 (m, 2H, H39 + H45), 7.19 (t, J= 7.5 Hz, 1H, H44), 6.98 (s, 1H, H30), 6.95 (s, 2H, H1), 6.65 (dd, J= 16.9, 10.3 Hz, 1H, H34), 6.39 (bs, 1H, H13), 6.25 (dd, J= 16.9, 1.4 Hz, 1H, H35), 5.74 (dd, J= 10.3, 1.3 Hz, 1H, H35), 3.93 (s, 3H, H49), 3.90 (s, 3H, H31), 3.57 (d, J= 4.8 Hz, 2H, H3), 3.55 (d, J= 4.4 Hz, 2H, H4), 3.52-3.46 (m, 12H, H5-H10), 3.39 (t, J= 6.0 Hz, 2H, H11), 3.48-3.21 (m, 2H, H22, overlap with water signal), 3.16-3.05 (m, 2H, H12), 3.04-2.94 (m, 2H, H23), 2.77 (s, 3H, H21), 2.68 (s, 3H, H24), 2.63 (bs, 2H, H17), 2.19 (t, J= 8.2 Hz, 2H, H18), 1.53 (d, J = 8.4 Hz, 2H, H19), 1.41 (quint, J = 10.9 Hz, 2H, H18), 1.23-1.09 (m, 2H, H19) ppm.

[0669] 13C NMR (126 MHz, DMSO-d6) 6 = 170.36 (C2), 163.88 (C14), 163.36 (C20), 163.23 (C40), 162.91 + 162.88 (C15), 162.77 (C33), 157.11 (C37), 152.54 (C38), 147.20 (C29), 139.81 (C25), 137.69 (C47), 135.07 (C48), 134.12 (C1), 132.14 (C34), 125.56 (C35), 125.36 (C26), 125.10 (C42), 122.88 (C28), 122.12 (C45), 121.17 + 121.14 (C43-C44), 116.20 (C27), 112.06 (C41), 110.24 (C46), 106.51 (C39), 104.77 (C30), 69.50 + 69.46 + 69.44 + 69.37 + 69.24 + 69.22 + 69.03 (C5-11), 66.64 (C4), 60.86 (C17), 55.98 (C31), 53.18 (C23), 46.87 (C22), 41.86 (C24), 40.64 (C12), 36.66 (C3), 34.60 (C21), 32.73 (C49), 30.70 (C18), 23.24 + 23.22 (C19) ppm.

[0670] HRMS (m / z): calcd. C51H67N11O16Pt (M + H)+= 1285.4488; found, 1285.4493. Elemental analysis (%): calcd. for C51H67N11O16Pt*1.5TFA*H2O, C: 43.99, H: 4.82, N: 10.45; found, C: 43.69, H: 4.75, N: 10.12.

[0671] 2. Synthesis of KP3038 (see Scheme 6):

[0672] KP2839-fb (106 mg, 0.22 mmol) and CarboPt-4 (215 mg, 0.24 mmol) were combined and simultaneously dissolved in 10 mL dry DMF. The mixture was stirred for 160 min under Ar at r.t., then a solution of Mal-PEG(4)-NH2(163 mg, 0.38 mmol) in 2.7 mL dry DMF was added. The mixture was stirred for 3 h under Ar at r.t., then the solvent was removed in vacuo at 40°C to give the crude as a yellow oil, which was purified by silica column chromatography using a 5-10% MeOH gradient in DCM as the eluent. After solvent removal, KP3038-1 was obtained as an orange solid (137 mg containing 7% DCM residue, 42%). The molar ratio of exo / endo was 1.00: 0.78, according to NMR.1H NMR (500 MHz, DMSO-d6) 6 = 9.16 (s, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.31 (d, J= 5.3 Hz, 1H), 8.27 (d, J= 7.6 Hz, 1H), 7.88 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.99-6.84 (m, 1H), 6.79-6.48 (m, 7H), 6.45 (bs, 1H), 6.36 (s, 1.09H, CHmai.exo), 6.24 (d, 1H, overlap with signal at 6.22 ppm), 6.22 (s, 0.85H, CHmal-endo), 5.73 (d, 1H, overlap with DCM signal), 3.90 (s, 3H), 3.88 (s, 3H), 3.52-3.43 (m, 14H), 3.37-3.35 (m, 4H, overlap with water signal), 3.32-3.28 (m, 2H, overlap with water signal), 3.27 (s, 0.95H, C / 7endo) 3.10-3.01 (m, 2H), 2.99-2.82 (m, 2H), 2.89 (s, 1.1 OH, CHexo) 2.78-2.63 (m, 4H), 2.59 (s, 2H), 1.78 (quint, J = 8.0 Hz, 2H) ppm. 1.63 (s, 2.36H, C / 73,endo) 1.53 (s, C / 73,exo) ppm. 4H below the DMSO signal. Ca. 7% of deprotected maleimide species could be observed at 7.03 ppm MS (m / z): calcd. C55H73N11O17Pt (M + Na)+= 1377.47; found, 1377.46.

[0673] KP3038-1 (135 mg, 0.090 mmol) was dissolved in 3.5 mL DMSO and TFA (21 pL, 0.27 mmol) was added. The mixture was heated to 94°C oil bath temperature, stirred for 135 min and the volatiles were removed at the same temperature in vacuo. The residue was purified via preparative HPLC on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) using a mixture of 29% AcN and 71% MQ-H₂O with 0.1% TFA as the eluent. The product fractions were combined, AcN removed in vacuo at 40°C and the aqueous phase lyophilized. The lyophilizate was dried in vacuo at 40°C for 24 h. KP3038 was obtained as a yellow solid (97 mg, MW according to EA = 1448.25 g / mol, 74%).1H NMR (500 MHz, DMSO-d6) 5 = 9.04 (s, 1H, H32), 8.79 (bs, 1H, H36), 8.66 (s, 2H, H27 + H48), 8.27 (d, J= 6.0 Hz, 1H, H38), 8.23 (d, J= 8.1 Hz, 1H, H43), 7.55 (d, J= 8.2 Hz, 1H, H46), 7.31 (d, J = 6.1 Hz, 1H, H39), 7.28 (t, J= 7.6 Hz, 1H, H45), 7.19 (t, J= 7.5 Hz, 1H, H44), 7.00 (s, 1H, H30), 6.95 (s, 2H, H1), 6.64 (dd, J= 17.0, 10.3 Hz, 1H, H34), 6.65-6.29 (m, 6H, H15), 6.24 (dd, J= 17.0, 1.7 Hz, 1H, H35), 6.03 (bs, 1H, H13), 5.74 (dd, J = 10.3, 1.6 Hz, 1H, H35), 3.93 (s, 3H, H49), 3.88 (s, 3H, H31), 3.58-3.56 (m, 2H, H3), 3.56-3.54 (m, 2H, H4), 3.52-3.46 (m, 12H, H5-H10), 3.39 (t, J = 6.2 Hz, 2H, H11), 3.33 (t, J = 7.1 Hz, 2H, H22), 3.10 (t, J = 6.2 Hz, 2H, H12), 3.03 (t, J = 6.9 Hz, 2H, H23), 2.75 (s, 3H, H21), 2.70 (s, 3H, H24), 2.57-2.51 (m, 4H, H18), 1.82 (quint, J= 7.9 Hz, 2H, H19) ppm.13C NMR (126 MHz, DMSO-d6) 5 = 176.17 (C16), 170.38 (C2), 163.37 (C40), 162.85 (C14 + C33), 162.45 (C20), 157.01 (C37), 151.06 (C38, only in 2D), 147.29 (C29), 140.20 (C25, only in 2D), 137.71 (C47), 135.18 (C48), 134.13 (C1), 132.13 (C34), 125.60 (C35), 125.27 (C26 or C28), 125.11 (C42), 122.53 (C26orC28, onlyin2D), 122.15 (045), 121.20 (C43 + C44), 116.51 (C27), 112.04 (C41), 110.26 (C46), 106.48 (C39), 104.73 (C30), 69.52 + 69.48 + 69.46 + 69.38 + 69.26 + 69.23 (C5-C11), 66.66 (C4), 56.00 (C31), 55.36 (C17), 53.47 (C23), 46.79 (C22), 41.73 (C24), 40.62 (C12), 36.67 (C3), 34.57 (C21), 32.76 (C49), 32.08 + 29.95 (C18), 15.28 (C19) ppm. HRMS (m / z): calcd. C49H65N11O16Pt (M + Na)+= 1281.4151; found, 1281.4170. Elemental analysis (%): calcd. for C49H65N11O16Pt*1.5TFA*H2O, C: 43.13, H: 4.77, N: 10.64; found, C: 43.22, H: 4.69, N: 10.53.

[0674] 3. Synthesis of OxaPEG-Carbo-KP2839 (see Scheme 7)

[0675] CarboPt-4 (24 mg, 0.028 mmol) and KP2839-fb (12.3 mg, 0.025 mmol) were placed in a Schlenk flask, which was then evacuated and purged with Ar 3x. The solids were dissolved in 1.3 mL dry DMF and the resulting solution was stirred at r.t. for 3 h. NEta (19.7 pL, 0.14 mmol) and Oxadiazole-PEG(4)-NH2 (16.4 mg, 0.031 mmol) were added under Ar and stirring was continued for 2 h at r.t. All volatiles were removed in vacuo on the Schlenk line at 30°C to give the crude as a yellow oil, which was purified via preparative HPLC on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) using a mixture of 37% AcN and 63% MQ-H₂O with 0.1% TFA as the eluent. The product fractions were combined and lyophilized. OxaPEG-Carbo-KP2839 was obtained as a yellow solid (10 mg, 25%).1H NMR (600 MHz, MeOD-d4) 6 = 8.54 (s, 1H), 8.34 (bs, 2H), 8.00 (d, J = 8.3 Hz, 2H), 8.05-7.92 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.37-7.30 (m, 2H), 7.28-7.21 (s, 1H), 7.11 (d, J= 7.3 Hz, 2H), 7.03 (bs, 1H), 6.61 (dd, J= 16.9, 10.4 Hz, 1H), 6.37 (d, J= 16.9 Hz, 1H), 5.83 (d, J= 10.4 Hz, 1H), 4.21 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.88-3.84 (s, 2H), 3.73-3.68 (d, 2H), 3.67-3.63 (m, 2H), 3.63-3.59 (d, 2H), 3.58-3.54 (m, 2H), 3.54 (s, 3H), 3.47-3.37 (m, 4H), 3.27-3.03 (m, 4H), 2.92-2.69 (m, 3H), 2.82 (s, 3H), 2.68-2.60 (s, 4H), 1.96 (quint, J = 7.8 Hz, 2H) ppm. HRMS (m / z): calcd. C52H66N12O17PtS (M + H)+= 1359.4125; found, 1359.4128.

[0676] 4. Synthesis of OxaPip-Carbo-KP2839 (see Scheme 7):

[0677] CarboPt-4 (100 mg, 0.12 mmol), KP2839 (83 mg, 0.11 mmol) and ca. 20 beads of molecular sieves were combined in a Schlenk flask, which was then evacuated and purged with Ar 3x. The solids were dissolved in 3 mL dry DMF, then DIPEA (42 pL, 0.24 mmol) was added and the mixture was stirred for 1 h at r.t. A solution of Oxadiazole-Pip-NH2 (132 mg, 0.18 mmol) in 3 mL dry DMF over molecular sieves, which was prepared in the same way, was added at r.t. and thereafter again DIPEA (158 pL, 0.89 mmol) was added. The reaction was stirred for 5 h at r.t. and then quenched with TFA (93 pL, 1.20 mmol). Et2O was added until a yellow precipitate formed and the supernatant was decanted. The solid residue was died in vacuo and purified via preparative HPLC on an XBridge BEH C18 OBD Prep Column (19 mm x 250 mm) using a mixture of 29% AcN and 71% MQ-H₂O with 0.1% TFA as the eluent. The product fractions were combined and lyophilized. OxaPip-Carbo-KP2839 was obtained as a yellow solid (54 mg, 30%).

[0678] 1H NMR (600 MHz, MeOD-d4) 6 = 8.53 (s, 1H), 8.48-8.15 (m, 2H), 8.04 (d, J= 8.4 Hz, 2H), 7.95 (d, J = 5.0 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.37-7.29 (m, 2H), 7.23 (t, J = 6.8 Hz, 1 H), 7.16 (d, J= 8.7 Hz, 2H), 7.06 (s, 1H), 6.60 (dd, J= 16.7, 10.4 Hz, 1H), 6.38 (d, J= 16.9 Hz, 1H), 5.84 (d, J = 10.3 Hz, 1H), 4.34 (t, J= 4.6 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.55 (s, 3H), 3.43 (t, J= 6.0 Hz, 2H), 3.41-3.33 (m, 4H), 3.29-3.10 (m, 9H), 3.07 (s, 2H), 2.86 (s, 3H), 2.95-2.73 (m, 3H), 2.69 (s, 2H), 2.57 (s, 2H), 1.92 (quint, J= 7.6 Hz, 2H) ppm. 1 H below the MeOH signal. HRMS (m / z): calcd. C52H66N14O14PtS (M + H)+= 1338.4324; found, 1338.4338.

[0679] The compounds MalPEG-Carbo-KP2840, MalPEG-Carbo-KP2839, MalPip-Carbo-KP2839, MalPEG-Carbo-KP4012, MalPip-Carbo-KP4012, MalPEG-Carbo-Rezivertinib, MalPEG-Carbo-Mobocertinib (also referred to as KP4070), MalPEG-Carbo-Almonertinib, MalPip-Carbo-Rezivertinib, MalPip-Carbo-Mobocertinib, MalPip-Carbo-Almonertinib, OxaPEG-Carbo- KP4012, OxaPip-Carbo-Rezivertinib, OxaPip-Carbo-Mobocertinib, OxaPip-Carbo-Almonertinib, OxaPip-Carbo-KP4012, MalPip-Oxali-KP2839, MalPip-Oxali-KP4012, MalPip-Oxali-Rezivertinib, MalPip-Oxali-Mobocertinib, MalPip-Oxali-Almonertinib, OxaPip-Oxali-KP2839, OxaPip-Oxali-KP4012, OxaPip-Oxali-Rezivertinib, OxaPip-Oxali-Mobocertinib, OxaPip-Oxali-Almonertinib, KP4060, KP4061, KP4062, and KP4072 can be prepared analogously to the synthesis procedures described herein above.

[0680] Procedure for the synthesis of ligand KP4010 (see Scheme 8):

[0681] Isopropyl 2-chloro-4-(1-methyl-1 / 7-indol-3-yl)pyrimidine-5-carboxylate (0.500 g, 1.52 mmol) was dissolved in ACN (12 mL). Subsequently, p-toluene sulfonic acid (0.24 g, 1.27 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.29 mg, 1.55 mmol) were added to the solution. The reaction mixture was stirred at reflux for 17 h. The solution was filtered and the filtrate concentrated in vacuo. The crude KP4010-1 was obtained as an orange resin in 108% yield (1.02 g), with some p-TsOH and educt residues still present according to the NMR spectrum.1H NMR (500 MHz, DMSO-d6) 6: 9.04 (s, 1H), 8.84 - 8.80 (m, 1H), 8.71 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 13.4 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.10 - 5.00 (m, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 1.17 (d, J = 6.3 Hz, 6H) ppm. MS (m / z): calcd. C24H22FN5O5 (M + Na)+= 502.15; found, 502.15 and C24H22FN5O5 (M - H)’ = 478.15; found, 478.06.

[0682] Crude KP4010-1 (0.727 g, 1.52 mmol) was solved in DMF (7.0 mL). tert-butyl methyl(2-(methylamino)ethyl)carbamate (0.423 g, 2.24 mmol) and K2CO3(0.436 g, 3.16 mmol) were added. The reaction mixture was stirred at 100°C for 17 h. The solution was allowed to reach room temperature and cooled for 10 min in an ice bath. Next, the mixture was transferred dropwise into 50 mL ice cold water. The resulting precipitate was filtered and washed with another 50 mL ice cold water. After drying, the precipitate was dissolved in DCM and inorganic salts were filtered off. The solvent was evaporated under reduced pressure and the product dried in vacuo. KP4010-2 was obtained as a red oil in 95% yield. (0.938 g, 1.45 mmol).1H NMR (500 MHz, DMSO-d6) 6: 8.82 (s, 1H), 8.65 (s, 1H), 8.36 (d, J = 26.7 Hz, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.81 (d, J = 52.0 Hz, 1H), 5.12 - 4.99 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.40 (d, J = 11.9 Hz, 4H, overlap with water signal), 2.87 (s, 3H), 2.77 (s, 3H), 1.35 (d, J = 14.3 Hz, 9H), 1.17 (d, J = 6.2 Hz, 6H) ppm. MS (m / z): calcd. C33H41N7O7 (M + Na)+= 670.30; found, 670.35 and C33H41N7O7 (M - H)’ = 646.30; found, 646.36.

[0683] KP4010-2 (0.938 g, 1.44 mmol) was dissolved in EtOH (30 mL). Iron (0.247 g, 4.42 mmol), NH4CI (0.064 g, 1.19 mmol) and H2O (10 mL) were added to the mixture. The solution was stirred at reflux for 3.5 h. The solution was allowed to cool to room temperature and further filtered over Celite. Saturated NaHCO3(10 mL) was added to the filtrate and stirred for 15 min. The resulting precipitate was filtered again over Celite. The mixture was diluted with H2O (20 mL) and the product extracted with DCM (3x 25 mL). The combined organic phases were washed once with brine (20 mL). Solvents were evaporated and the product further purified using a silica column with 2.5 % MeOH in DCM as eluent. KP4010-3 was obtained as a dark yellow oil in 93% yield. (0.834 g, 1.35 mmol).1H NMR (500 MHz, DMSO-d6) 6: 8.62 (s, 1H), 8.53 (s, 1H), 7.94-7.93 (m, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.07 (t, J = 7.4 Hz, 1H), 6.77 (s, 1H), 5.04 - 4.98 (m, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 2.94 (t, J = 6.5 Hz, 2H), 2.80-2.77 (m, 3H), 2.64 (s, 3H), 1.40 (s, 9H), 1.16 (d, J = 6.2 Hz, 6H) ppm. One CH2signal is below the water signal. MS (m / z): calcd. C33H43N7O5 (M + Na)+= 640.32; found, 640.34 and C33H43N7O5 (M - H)- = 616.32; found, 616.38.

[0684] KP4010-3 (0.834 g, 1.35 mmol) was dissolved in dry DCM (15.5 mL) and DIPEA (471 pL, 2.70 mmol) was added. The solution was cooled to 0°C, by stirring in an ice bath for 15 min. Meanwhile, acryloyl chloride (110 pL, 1.35 mmol) was dissolved in dry DCM (4.1 mL) and added slowly to the cold reaction mixture (for 20 min: 80 pL / min flow). The solution was allowed to reach room temperature. Solvents were evaporated to yield 1.136 g crude product, which was purified using a silica column with 2.5% MeOH in DCM as eluent. KP4010-4 was obtained as a dark-yellow oil in 78% yield (0.711 g, 1.05 mmol).1H NMR (500 MHz, DMSO-d6) 6: 9.07 (s, 1H), 8.65 - 8.64 (m, 2H), 8.13 (s, 1H), 7.74 (s, 1H), 7.49 (d, J = 10.9 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.97 (s, 1H), 6.66 (dd, J = 16.6, 10.3 Hz, 1H), 6.26 (d, J = 16.8 Hz, 1H), 5.74 (d, 1H, appears together with the DCM signal), 5.02 - 4.97 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.99 (s, 2H), 2.86 - 2.65 (m, 7H), 1.37 (s, 9H), 1.12 (d, J = 6.2 Hz, 6H) ppm. One CH2signal is hidden under the water signal.

[0685] KP4010-4 was dissolved in DCM (13 mL) and TFA (2.92 mL, 38.1 mmol) was added to the solution. The mixture was stirred for 1 h. Next, all solvents were removed under reduced pressure, the product dissolved in H2O (120 mL) and lyophilized. KP4010 was obtained as an orange yellow powder as TFA salt hydrate in 91% yield (0.767 g, 0.96 mmol). The compound was purified using preparative HPLC with a gradient from 35-40% ACN in H2O with 0.1 % TFA as additive.1H NMR (500 MHz, DMSO-d6) 6: 9.32 (s, 1H, H14), 8.67 (s, 1H, H7), 8.65 (s, 1H, H10), 8.60 (s, 1H, H6 or H11), 8.48 (d, J = 4.2 Hz, 1H, H21), 8.09 (s, 1H, H6 or H11), 7.80 (s, 1H, H5), 7.50 (d, J = 8.3 Hz, 1H, H2), 7.20 (t, J = 7.5 Hz, 1H, H3), 7.06 (t, J = 7.4 Hz, 1H, H4), 6.99 (s, 1H. H12), 6.67 (dd, J = 16.9, 10.2 Hz, 1H, H15), 6.30 (dd, J = 17.0, 1.6 Hz, 1H, H18), 5.80 (d, J = 11.5 Hz, 1H, H16), 5.01 (hept, J = 6.2 Hz, 1H, H8), 3.87 (s, 3H, H1), 3.85 (s, 3H, H13), 3.22 (t, J = 5.8 Hz, 2H, H20), 3.15-3.09 (m, 2H, H19), 2.62 (d, J = 5.4 Hz, 3H, H21), 2.60 (s, 3H, H18), 1.13 (d, J = 6.3 Hz, 6H, H9) ppm.13C NMR (176 MHz, DMSO) 5: 166.21 (Cq), 163.34 (Cq), 161.05 (Cq), 160.20 (Cq), 160.01 (C16), 148.63 (Cq), 140.23 (Cq), 136.82 (Cq), 134.53 (C9 or C23), 132.11 (C25), 126.72 (C26), 126.21 (Cq), 125.47 (Cq), 123.94 (Cq), 121.91 (C4), 121.08 (C6), 120.58 (C5), 118.10 (C9 or C23), 113.33 (Cq), 111.92 (Cq), 110.32 (C3), 105.07 (C20), 68.11 (C13), 56.12 (C27), 50.63 (C30), 45.59 (C29), 42.62 (C28), 32.95 (C1), 32.45 (C31), 21.34 (C14 and C15) ppm. MS (m / z): calcd. C31H37N7O4 (M + H)+= 572.30; found, 572.40 and C31H37N7O4 (M - H)’ = 570.28; found, 570.19.

[0686] Procedure for the synthesis of ligand KP4011 (see Scheme 8):

[0687] 3-(2-chloropyrimidin-4-yl)-1-cyclopropyl-1 / - / -indole (0.457 g, 1.70 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.353 g, 1.90 mmol) were dissolved in ACN (10 mL) and p-toluene sulfonic acid (0.288 mg, 1.52 mmol) was added. The reaction was stirred for 40 h at 80°C for 36 h. The solution was filtered and the filtrate concentrated in vacuo. Crude KP4011-1 was obtained as yellow brown resin in 102% yield (0.727 g) with p-TsOH and other impurities still present according to the NMR spectrum.1H NMR (500 MHz, DMSO-d6) 5: 8.81 (d, J = 7.0 Hz, 1H), 8.63 (s, 1H), 8.33 (d, J = 6.2 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H, overlap with bs 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 6.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.00 (s, 3H), 3.68 - 3.62 (m, 1H), 1.17 - 1.14 (m, 2H), 1.11 - 1.07 (m, 2H) ppm. MS (m / z): calcd. C22H18FN5O3 (M + H)+= 420.15; found, 420.14 and C22H18FN5O3 (M - H)’ = 418.13; found, 418.02.

[0688] The crude KP4011-1 (0.727 g) was dissolved in DMF (8 mL). terf-butyl methyl(2-(methylamino)ethyl)carbamate (0.466 g, 2.47 mmol) and K2CO3(0.485 g, 3.51 mmol) were added to the solution. The reaction mixture was stirred at 100°C for 17 h. The solution was allowed to reach room temperature and cooled for 10 min in an ice bath. Next, cold water (20 mL) was added to the reaction mixture. The resulting precipitate was filtered and dried over P2O5. After drying the precipitate was dissolved in MeOH and inorganic salts were filtered off. The solvent was evaporated under reduced pressure and the product dried in vacuo. Crude KP4011-2 was obtained as a red oil in 47% yield (0.479 g).1H NMR (500 MHz, DMSO-d6) 6: 8.69 (d, J = 22.8 Hz, 1 H), 8.36 - 8.33 (m, 3H, three singlets lying over each other), 8.09 (s, 1 H), 7.64 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 5.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 41.8 Hz, 1H), 3.97 (s, 3H), 3.60 - 3.58 (m, 1H), 3.55 - 3.39 (m, 4H, overlap with water signal), 2.87 (s, 3H), 2.77 (s, 3H), 1.35 (d, J = 11.4 Hz, 9H), 1.15 - 1.10 (m, 2H), 1.08 - 1.03 (m, 2H) ppm. MS (m / z): calcd. C31H37N7O5 (M + H)+= 588.29; found, 588.35 and C31H37N7O5 (M - H)’ 586.28; found, 586.32.

[0689] Crude KP4011-2 (0.209 g, 0.36 mmol) was dissolved in a mixture of EtOH (7 mL) and water (2 mL). Next, iron (0.113 g, 2.03 mmol) and NH4CI (0.015 g, 0.28 mmol) were added to the mixture. The solution was stirred at reflux for 4 h, subsequently allowed to cool to room temperature and further filtered overCelite. Saturated NaHCO₃ (10 mL) was added to the filtrate, until the solution reached pH 9 and stirred for 15 min. The resulting precipitate was filtered again over Celite. The product was extracted with DCM (3x 15 mL). The combined organic phases were dried over MgSO4, filtered and solvents were evaporated. Finally, the product was dried in vacuo. Crude KP4011-3 was obtained as orange red oil in 76% yield (0.150 g).1H NMR (500 MHz, DMSO-d6) 6: 8.44 (d, J = 8.1 Hz, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.80 (s, 1H), 7.63 (t, J = 8.2 Hz, 2H), 7.46 (s, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 7.16 (s, 1H), 6.77 (s, 1H), 4.38 (s, 2H), 3.74 (s, 3H), 3.57 - 3.54 (m, 1H), 2.94 (t, J = 6.6 Hz, 2H), 2.78 (s, 3H), 2.63 (d, J = 1.6 Hz, 4H), 1.40 (s, 9H), 1.13 - 1.11 (m, 2H), 1.10 - 1.05 (m, 2H) ppm. MS (m / z): calcd. C31H39N7O3 (M + H)+= 558.32; found, 558.36 and C31H39N7O3 (M -H)- = 556.30; found, 556.35.

[0690] Crude KP4011-3 (0.150 g, 0.27 mmol) and DIPEA (0.112 pL, 0.64 mmol) were dissolved in dry DCM (3.1 mL) and cooled in an ice bath for 15 min. Meanwhile, acryloyl chloride (26 pL, 0.32 mmol) was dissolved in dry DCM (1 mL) and added dropwise (40 pL / min) to the reaction mixture. After all substrates were combined, the solution was left to stir for 5 min and subsequently all solvents were evaporated using reduced pressure. The crude sample was purified using a silica column with EtOAc / hexane 40%:60% v / v as eluent. KP4011-4 was obtained as an orange oil in 81% yield (0.132 g). MS (m / z): calcd. C34H41N7O4 (M + H)+= 612.33; found, 612.38 and C34H41N7O4 (M - H)’ = 610.31; found, 610.36.

[0691] Crude KP4011-4 (0.132 g, 0.22 mmol) was dissolved in DCM (2.0 mL) and TFA (0.53 mL, 7.10 mmol) was added. The solution was stirred for 1 h 15 min. All solvents were evaporated under reduced pressure and the product dried in vacuo. The product was purified with preparative HPLC using 27% ACN in H2O including 0.1% TFA as additive. KP4011 was obtained as yellow TFA salt hydrate in 24% yield (0.027 g, 0.05 mmol).1H NMR: (500 MHz, DMSO-d6) 6: 9.40 (s, 1H, H11), 8.62 (s, 2H, H22 and H15), 8.54 (s, 2H, H12 and H13), 8.28 (d, J = 4.6 Hz, 2H, H9 and H10), 7.66 (d, J = 8.1 Hz, 1H, H4), 7.40 (d, J = 5.6 Hz, 1H, H6), 7.28 (t, J = 7.4 Hz, 1H, H5), 7.15 (d, J = 6.6 Hz, 1H, H7), 7.02 (s, 1H, H8), 6.69 (dd, J = 16.8, 10.3 Hz, 1H, H16), 6.26 (d, J = 16.9 Hz, 1H, H18), 5.77 (d, J = 10.3 Hz, 1H, H17), 3.84 (s, 3H, overlap with the water signal, H14), 3.61 (s, 1 H, overlap with the water signal, H3), 3.25 (d, J = 5.3 Hz, 2H, H20), 3.16 (d, J = 5.0 Hz, 2H, H21), 2.65 -2.60 (m, 6H, H23 and H19), 1.12 (t, J = 10.2 Hz, 2H, H1 or H2), 1.07 (s, 2H, H1 or H2) ppm.13C NMR (176 MHz, DMSO) 5: 163.42 (Cq), 158.65 (Cq), 158.46 (Cq), 158.27 (Cq), 158.09 (Cq), 138.47 (Cq), 134.69 (C21 or C18, only visible in HSQC), 131.99 (C24), 126.76 (C25), 125.73 (Cq), 125.56 (Cq), 122.87 (C6), 122.86 (C13 or C14), 122.38 (C8), 121.93 (C13 or C14), 118.88 (C21 or C18, only visible in HSQC), 112.30 (C5), 111.15 (Cq), 106.95 (C7), 105.17 (C11), 56.08 (C22), 50.59 (C27), 45.59 (C28), 42.61 (C26), 39.52 (Cq), 32.44 (C29), 27.75 (C3), 6.01 (C1 and C2) ppm. MS (m / z): calcd. C29H33N7O2 (M + H)+= 512.27685; found, 512.2772 and calcd. C29H33N7O2 (M + 2H)+2= 256.64206; found, 256.6420. Procedure for the synthesis of ligand KP4012 (see Scheme 8):

[0692] 3-(2-chloropyrimidin-4-yl)-1H-indole (717 mg, 3.12 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (581 mg, 3.12 mmol) were dissolved in ACN (53 mL) and p-toluene sulfonic acid (534 mg, 2.81 mmol) was added. The mixture was stirred at reflux for 17 h and the product subsequently filtered off. KP4012-1 was obtained as yellow solid in 82% yield (0.970 g, 2.56 mmol).1H NMR (500 MHz, DMSO-d6) 6: 12.27 (s, 1H), 8.84 (d, J= 7.7 Hz, 1H), 8.61 (s, 1H), 8.33 (d, J= 6.2 Hz, 1H), 8.24 (s, 1H), 7.53 -7.45 (m, 4H), 7.23 (t, J= 9.2, 5.1 Hz, 1H), 7.11 (d, J= 7.8 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 4.01 (s, 3H) ppm. MS (m / z): calcd. C19H15FN5O3 (M+H)+= 380.35; found: 380.13.

[0693] KP4012-1 (0.970 g, 2.56 mmol) and tert-butylmethyl(2-(methylamino)ethyl)carbamate (0.876 g, 4.66 mmol) were dissolved in DMF (10 mL), K2CO3(0.858 g, 6.21 mmol) was added and the mixture was stirred at 100° C for 15 h. The product was precipitated by adding the mixture to cold water (200 mL), resulting in a red solid. The precipitate was filtered off, dried and purified by silica column chromatography using 10 % acetone in DCM as the eluent. After solvent removal, KP4012-2 was obtained as a red oil in 75% yield (1.050 g, 1.92 mmol).1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.68 (d, J= 19.7 Hz, 1H), 8.35 (d, J= 8.0 Hz, 1H), 8.32 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.45 (d, J= 8.1 Hz, 1H), 7.29 (d, J= 5.3 Hz, 1H), 7.17 (t, J= 7.3 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.84 (d, J = 40.7 Hz, 1 H), 3.98 (s, 3H), 3.40 (t, J = 6.1 Hz, 2H), 2.87 (s, 3H), 2.77 (s, 3H), 1.36 (s, 9H) ppm. 2H below the water signal. MS (m / z): calcd. C28H33N7O5 (M+H)+= 548.62; found: 548.31.

[0694] KP4012-2 was suspended in a mixture of EtOH (40 mL) and H2O (12 mL) before Fe (0.642 g, 11.50 mmol) and NH4CI (77 mg, 1.44 mmol) were added. The mixture was heated to 100° C and stirred for 19 h. Subsequently all volatiles were removed. The residue was taken up in DCM, filtered over celite and dried. The filtrate was purified via silica column chromatography using 3% MeOH in DCM as the eluent, resulting in KP4012-3 as a yellow oil in 91% yield (0.902 g, 1.74 mmol).1H NMR (500 MHz, DMSO-d6) 5 11.75 (s, 1 H), 8.42 (d, J = 7.9 Hz, 1 H), 8.30 (d, J = 2.5 Hz, 1H), 8.26 (d, J= 5.3 Hz, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.21 (d, J = 5.4 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.11 (t, J= 7.4 Hz, 1H), 6.77 (s, 1H), 4.40 (s, 2H), 3.75 (s, 3H), 2.94 (t, J= 6.6 Hz, 2H), 2.79 (d, J= 17.5 Hz, 3H), 2.63 (s, 3H), 1.40 (s, 9H) ppm.

[0695] 2H below the water signal. MS (m / z): calcd. C28H35N7O3 (M+H)+= 518.63; found: 518.37.

[0696] KP4012-3 and DIPEA (593 pL, 3.49 mmol) were dissolved in dry DCM (20 mL) and cooled to ca. -80° C using an acetone / dry ice bath. A solution of acryloyl chloride (146 pL, 1.74 mmol) in dry DCM (5 mL) was added under Ar atmosphere at a flow rate of 40 pL / min. After the addition, the mixture was warmed up overnight. The acetone bath was removed and stirring was continued at room r.t. for 2 h. The reaction mixture was diluted with DCM to a total of 50 mL and washed 1x with saturated NaHCO₃ (50 mL) solution. The organic phase was dried over Na2SC>4 and filtered. The filtrate was reduced in vacuo, and purified by silica column chromatography using 10 % acetone in DCM as the eluent. KP4012-4 was obtained as a yellow-brown oil in 74% yield (0.739 g, 1.29 mmol).1H NMR (500 MHz, DMSO-d6) 5 11.77 (s, 1H), 9.07 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.31 (d, J= 7.9 Hz, 1H), 8.28 (d, J= 5.3 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 5.3 Hz, 1H), 7.15 (t, J= 7.6 Hz, 1H), 7.08 (t, J= 7.5 Hz, 1H), 6.96 (s, 1H), 6.64 (dd, J = 16.8, 10.4 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 11.4 Hz, 1H), 3.86 (s, 3H), 3.38 - 3.35 (m, 1 H), 2.98 (s, 2H), 2.74 (s, 3H), 2.71 (s, 3H), 1.37 (s, 9H) ppm. 2H below the water signal. MS (m / z): calcd. C31H37N7O4 (M+H)+= 572.68; found: 572.39.

[0697] KP4012-4 (0.739 g, 1.29 mmol) was dissolved in DCM (17 mL) and TFA (3.56 mL, 46.54 mmol) was added. The mixture was stirred at r.t. for 1 h and the solvent was removed in vacuo. The residue was then dissolved in H2O and lyophilized. KP4012 was obtained as a bright-yellow TFA salt hydrate in 95% yield (0.577 g, 1.22 mmol).1H NMR (500 MHz, DMSO-d6) 6 12.26 (s, 1H), 9.40 (s, 1H), 8.66 (s, 1H), 8.58 (s, 2H), 8.43 (s, 1H), 8.24 (d, J= 5.6 Hz, 2H), 7.48 (d, J= 8.1 Hz, 1H), 7.43 (d, J= 6.3 Hz, 1H), 7.20 (t, J= 7.6 Hz, 1H), 7.08 (t, J= 7.2 Hz, 1H), 7.05 (s, 1H), 6.68 (dd, J = 16.9, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.7 Hz, 1H), 5.77 (d, J = 11.7 Hz, 1H), 3.84 (s, 3H), 3.27 (t, J = 5.7 Hz, 2H), 3.20 - 3.12 (m, 2H), 2.67 - 2.61 (m, 6H) ppm. MS (m / z): calcd. C26H29N7O2 (M+H)+= 472.57; found: 472.25.

[0698] Procedure for the synthesis of complex KP4060 (see Scheme 9):

[0699] OxaliPt-4 (0.250 g, 0.30 mmol) was dissolved in DMF (12 mL, 25 pM). pMal-PEG4-NH2 (0.233 g, 0.56 mmol) was dissolved in DMF (4 mL) and added to the Oxali Pt-4 solution. The mixture stirred for 17 h at room temperature. KP4010 (0.241 g, 0.30 mmol) and subsequently TEA (93 pL, 0.67 mmol) were added to the mixture. After 40 min the solvent was evaporated in vacuo. The product was purified using a silica column with 5% MeOH in DCM as eluent. KP4060-1 was obtained as a yellow oil in 38% yield (0.169 g, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) 5: 9.44 (s, 2H), 9.10 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.59 - 8.53 (m, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 6.36 (s, 1.85H, CHmal-exo), 6.25 (d, J = 16.7 Hz, 1H), 6.22 (s, 0.11H, CHmal-endo), 5.72 (d, 1H, overlap with DCM signal), 5.05-4.95 (m, 1H), 3.87 - 3.85 (m, 6H), 3.53-3.39 (m, 18H), 3.27 (s, 0.33H, CHmal-endo, overlap with water signal), 3.07 (s, 2H), 2.98 (s, 1H), 2.88 (s, 1.67H, CHmal-exo), 2.75 (s, 2H), 2.67 (s, 3H), 2.14 (s, 2H), 1.62 (s, 0.33H, CHmal-endo), 1.53 (s, 5.89H, CHmal-exo), 1.49 (s, 2H), 1.37 (s, 2H), 1.15 -1.12 (m, 8H) ppm. MS (m / z): calcd. C61H81N11O19Pt (M + Na)+= 1489.53; found, 1489.52 and CeiHsiNnO Pt (M - H)’ = 1465.53; found, 1465.62. KP4060-1 (0.169 g, 0.12 mmol) was dissolved in DMSO (5.3 mL, 0.02 mM) and TFA (27 pL, 0.35 mmol) was added. The mixture was heated to 95°C and stirred for 1h 45 min. The sample was purified using preparative HPLC with 40-42% ACN gradient in H2O, with 0.1% TFA as the eluent. ACN was evaporated and the aqueous residue was frozen and lyophilized. KP4060 was obtained as a yellow TFA-salt in 56% yield (0.088 g, 0.06 mmol).1H NMR (500 MHz, DMSO-d6) 5: 9.77 - 8.97 (m, 4H, NH2oxPt), 8.68 (s, 1 H, CHKP4010), 8.65 (s, 1H, CHKP4010), 8.54 (s, 2H, 2x CH KP4010), 8.43 (s, 1H, NH KP4010), 8.11 (s, 1H, CHKP4010), 7.76 (s, 1H, NH KP4010), 7.49 (d, J = 8.2 Hz, 1H, CHKP4010), 7.20 (t, J = 7.6 Hz, 1H, CHKP4010), 7.07 (s, 1H, CHKP4010), 7.01 (d, J = 4.9 Hz, 2H, 2x CHMalemide), 6.75 (s, 1 H, NH carbamate from maiemide), 6.68 (dd, J = 16.7, 10.4 Hz, 1H, CH KP4010 acryl), 6.25 (d, J = 16.8 Hz, 1H, CH2 KP4010 acryl trans H), 5.74 (d, J = 11.2 Hz, 1H, CH2 KP4010 acryl cis H), 5.00 (dt, J = 12.4, 6.2 Hz, 1H, CH KP4010 ester), 3.87 (s, 6H, 2x CH3 KP4010), 3.56 (t, J = 5.8 Hz, 2H, CH2PEG4), 3.54 - 3.47 (m, 18H, CH2PEG4), 3.36 (s, 3H, CH3KP4010), 3.30 (s, 2H, CH2KP4010), 3.07 (s, 2H, CH2KP4010), 2.74 (s, 1 H, CH oxPt), 2.67 (s, 1 H, CH oxPt), 2.62 - 2.56 (m, 3H, CH3KP4010), 2.14 (s, 2H, CH2oxpt), 1.49 (s, 2H, CH2oxPt), 1.38 (s, 2H, CH2oxPt), 1.12 (d, J = 6.2 Hz + br. s, 8H, CH2OxPt and 2x CH3KP4010-ester) ppm.13C NMR (176 MHz, DMSO) 5: 170.96 (Cq), 166.18 (Cq), 164.11 (Cq), 163.37 (CHKP4010), 161.15 (Cq), 160.01 (Cq), 159.75 (Cq), 158.49 (Cq), 158.28 (Cq), 158.08 (CH KP4010), 157.88 (Cq), 136.86 (Cq), 134.70 (CHKP4010), 134.59 (2x CHmaleimide), 132.31 (CH KP4010 acryl), 129.69 (Cq), 129.53 (Cq), 126.44 (Cq), 126.21 (CH2KP4010 acryl), 124.87 (Cq), 121.96 (Cq), 121.09 (CHKP4010), 120.68 (CHKP4010), 118.15 (CHKP4010, only visible in HSQC), 113.19 (Cq), 112.04 (Cq), 110.34 (CHKP4010), 104.44 (Cq), 69.80 (Cq), 69.76 (Cq), 69.65 (Cq), 69.53 (CH2PEG4), 69.43 (CH2KP4010), 69.27 (CH3KP4010), 68.15 (CH KP4010 ester), 66.96 (CH2PEG4), 61.09 (Cq), 56.14 (CH3KP4010), 53.40 (Cq), 53.01 (Cq), 46.71 (Cq), 41.70 (CH3KP4010), 40.72 (CH2KP4010), 39.52 (DMSO), 36.84 (CH2PEG4), 34.94 (CH oxPt), 34.85 (CH oxPt), 32.98 (CH3KP4010), 30.98 (CH2oxPt), 23.52 (CH2oxPt), 21.37 (2x CH3KP4oioester) ppm. MS (m / z): ealed. CssHysNuOisPt (M + Na)+= 1393.47; found, 1394.67 and CssH sNuOisPt (M - H)’ = 1369.47; found, 1370.49. Elemental analysis (%): ealed. For CssHysNuOisPt *1 TFA, 0:46.09, H: 5.02, N: 10.37; found C:46.15, H: 5.00, N: 10.39.

[0700] Procedure for the synthesis of complex KP4061 (see Scheme 9):

[0701] KP4011 (25 mg, 0.04 mmol) and OxaliPt-4 (28 mg, 0.04 mmol) were dissolved in DMF (0.5 mL) with TEA (12 pL, 0.086 mmol) and the solution stirred for 2 h at room temperature. pMal-PEG4-NH2(25 mg, 0.06 mmol) was added to the mixture and the reaction continued to stir for 17 h. Solvents were evaporated in vacuo. The crude was solved in DCM (5 mL) and washed once with water (20 mL). The water was extracted with DCM (3x 10 mL) and the combined organic phases dried over Na2SO4. The solvents were evaporated using reduced pressure and the residue purified by silica column chromatography using a 5-10% MeOH gradient in DCM as the eluent. KP4061-1 was obtained as a yellow solid in 16% yield (9.8 mg). The crude KP4061-1 was solved in DMSO (316 pL) and heated to 100°C for 2 h. The solvents were evaporated in vacuo to yield crude KP4061. The product was purified using a preparative HPLC with 36% ACN in H2O with 0.1% TFA additive as gradient. ACN was evaporated under reduced pressure and the aqueous phase was lyophilized. KP4061 was obtained as a yellow solid in 55% yield (5.0 mg).1H NMR: (500 MHz, DMSO-d6) 6: 9.43 - 9.18 (m, 3H), 8.62 - 8.21 (m, 5H), 7.67 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.19 (s, 1H), 7.04 - 6.86 (m, 3H), 6.75 (s, 1H), 6.69 -6.66 (m, 1H), 6.19 (d, J = 17.2 Hz, 1H), 5.71 (d, J = 10.5 Hz, 1H), 3.89 - 3.82 (m, 3H), 3.63 (s, 1 H,), 3.57 - 2.86 (m, 26H), 2.75 - 2.73 (m, 3H), 2.68 - 2.64 (m, 3H), 2.60-2.58 (m, 2H), 2.15 (s, 2H), 1.50 (s, 2H), 1.39 (s, 2H), 1.16 - 1.05 (m, 6H) ppm.

[0702] Procedure for the synthesis of complex KP4062 (see Scheme 9):

[0703] OxaliPt-4 (50 mg, 0.07mmol) and KP4012 (42 mg, 0.05 mmol) were dissolved in DMF (3 mL), TEA (19 pL, 0.13 mmol) was added and the mixture was stirred for 2 h at 25° C. pMal-PEG4-NH2 (44 mg, 0.10 mmol) was dissolved in DMF (1 mL), added to the mixture and stirred for 17 h. All volatiles were removed in vacuo and the residue purified by silica column chromatography using a 5-10 % MeOH gradient in DCM as the eluent. KP4062-1 was obtained as orange solid (16 mg, 0.01 mmol, 17 %). The molar ratio of exo / endo was 1.00: 0.08, according to NMR.1H NMR (500 MHz, DMSO-d6) 5 11.78 (s, 1H), 9.73 - 9.24 (m, 2H), 9.12 (d, J= 17.5 Hz, 1H), 8.71 (d, J= 8.1 Hz, 1H), 8.54 (bs, 1H), 8.44 (s, 2H), 8.32 (d, J= 7.6 Hz, 1H), 8.28 (d, J= 5.3 Hz, 1H), 7.91 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.24 (d, J= 5.3 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.91 (d, J= 43.0 Hz, 1H), 6.76 (s, 1H), 6.72 - 6.62 (m, 1H), 6.36 (s, 1.86H, CHmal-exo), 6.34 - 6.28 (m, 0.14H, CHmal-endo), 6.24 (d, J= 18.4 Hz, 1H), 5.71 (d, J= 10.7 Hz, 1H), 3.94 - 3.82 (m, J = 14.3 Hz, 3H), 3.55 - 3.37 (m, 20H, overlap with water signal), 3.27 (s, 0.21 H, CHendo), 3.20 - 3.01 (m, J = 12.9 Hz, 2H), 3.01 - 2.81 (m, J = 43.9 Hz, 2H), 2.89 (s, 1.79H, CHexo), 2.80 -2.64 (m, J = 35.8 Hz, 3H), 2.62 -2.53 (m, J= 9.0 Hz, 3H), 2.14 (bs, 2H), 1.63 (s, 0.32H, CH3,endo), 1.53 (s, 5.68H, CH3,exo), 1.49 (bs, 2H), 1.37 (bs, 2H), 1.20 - 1.08 (m, 2H) ppm.

[0704] 2H below the DMSO signal. MS (m / z): calcd. C56H74N11O17Pt (M + H)+= 1368.34; found: 1368.48.

[0705] KP4062-1 (16 mg, 0.01 mmol) was dissolved in DMSO (1 mL) and TFA (4.6 pL, 0.06 mmol) was added. The solution was heated to 94° C and stirred for 3 h, then all volatiles were removed in vacuo. The residue was purified by preparative HPLC using a mixture of 30.5 % AcN and 69.5 % Milli-Q water with 0.1 % TFA as the eluent. ACN was removed in vacuo, the product fractions combined and lyophilized. KP4062 was obtained as yellow solid (10 mg, 0.008 mmol, 66 %).1H NMR (500 MHz, DMSO-d6) 511.89 (s, 1H, H49), 9.51 -9.25 (m, J= 31.0 Hz, 2H, H16), 8.95 (s, 1H, H32), 8.71 (bs, 1H, H36), 8.58 (s, 1H, H27), 8.53 (d, J= 2.9 Hz, 1H, H48), 8.43 - 8.35 (m, 1H, H16), 8.35- 8.29 (m, 1H, H16), 8.27 (d, J= 8.0 Hz, 1H, H38), 8.23 (d, J= 6.0 Hz, 1H, H43), 7.48 (d, J= 8.1 Hz, 1H, H46), 7.34 (d, J= 5.9 Hz, 1H, H39), 7.20 (t, J= 7.1 Hz, 1H, H45), 7.13 (t, J = 7.2 Hz, 1H, H44), 6.98 (s, 1H, H30), 6.95 (s, 2H, H1), 6.62 (dd, J = 17.0, 10.3 Hz, 1H, H34), 6.36 (bs, 1H, H13), 6.24 (dd, J= 17.0, 1.7 Hz, 1H, H35), 5.72 (dd, J = 10.3, 1.7 Hz, 1H, H35), 3.89 (s, 3H, H31), 3.58 (d, J = 4.7 Hz, 2H, H3), 3.56 (d, J = 4.7 Hz, 2H, H4), 3.53 - 3.46 (m, 12H, H5-H10), 3.40 (t, J= 6.1 Hz, 2H, H11), 3.46 - 3.17 (m, J= 39.9 Hz, 2H, H22), 3.16 -3.06 (m, 2H, H12), 3.05 - 2.98 (m, J = 6.4 Hz, 2H, H23), 2.77 (s, 3H, H21), 2.69 (s, 3H, H24), 2.66 - 2.60 (m, 2H, H17), 2.19 (bs, 2H, H18), 1.54 (d, J= 9.2 Hz, 2H, H19), 1.47 - 1.34 (m, 2H, H18), 1.17 (s, 2H, H19) ppm.13C NMR (126 MHz, DMSO-d6) 6 170.32 (C2), 164.36 (C40), 163.85 (C14), 163.34 (C20), 162.87 + 162.84 (C15), 162.77 (C33), 140.71 (C25, cross peak in HMBC observed), 137.09 (C47), 134.08 (C1), 131.95 (C34), 131.39 (C48), 125.60 (C35), 125.24 (C26), 124.72 (C42), 122.12 (C45), 121.43 (C43), 120.88 (C44), 117.59 (C27), 112.99 (C41), 111.79 (C46), 106.54 (C39), 104.84 (C30), 69.48 + 69.43 + 69.41 + 69.35 + 69.21 (C5-C10, one C not observed due to overlap with another signal), 69.00 (C11), 66.61 (C4), 60.83 (C17), 55.91 (C31), 53.09 (C23), 46.83 (C22), 41.73 (C24), 40.62 (C12), 36.64 (C3), 34.57 (C21), 30.68 (C18), 23.21 + 23.19 (C19). C28 + C29 + C37 + C38 are not visible in the NMR. HRMS (m / z): calcd. C50H66N11O16Pt (M+H)+= 1271.4331; found: 1271.4332.

[0706] Procedure for the synthesis of complex KP4070 (also referred to as MalPEG-Carbo-Mobocertinib) see Scheme 9):

[0707] CarboPt-4 (50 mg, 0.06mmol) and KP4010 (36 mg, 0.06 mmol) were dissolved in DMF (2.6 mL), TEA (19 pL, 0.14 mmol) was added and the mixture was stirred for 15 min at 25° C. pMal-PEG4-NH2 (39 mg, 0.10 mmol) was dissolved in DMF (0.6 mL), added to the mixture and stirred for 24 h. All volatiles were removed in vacuo and the residue purified by silica column chromatography using a 5-10 % MeOH gradient in DCM as the eluent. KP4070-1 was obtained as yellow solid (33 mg, 0.02 mmol, 36 %).1H NMR (500 MHz, DMSO-d6) 6: 9.11 (s, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.98 - 9.82 (m, 1H), 6.75 - 6.40 (m, 7H), 6.36 (s, 1.7H, CHMal-exo), 6.24 (d, J = 16.8 Hz, 1H), 6.22 (s, 0.3H, CHMal-endo), 5.74 (d, J = 11.6 Hz, 1H, overlap with DCM signal), 5.05 - 4.94 (m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.53 - 3.38 (m, 18H), 3.37 -3.30 (8H, overlap with the water signal), 3.10 - 3.04 (m, 2H), 3.00 -2.94 (m, 2H), 2.89 (s, 1.7H, CHMai-exo), 2.80 -2.60 (m, 6H, overlap with DMSO signal), 1.83 - 1.74 (m, 2H), 1.63 (s, 0.86H, CH3 Mal-endo), 1.53 (s, 5.00H, CH3 Mal-exo), 1.12 (d, J = 6.2 Hz, 6H) ppm.

[0708] KP4070-1 (33 mg, 0.02 mmol) was dissolved in DMSO (1 mL) and TFA (5 pL, 0.07 mmol) was added. The solution was heated to 94° C and stirred for 2 h, then all volatiles were removed in vacuo. The residue was purified by preparative HPLC using a mixture of 40 % ACN and 60 % Milli-Q water with 0.1 % TFA as the eluent. ACN was removed in vacuo and lyophilized. KP4070 was obtained as yellow solid (11 mg, 0.008 mmol, 36 %).1H NMR (500 MHz, DMSO-d6) 5: 9.19 (s, 1H), 8.67 (s, 1H), 8.65(s, 1H), 8.51 (s, 1H), 8.11 (d, 1H), 7.76 (s, 1H), 7.49 (d, J = 8.2 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.02 (s, 2H), 6.99 - 6.90 (m, 1H), 6.79 -6.34 (m, 7H), 6.25 (d, J = 16.8 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 5.00 (p, J = 6 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.56- 3.51 (8H, overlap with the water signal) 3.50 - 3.42 (m, 18H), 3.37-3.32 (m, 2H), 3.31 - 3.25 (m, 2H), 3.06 (s, 3H), 2.73 (s, 3H), 1.83 - 1.73 (m, 2H), 1.13 (d, J = 6.2 Hz, 6H) ppm.

[0709] Procedure for the synthesis of complex KP4072 (see Scheme 9):

[0710] CarboPt-4 (50 mg, 0.07 mmol) and KP4012 (39 mg, 0.06 mmol) were dissolved in DMF (3 mL), TEA (21 pL, 0.15 mmol) was added and the mixture was stirred for 2 h at 25° C. pMal-PEG4-NH2 (45 mg, 0.10 mmol) was dissolved in DMF (1 mL), added to the mixture and stirred for 72 h. All volatiles were removed in vacuo and the residue purified by silica column chromatography using an 8-9 % MeOH gradient in DCM as the eluent. KP4072-1 was obtained as orange solid (52 mg, 0.04 mmol, 55 %). The molar ratio of exo / endo was 1.00: 0.11, according to NMR.1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.31 (d, J= 8.1 Hz, 1H), 8.28 (d, J= 5.3 Hz, 1H), 7.91 (s, 1H), 7.43 (d, J= 8.1 Hz, 1H), 7.24 (d, J= 5.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.91 (bs, 1H), 6.71 - 6.47 (m, 7H), 6.42 (bs, 1H), 6.36 (s, 1.88H, CHmal-exo), 6.23 (d, J= 16.2 Hz, 1H), 6.21 (s, 0.20H, CHmal-endo), 5.71 (d, J = 10.7 Hz, 1H), 3.86 (s, 3H), 3.54- 3.35 (m, 20H, overlap with water signal), 3.27 (s, 0.24H, CHendo), 3.09 - 3.02 (m, 2H), 2.98 - 2.80 (m, 2H), 2.89 (s, 1.76H, CHexo), 2.77 - 2.65 (m, J = 29.9 Hz, 4H), 2.57 (s, 2H), 1.83 - 1.74 (m, 2H), 1.63 (s, 0.33H, CH3,endo), 1.53 (s, 5.67H, CH3,exo) ppm. 4H under DMSO signal. MS (m / z): calcd. C54H72N11O17Pt (M + H)+= 1342.31; found: 1342.46. KP4072-1 (47 mg, 0.04 mmol) was dissolved in DMSO (3 mL) and TFA (13.4 pL, 0.18 mmol) was added. The solution was heated to 94° C and stirred for 3 h, then all volatiles were removed in vacuo. The residue was purified by preparative HPLC using a mixture of 28 % AON and 72 % Milli-Q water with 0.1 % TFA as the eluent. AON was removed in vacuo, the product fractions combined and lyophilized. KP4072 was obtained as yellow solid (18 mg, 0.014 mmol, 41 %).1H NMR (500 MHz, DMSO-d6) 5 11.89 (s, 1H, H49), 8.97 (s, 1H, H32), 8.69 (bs, 1H, H36), 8.56 (s, 1 H, H27), 8.52 (d, J = 3.0 Hz, 1 H, H48), 8.26 (d, J = 8.0 Hz, 1 H, H38), 8.23 (d, J = 6.0 Hz, 1 H, H43), 7.48 (d, J= 8.1 Hz, 1H, H46), 7.34 (d, J = 6.0 Hz, 1H, H39), 7.20 (t, J= 11.1, 4.0 Hz, 1H, H45), 7.12 (t, J= 7.2 Hz, 1H, H44), 6.98 (s, 1H, H30), 6.96 (s, 2H, H1), 6.60 (dd, J= 17.0, 10.3 Hz, 1H, H34), 6.56 -6.29 (m, J= 42.9 Hz, 6H, H15), 6.24 (dd, J= 17.0, 1.8 Hz, 1H, H35), 6.01 (bs, 1H, H13), 5.72 (dd, J = 10.3, 1.7 Hz, 1H, H35), 3.87 (s, 3H, H31), 3.59 - 3.57 (m, J = 4.8 Hz, 2H, H3), 3.57 - 3.54 (m, J = 6.9, 3.3 Hz, 2H, H4), 3.52 - 3.48 (m, 12H, H5-H10), 3.40 (t, J = 6.2 Hz, 2H, H11), 3.35 -3.31 (m, 2H, H22), 3.10 (t, J= 6.2 Hz, 2H, H12), 3.03 (t, J = 7.0 Hz, 2H, H23), 2.75 (s, 3H, H21), 2.69 (s, 3H, H24), 2.57 - 2.52 (m, 4H, H18), 1.87 - 1.78 (m, 2H, H19) ppm.13C NMR (126 MHz, DMSO-d6) 5 176.16 (C16), 170.35 (C2), 164.30 (C40 or 41), 162.85 (C14 + C33), 162.45 (C20), 152.68 (C43, only in 2D), 147.99 (C28 orC29), 137.11 (C42), 134.11 (C1), 131.98 (C34), 131.34 (C48), 125.64 (C35), 125.20 (C47), 124.75 (C25 or C26), 122.11 (C44), 121.44 (C38 or C45), 120.86 (C38 or C45), 117.65 (C27), 113.03 (C40 or C41), 111.81 (C46), 106.57 (C39), 104.80 (C30), 69.51 + 69.47 + 69.45 + 69.37 + 69.25 + 69.23 (C5-C11), 66.64 (C4), 55.94 (C31), 55.36 (C17), 53.40 (C23), 46.79 (C22), 41.63 (C24), 40.62 (C12), 36.66 (C3), 34.56 (C21), 29.97 + 27.99 (C18), 15.26 (C19) ppm. C37 is not visible in the NMR.

[0711] HRMS (m / z): calcd. C48H63N11O16Pt (M+Na)+= 1267.4000; found: 1267.3995.

[0712] Example 2: In vitro and in vivo assays for anticancer activity

[0713] Chemicals:

[0714] Osimertinib mesylate was purchased from MedChemExpress and carboplatin from TCI. All other chemicals were purchased from Sigma Aldrich.

[0715] Cell culture:

[0716] Detailed information on source as well as culture and MTT seeding conditions for used cell lines are provided in Table 1. All cells were grown under standard cell culture conditions and regularly checked for mycoplasma contamination. The medium was supplemented with 10 % fetal bovine calf serum (FBS) (purchased from PAA Linz, Austria).

[0717] Table 1: Cell models and corresponding details of the cell panel used in this study.

[0718] Cell line Tissue Type Medium Source

[0719] HCC827 Human NSCLC RPMI ATCC

[0720] HCC827 / erlo Human NSCLC RPMI Established at Center for Cancer Research, Vienna (Caban M et al., Cancer Lett, 2023, 565, 216237) H1650 Human NSCLC RPMI ATCC

[0721] H1975 Human NSCLC RPMI ATCC

[0722] CT26 Murine colorectal carcinoma DMEM: F12 ATCC

[0723] (1:1)

[0724] ATCC, American tissue cell collection; NSCLC, non-small cell lung cancer Selection of novel HCC827 / erlo clones with acquired erlotinib resistance:

[0725] HCC827 cells were selected with erlotinib by continuous treatment with 20 pM erlotinib once a month (Caban M et al., Cancer Lett, 2023, 565, 216237, doi: 10.1016 / j.canlet.2023.216237). The resistance of the cell models was checked by cell viability assays following 72 h drug treatment with increasing concentrations. Furthermore, the cells were tested in a combination treatment with crizotinib to confirm the MET dependence of their resistance.

[0726] Cell viability assays:

[0727] Cells were plated (depending on the cell model 2-7x 103cells / well) in 96-well plates and allowed to recover for 24 h. Subsequently, the indicated drugs were added. After 72 h exposure, the proportion of viable cells was determined by MTT assay following the manufacturer’s recommendations (EZ4LI kit, Biomedica). Cytotoxicity was expressed as IC50 values calculated from full dose-response curves using Graph Pad Prism software.

[0728] Clonogenicity assay:

[0729] Cells were plated in 24-well plates (2-3 x 103in 500 pL growth medium per well) and left to recover for 24 h in the incubator. Then the cells were treated with prediluted ascending concentrations of the tested compounds. After 10 days, the cells were fixed with methanol for 20 min at 4°C and stained with crystal violet (0.01% in phosphate-buffered saline (PBS)). The fluorescence of crystal violet was detected with the Typhoon scanner (Typhoon TRIO Variable Mode Imager, GE Healthcare Life Sciences) after excitation by the red laser (633 nm). Quantification was performed using Imaged software. The received values were visualized as dose-response curves by Graph Pad Prism 8 software (Graph Pad software, USA).

[0730] General procedures for animal studies:

[0731] Eight to twelve week-old C. B.17 SCID or Balb / c mice were purchased from Envigo, Italy. The animals were kept in a pathogen-free environment and every procedure was done in a laminar airflow cabinet. Experiments were done according to the regulations of the Ethics Committee for the Care and Use of Laboratory Animals at the Medical University Vienna (proposal number 2022-0.770.291), the U. S. Public Health Service Policy on Human Care and Use of Laboratory Animals as well as the United Kingdom Coordinating Committee on Cancer Prevention Research's Guidelines for the Welfare of Animals in Experimental Neoplasia. To ensure animal welfare throughout the experiment, the body weight of the mice was assessed once a day.

[0732] Xenograft and allograft experiments:

[0733] For the therapy experiments, the cancer cells (1 x 106for H1650, 1 x 106for H1975, 2.5 x 106for HCC827 / erlo, 0.5 x 106for CT26) were injected subcutaneously into the right flank of the mice. Animals were randomly assigned to treatment groups and therapy was started when clear tumor formation was observed. Animals were treated intravenously with 72.5 mg / kg KP3038 or 76.6 mg / kg KP3037 (both dissolved in 20% propylene glycol in 5% glucose, dose equimolar to 25 mg / kg free osimertinib) twice a week for two weeks. Animals in the control group received 20% propylene glycol in 5% glucose (i.v.) only. Osimertinib mesylate treatment was given orally at a dose of 30 mg / kg dissolved in 5% hydroxypropyl methyl cellulose for 5 consecutive days per week for 2 weeks. Carboplatin and oxaliplatin were dissolved in 5% glucose and applied i.v. at a dose of 60 mg / kg or 6 mg / kg, respectively (in both cases the maximum tolerated dose, MTD), twice a week. Animals were monitored for distress development every day and tumor size was assessed regularly by caliper measurement. Tumor volume was calculated using the formula: (length x width2) I 2. On the last day of the experiment, animals were sacrificed by cervical dislocation.

[0734] Serum pharmacokinetics (PK) and tumor accumulation in CT-26-bearing mice:

[0735] CT-26 cells (5x105in 50 pl serum-free medium) were injected into the right flank of male Balb / c mice. Ten days after cell injection, the drugs were applied i.v. (n=4 per treatment group): Animals were treated intravenously with 72.5 mg / kg KP3038 (dissolved in 20% propylene glycol in 5% glucose) or 60 mg / kg carboplatin (dissolved in 5% glucose). For serum PK, blood was collected after 5 min, 30 min, 5 h and 24 h (2 mice per time point) via the facial vein. The serum was separated by centrifugation (two times 10 min at 900 g). The organ distribution was determined after 5 h and 24 h (2 animals per time point). Therefore, the animals were sacrificed via cervical dislocation and the tumor was harvested. All collected samples were stored at -20°C and further processed for platinum measurements via ICP-MS. HNO3 (67-69%, suprapur for trace metal analysis, NORMATOM; Distributor: VWR international, Austria) and cone. H2O2suprapur (Merck, hydrogen peroxide 30%) were used without further purification. Digestion of tissue (approx. 15-30 mg gravimetrically weighted) was performed with 2 mL of approx. 20% nitric acid and 100 pL H2O2using an open vessel graphite digestion system (coated graphite heating plate, coated sample holder-top for 25 mL vials, PFA vials and PFA lids; Labter, ODLAB; Distributor: AHF Analysentechnik AG, Germany). Digested samples were diluted in Milli-Q water (18.2 MQ cm, Milli-Q Advantage, Darmstadt, Germany). The platinum concentration was determined by ICP-MS analysis. Therefore, platinum and rhenium standards were derived from CPI International (Amsterdam, The Netherlands). The total platinum content was determined with a quadrupole-based ICP-MS instrument Agilent 7800 (Agilent Technologies, Tokyo, Japan) equipped with the Agilent SPS 4 autosampler (Agilent Technologies, Tokyo, Japan) and a MicroMist nebulizer at a sample uptake rate of approximately 0.2 mL / min. An RF power of 1550 Wwas used as well as nickel cones. Argon was used as plasma gas (15 L / min) and as carrier gas (~1.1 L / min). The dwell time was set to 0.1 s and the measurements were performed in 6 replicates with 100 sweeps. Rhenium served as internal standard for platinum. The Agilent MassHunter software package (Workstation Software, version C.01.04) was used for data processing.

[0736] Immunohistochemistry:

[0737] Fresh sections from paraffin-embedded H1975 tumors harvested from animals after 24 h drug treatment were deparaffinized and dehydrated. In brief, after antigen retrieval by boiling for 30 min in 10 mM citrate buffer (pH 6.0), sections were incubated with pEGFR-specific antibody (Tyr1068, Cell signaling, 1:200) in a humid chamber for 1 h at rt. Antibody binding was detected using the UltraVision LP detection system according to the manufacturer’s instructions (Thermo Fisher Scientific Inc.). Color was developed using 3,3'-diaminobenzidine (DAB; Dako). Stained slides were scanned with a Slide Scanner (3DHISTECH Pannoramic Scan II), together with a DS-U3 control unit and the adequate NIS-Elementssoftware (all from Nikon Instruments). Evaluation and quantification of the staining was done by HALO software.

[0738] Results:

[0739] The albumin-binding, EGFR-functionalized carboplatin derivative (KP3038) showed an activity profile different from treatment with platinum drugs or osimertinib. In more detail, KP3038 was highly active in H1650 NSCLC cells (overexpression of L858R-mutated EGFR, partially resistant to EGFR inhibitor therapy due to PTEN loss, resistant to platinum drugs like oxaliplatin and carboplatin) (see Figure 1), in HCC827 / erlo NSCLC cells (overexpression of E746 - A750 deletion-mutated EGFR, resistant to EGFR inhibitor therapy including osimertinib due to C-Met overexpression) (see Figure 2), in CT26 colon cancer cells (expression of wildtype EGFR, resistant to EGFR inhibitor therapy including osimertinib due to lack of EGFR dependency, platinum-resistant) (see Figure 3), and in H1975 NSCLC cells (overexpression of L858R / T790M-mutated EGFR, resistant to therapy with 1stand 2ndgeneration EGFR inhibitors like erlotinib and gefitinib due T790M mutation, resistant to platinum drugs like oxaliplatin and carboplatin) (see Figure 4). The strong anticancer effect of KP3038 not only resulted in reduced tumor growth, but also distinctly prolonged overall survival of the treated animals (by ~100%). These effects are remarkable, as in HCC827 / erlo and CT26 cells osimertinib had no relevant activity and thus no impact on overall survival. Also in H1650 cells, KP3038 was superior to osimertinib, as the tumors rapidly relapsed upon stop with osimertinib therapy (increase in overall survival after osimertinib therapy only about ~25%). In the highly osimertinib-responsive H1975 cells, KP3038 had similar activity to osimertinib, and also the oxaliplatin-releasing derivative KP3037 showed promising activity. KP3038 treatment was well tolerable, which is noteworthy, as in a combination experiment of osimertinib with carboplatin or oxaliplatin, both combination therapy groups had to be stopped and all animals sacrificed after 2 drug applications (on day 19) due to toxicity and death of one animal (see Figure 5). This better tolerability of KP3038 can be attributed 1) to its prodrug nature, which was confirmed by in vitro experiments in H1975 cells (see Figure 6), where in contrast to osimertinib, KP3038 displayed only activity in cell treated for 9 days (clonogenic assays), while no activity was seen after 3 days (MTT assays), and 2) to its improved pharmacological profile especially indicated by enhanced plasma retention of KP3038 (see Figure 7).

[0740] The albumin-binding, EGFR-functionalized carboplatin derivative KP3038 was also highly active in a tumor model which contained a 1:1:1 mixture of three different HCC827 NSCLC subclones with different resistance phenotypes (parental HCC827 - sensitive to EGFR inhibition, HCC827 / erlo - resistant to EGFR inhibition due to c-met overexpression, HCC827 / EPR -resistant to first generation EGFR inhibitors due to a T750M mutation of the EGFR; see Figure 8). Notably, also the oxaliplatin derivative KP3037 displayed strong antitumor activity against CT26 colon cancer cells (expression of wildtype EGFR, resistant to EGFR inhibitor therapy including osimertinib due to lack of EGFR dependency, platinum-resistant; see Figure 9). An additional experiment in H1975 NSCLC cells (overexpression of L858R / T790M-mutated EGFR, resistant to therapy with 1stand 2ndgeneration EGFR inhibitors like erlotinib and gefitinib due to a T790M mutation, resistant to platinum drugs like oxaliplatin and carboplatin; see Figure 10) revealed that KP3037 and KP3038 had superior activity both to osimertinib when given only 2-times a week at equimolar concentrations as well as to a MTD combination of osimertinib with carboplatin. These strong anticancer effects of KP3037 and KP3038 not only resulted in reduced tumor growth, but also distinctly prolonged overall survival of the treated animals. The EGFR-inhibitory potential of KP3037 and KP3028 in H1975 xenografts was confirmed by histological stains for EGFR phosphorylation of tumors after 24h therapy (see Figure 11).

Claims

1. CLAIMS1. A compound of the following formula (I)4. 6.wherein:7.R1and R2are joined together to form a moiety (A1), (A2) or (A3), or R1and R2are each -Cl:8.O9.-l-o- +4 o o11.

12. (A1) (A3);13.R3and R4are joined together to form a moiety (B1), or R3is a moiety (B2) and R4is -NH3, or R3is -NH3and R4is a moiety (B2), or R3and R4are each -NH3:

15. 17.R5is selected from -NH-, -N(Ci-s alkyl)-, -O-, and a covalent bond; R6is -(Co-3 alkylene)-(CH2-0-CH2)y-(Co-3 alkylene)- or C1-10 alkylene, wherein y is an integer of 1 to 10, wherein one or more -CH2- units comprised in said C1-10 alkylene are each optionally replaced by a group independently selected from -O-, -CO-, -C(=O)O-, -O-C(=O)-, -NH-, -N(C1-8alkyl)-, -NH-CO-, -N(C1-8alkyl)-CO-, -CO-NH-, -CO-N(C1-8alkyl)-, carbocyclylene and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more groups R61;18.R7is a moiety (D1), (D2), (D3) or (D4):

20.

21. (D1) (D2) (D3) (D4);22.each R71is independently selected from hydrogen, halogen, C1-5 alkyl and C1-5 haloalkyl;23.R72is selected from a covalent bond, C1-5 alkylene, -O-, -NH- and -N(Ci-s alkyl)-;24.each R73is independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-s alkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-CO-(Ci-s alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-s alkyl), -(C0-3 alkylene)-O-CO-(Ci-s alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl;25.R74is selected from a covalent bond, C1-5 alkylene, C2-5 alkenylene, -(C0-3 alkylene)-0-(Co-3 alkylene)-, -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)-, -(C0-3 alkylene)-NH-(Co-3 alkylene)-, and -(C0-3 alkylene)-N(Ci-5 alkyl)-(Co-3 alkylene)-, wherein the carbocyclylene moiety in said -(C0-3 alkylene)-carbocyclylene-(Co-3 alkylene)- and the heterocyclylene moiety in said -(C0-3 alkylene)-heterocyclylene-(Co-3 alkylene)-are each optionally substituted with one or more groups R78; R75and R76are each independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, and C1-5 haloalkyl;26.R77is selected from C1-5 haloalkyl, C2-5 alkenyl, and C2-5 alkynyl;27.R8is a moiety (E1) or (E2):

28. / R1229. / NZ30.R1131.I N RBZ 'R1433.

36. 38.R11is C1-5 alkylene, wherein one -CH2- unit comprised in said C1-5 alkylene is optionally replaced by a group -CHR111-, wherein R111, if present, is joined with either R12or R13, if present, to form together a C1-5 alkylene;39.R12is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R121;40.R13, if present, is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R131;41.R14is43.

44. X is C(-R145) or N;45.R141is selected from hydrogen, C1-8alkyl, halogen, C1-8 haloalkyl, -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-8 alkyl), -(C0-3 alkylene)-CO-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-O-cycloalkyl, and -(C0-3 alkylene)-CO-O-heterocycloalkyl;46.R142is selected from hydrogen, C1-8alkyl, C2-8alkenyl, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl; or R142and a group R147are joined together to form a C3-5 alkylene, wherein said R147is attached to the carbon ring atom directly adjacent to the nitrogen ring atom carrying R142;47.R143, R144and R145are each independently selected from hydrogen, C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(C1-8 haloalkyl), and -(C0-3 alkylene)-CN;48.R146is selected from hydrogen, C1-8alkyl, C2-8alkenyl, C1-8 haloalkyl, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl;49.each R147is independently selected from C1-8alkyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(Ci-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl;50.each R61, R78, R9, R10, R121, and R131is independently selected from C1-8alkyl, C2-8alkenyl, C2-8 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O-(Ci-8 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-8 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-8 haloalkyl), -(C0-3 alkylene)-O-(Ci-8 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-8 alkyl), -(C0-3 alkylene)-O-CO-(Ci-8 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-s alkyl), -(C0-3 alkylene)-CO-N(Ci-8 alkyl)(Ci-s alkyl), -(C0-3 alkylene)-NH-CO-(Ci-8 alkyl), -(C0-3 alkylene)-N(Ci-8 alkyl)-CO-(Ci-8 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(C1-8 alkyl), -(C0-3 alkylene)-SO2-N(C1-8 alkyl)(C1-8 alkyl), -(C0-3 alkylene)-NH-SO2-(C1-8 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-8 alkyl), -(C0-3 alkylene)-cycloalkyl, and -(C0-3 alkylene)-heterocycloalkyl;51.m is an integer of 0 to 6;52.n is an integer of 0 to 8;53.p is an integer of 0 to 4; and54.q is an integer of 0 to 5;55.or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein R1and R2are joined together to form a moiety (A1), wherein R3and R4are joined together to form a moiety (B1), and wherein n is 0.

3. The compound of claim 1, wherein R1and R2are joined together to form a moiety (A2), wherein R3and R4are each -NH3, and wherein m is 0.

4. The compound of any one of claims 1 to 3, wherein R5is -NH- or -N(Ci-s alkyl)-.

5. The compound of any one of claims 1 to 4, wherein R6is -(CH2)x-(CH2-O-CH2)y-(CH2)z-, -(CH2)x-(piperazin-1,4-diyl)-(CH2)a-, -(CH2)x-(piperazin-1,4-diyl)-CH2CH2-O-CH2CH2-, or C1-10 alkylene, wherein x is independently an integer of 0 to 3, wherein y is an integer of 2 to 6, wherein z is an integer of 0 to 3, and wherein a is an integer of 2 to 6.

6. The compound of any one of claims 1 to 5, wherein R7is61.

7. The compound of any one of claims 1 to 6, wherein R8is a group64.R1465.I N66.R12 / \R1267.yN' (CH2)1_3 (CH2)!.37NZ68.(CH2)2.4 Y (CH2)2.469.N. N O70.R13 / 'R14XR12orXR1472.

8. The compound of any one of claims 1 to 7, wherein R12, if present, and R13, if present, are each independently selected from hydrogen and C1-5 alkyl.

9. The compound of any one of claims 1 to 8, wherein R14is77.

78. o80.

10. The compound of any one of claims 1 to 6, wherein R8is a group having any one of the following formulae:

84.

86.

11. The compound of claim 1, which is a compound having any one of the following formulae:

89.

90. MalPEG-Carbo-Rezivertinib MalPEG-Carbo-Mobocertinib (also referred to as KP4070)91.

92. MalPEG-Carbo-KP2839 MalPip-Carbo-KP283993.

94. MalPEG-Carbo-KP4012 MalPip-Carbo-KP401295. 97.MalPip-Carbo-Rezivertinib MalPip-Carbo-Mobocertinib Mall’ip-Carbo-AIrnone rtinib99. 101.OxaPip-Carbo-Rezivertinib OxaPip-Carbo-Mobocertinib OxaPip-Carbo-Almonertinib103.

104. MalPip-Oxali-KP2839 O105.

106. MalPip-Oxali-KP4012107.

108. OxaPip-Oxali-Mobocertinib OxaPip-Oxali-Almonertinib OxaPip-Oxali-KP4012 KP4060110. 112.KP4061 KP4062113. 115.KP4072116.or a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 and optionally a pharmaceutically acceptable excipient.

13. The compound of any one of claims 1 to 11 or the pharmaceutical composition of claim 12 for use in the treatment or prevention of cancer.

14. The compound for use according to claim 13 or the pharmaceutical composition for use according to claim 13, wherein the cancer is selected from gastrointestinal cancer, colorectal cancer, colon cancer, liver cancer, pancreatic cancer, biliary tract cancer, hepatobiliary cancer, stomach cancer, genitourinary cancer, urothelial cancer, bladder cancer, testicular cancer, anal cancer, cervical cancer, malignant mesothelioma, osteogenic sarcoma, esophageal and / or esophagogastric cancer, laryngeal cancer, prostate cancer, lung cancer, breast cancer, hematological cancer, leukemia, lymphoma, multiple myeloma, gynecological cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer, uterine cancer, brain cancer, glioblastoma, astrocytoma, neuroblastoma, bone cancer, osteosarcoma, fibrosarcoma, Ewing’s sarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma, Merkel-cell cancer, head and / or neck cancer, squamous cell cancer, thymoma, neuroendocrine cancer, goblet cell cancer, and mouth cancer.

15. The compound for use according to claim 13 or 14 or the pharmaceutical composition for use according to claim 13 or 14, wherein the compound or the pharmaceutical composition is to be administered in combination with an anticancer drug and / or in combination with radiotherapy and / or immunotherapy.

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