Spirocyclic annulated 2-amino-3-cyano thiophene derivatives as KRAS degraders for the treatment of cancer

Abstract

The present invention relates to compounds of formula (I) wherein E is a moiety of formula (II) and wherein POI is a moiety of formula (IV) as degraders of KRAS for use in the treatment and / or prevention of oncological diseases.

Description

[0001] KRAS DEGRADING COMPOUNDS COMPRISING SPIROCYCLIC ANNULATED 2- AMINO-3-CYANO THIOPHENES

[0002] Field of the invention

[0003] The present invention relates to KRAS degrading compounds of formula (I)

[0004] (0 wherein E, LK and POI have the meanings given in the claims and specification, their use as degraders of KRAS, pharmaceutical compositions comprising the same and their medical uses, especially as agents for treatment and / or prevention of oncological diseases, e.g. cancer.

[0005] Background of the invention

[0006] V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase of the Ras family of proteins. KRAS mutations (e.g. amino acids G12, G13, Q61 , A146) are found in a variety of human cancers including lung cancer, colorectal cancer and pancreatic cancer (M. H. Hofmann, et al. Cancer Discov., 2022, 12, 924-937). Alterations (e.g. mutation, over-expression, gene amplification) in Ras family proteins / Ras genes have also been described as a resistance mechanism against cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 Jul;92(7):709- 22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 7 5(12):2489-500). In a subset of tumor indications such as gastric cancer, gastroesophageal junction cancer and esophageal cancer prominent amplification of the wildtype (WT) KRAS proto-oncogene acts as a driver alteration and renders tumor models bearing this genotype addicted to KRAS in vitro and in vivo (Wong et al. Nat Med., 2018, 24(7): 968-977). In contrast, nonamplified KRAS WT cell lines are KRAS independent, unless they carry secondary alterations in genes indirectly causing activation of KRAS (Meyers et al., Nat Genet., 2017, 49:1779-1784). Based on these data, a therapeutic window is expected for a KRAS targeting agent with a KRAS WT targeting activity.

[0007] Genetic alterations affecting e.g. codon 12 of KRAS substitute the glycine residue naturally occurring at this position for different amino acids such as aspartic acid (the G12D mutation or KRAS G12D), cysteine (the G12C mutation or KRAS G12C), valine (the G12V mutation or KRAS G12V) among others. Similarly, mutations within codons 13, 61 and 146 of KRAS are commonly found in the KRAS gene. Altogether KRAS mutations are detectable in 35 % of lung, 45% of colorectal, and up to 90% of pancreatic cancers (Herdeis et al., Curr Opin Struct Biol., 2021 , 71 :136-147).

[0008] PROteolysis TArgeting Chimeras, also known as “PROTACs”, have emerged as a promising therapeutic modality. They bind to proteins causing their degradation by inducing their ubiquitination.

[0009] Structurally, they are tripartite or heterobifunctional compounds comprising two ligands bound by a linker. One of the ligands recruits an E3 ligase, while the other binds to a protein of interest (POI), thereby forming a ternary complex (E3 ligase-degrader-POl). In view of the structural proximity between E3 ligase and POI induced by the degrader, the E3 ligase can trigger ubiquitination and subsequent degradation of the POI by the ubiquitin- proteasome system (UPS). Von-Hippel Lindau (VHL), cereblon (CRBN), Inhibitor of Apoptosis (IAP) and Mouse Double Minute 2 (MDM2) are among the E3 ligases targeted by PROTACs and corresponding ligands (e.g. VHL ligand, CRBN ligand) are incorporated in PROTAC structures.

[0010] Degraders possess several advantages over conventional medicinal chemistry modalities, especially inhibitors. For instance, their mechanism of action is catalytic and sub- stoichiometric, since after degradation of a POI, the responsible degrader molecule is released and can go on to induce the degradation of other POIs. In addition, a degrader does not need to bind to the target protein domain that is functionally responsible for the disease. On the contrary, the most ligandable domain can be targeted for degradation independent of its functionality or vulnerability to small molecule blockade. For this reason, degraders promise to expand the druggable proteome to targets thought to be undruggable. Degraders of wild-type (e.g. amplified or overexpressed) or mutant KRAS (e.g. G12A, G12C, G12D, G12V, G13D and / or Q61 H) are expected to deliver anti-cancer efficacy.

[0011] Therefore, there is still the need to provide compounds that can inhibit and / or degrade multiple KRAS variants.

[0012] KRAS degraders have, e.g., been described in WO 2019 / 195609, WO 2022 / 173032, WO 2023 / 141570, WO 2023 / 171781 , WO 2023 / 193085, WO 2023 / 215906, WO 2024 / 019103, WO 2024 / 029613, WO 2024 / 034593, WO 2024 / 055112, WO 2024 / 118960, WO 2024 / 118966, WO 2024 / 119278, WO 2024 / 120424 and WO 2024 / 131777. KRAS inhibitors comprising partially saturated, annulated 2-amino-3-cyano thiophenes as structural motif have been described in WO 2021 / 245051 , WO 2021 / 245055, WO 2023 / 099592, WO 2023 / 099608, WO 2023 / 099612, WO 2023 / 099623, WO 2023 / 099624, WO 2023 / 244599, WO 2024 / 238633, US 2024 / 368191 , CN117924327, KR20240101190 and KR2024041719.

[0013] KRAS degraders comprising partially saturated, annulated 2-amino-3-cyano thiophenes in the KRAS ligand part of the degrader have been described in WO 2023 / 099620 and Popow et al. (Science 385, 1338-1347 (2024)), and in WO 2024 / 233838.

[0014] Detailed description of the invention

[0015] Compounds

[0016] It has now been surprisingly found that compounds of formula (I) as herein defined can act as inhibitors and / or degraders of KRAS and thereby possess anti-tumour activity. Advantageously, the compounds of the invention can inhibit and / or degrade a variety of KRAS forms, including wild-type (e.g. amplified or overexpressed) as well as mutant KRAS, e.g. G12A, G12C, G12D, G12V, G13D and / or Q61 H. In particular, they can be effective against a panel of KRAS mutated forms. Thus, they may be used for example for the treatment of diseases mediated by KRAS and / or characterised by excessive or abnormal cell proliferation, in particular KRAS aberrant cancer.

[0017] In addition, the compounds of the invention advantageously possess desirable pharmacological properties, including but not limited to metabolic stability, plasma protein binding, solubility and permeability.

[0018] It is therefore an object of the present invention a compound of formula (I)

[0019] (0 wherein

[0020] E is a moiety of formula (II) denotes a single or double bond;

[0021] R7is -H or =0; r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN;

[0022] LK is a moiety of formula (III) , wherein

[0023] LK1is selected from the group consisting of Cs-ycycloalkylene, Cs-ycycloalkenylene, arylene, 3-12 membered heterocyclylene, 3-7 membered heteroarylene and C2-6alkynylene, wherein the Cs-ycycloalkylene, Cs-ycycloalkenylene, arylene, 3-12 membered heterocyclylene, 3-7 membered heteroarylene or C2-6alkynylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl, wherein any one or more carbon atom(s) of the C2-6alkynylene is optionally replaced by a hetereoatom selected from the group consisting of oxygen, nitrogen and sulfur;

[0024] LK2is selected from the group consisting of a bond, Ci-6alkylene, Ci-6alkoxylene and C2-6alkynylene, wherein the Ci-6alkylene, Ci-6alkoxylene or C2-6alkynylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl;

[0025] POI is a moiety of formula (IV)

[0026]

[0027] R1aand R1bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl;

[0028] R2aand R2bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; and / or, optionally, one of R1aor R1band one of R2aor R2btogether with the carbon atoms they are attached to form a cyclopropane ring;

[0029] Z is -(CR3aR3b)n-; each R3aand R3bis independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; or R3aand R3btogether with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; or

[0030] Z is sulphur (-S-); ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, cyano-Ci-ealkyl, halogen, -OH, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, -CN, Cs-scycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1 , 2 and 3;

[0031] W is nitrogen (-N=) or -CH=;

[0032] V is nitrogen (-N=) or -CH=; R5is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different substituent(s) selected from the group consisting of Ci-ealkyl, Ci-ealkoxy and 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl; or

[0033] R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl; m and q are each independently selected from the group consisting of 0, 1 and 2; or a salt thereof.

[0034] In other words, it is an object of the present invention a compound of formula (I*) or a salt thereof, wherein R1a, R1b, R2a, R2b, R4, R5, R7, R8,V, W, Z, m, p, q, r, ring A, LK1and LK2are as defined herein above or in any aspect disclosed herein.

[0035] E

[0036] In another aspect, E is a moiety of formula (ll-a)

[0037] (ll-a) , wherein denotes a single or double bond;

[0038] R7is -H or =0; r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, C^alkoxy, Ci.4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN.

[0039] In another aspect, E is a moiety of formula (ll-b) denotes a single or double bond;

[0040] R7is -H or =0; r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN.

[0041] In another aspect, E comprises a mixture of a moiety of formula (ll-a) and a moiety of formula (ll-b).

[0042] In another aspect, r is 0 or 1 .

[0043] In another aspect, each R8, if present, is halogen.

[0044] In another aspect, each R8, if present, is fluorine.

[0045] In another aspect, E is a moiety of formula (ll-c) denotes a single or double bond;

[0046] R7is -H or =0;

[0047] R8aand R8bare each independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN. In another aspect, E is a moiety of formula (I l-c) as defined above, wherein R8aand R8bare hydrogen.

[0048] In another aspect, E is a moiety of formula (I l-c) as defined above, wherein R8aand R8bare each independently hydrogen or halogen.

[0049] In another aspect, E is a moiety of formula (I l-c) as defined above, wherein R8aand R8bare each independently hydrogen or fluorine.

[0050] In another aspect, E is a moiety of formula (ll-c) as defined above, wherein R8ais hydrogen and R8bis halogen.

[0051] In another aspect, E is a moiety of formula (ll-c) as defined above, wherein R8ais halogen and R8bis hydrogen.

[0052] In another aspect, E is a moiety of formula (ll-c) as defined above, wherein R8ais hydrogen and R8bis fluorine.

[0053] In another aspect, E is a moiety of formula (ll-c) as defined above, wherein R8ais fluorine and R8bis hydrogen.

[0054] In another aspect, in particular when R7is -H, E is a moiety of formula (ll-d)

[0055] (ll-d) , wherein r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN.

[0056] In another aspect, in particular when R7is =0, E is a moiety of formula (ll-e)

[0057] (|l-e) , wherein r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN.

[0058] In another aspect, E is selected from the group consisting of

[0059]

[0060] In another aspect, E is

[0061] In another aspect, E is

[0062] In another aspect, E is

[0063] In another aspect, E is

[0064] LK

[0065] In another aspect, LK1is a 3-12 membered heterocyclylene, wherein the 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl; and

[0066] LK2is Ci-6alkylene, wherein the Ci-6alkylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0067] In another aspect, LK1is a 3-12 membered heterocyclylene, wherein the 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl; and LK2is Ci-6alkylene.

[0068] In another aspect, LK1is a 3-12 membered heterocyclylene, wherein the 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl and halogen(s); and

[0069] LK2is Ci-6alkylene.

[0070] In another aspect, LK1is selected from the group consisting of Cs-zcycloalkylene, Cs-ycycloalkenylene, arylene, 3-12 membered heterocyclylene and 3-7 membered heteroarylene, wherein the Cs-zcycloalkylene, Cs-zcycloalkenylene, arylene, 3-12 membered heterocyclylene or 3-7 membered heteroarylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-zcycloalkyl and 3-4 membered heterocyclyl.

[0071] In another aspect, LK1is selected from the group consisting of Cs-zcycloalkylene, Cs-ycycloalkenylene and 3-12 membered heterocyclylene, wherein the Cs-ycycloalkylene, Cs-ycycloalkenylene, 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0072] In another aspect, LK1is a 3-12 membered heterocyclylene, wherein the 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl. In this aspect, preferably, the 3-12 membered heterocyclylene is a 3-12 membered, nitrogen containing heterocyclylene.

[0073] In another aspect, LK1is 5-9 membered, nitrogen containing heterocyclylene, wherein the 5-9 membered, nitrogen containing heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0074] In another aspect, LK1is a ring selected from the group consisting of

[0075] any hydrogen atom is replaced by a bond to E; any other hydrogen atom is replaced by a bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0076] I any hydrogen atom is replaced by a bond to E; any other hydrogen atom is replaced by a bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0077] In another aspect, LK1is a ring selected from the group consisting of

[0078] one dotted bond (— ) denotes the bond to E; the other dotted bond (— ) denotes the bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0079] In another aspect, LK1is a ring selected from the group consisting of one dotted bond (— ) denotes the bond to E; the other dotted bond (— ) denotes the bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0080] In another aspect, LK1is a ring selected from the group consisting of one dotted bond (— ) denotes the bond to E; the other dotted bond (— ) denotes the bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0081] In another aspect, LK1is a ring selected from the group consisting of one dotted bond (— ) denotes the bond to E; the other dotted bond (— ) denotes the bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0082] In any aspect defining LK1as optionally substituted with one or more identical or different substituent(s), unless stated otherwise in that aspect, it is preferred that said optional substituent(s) is / are each independently Ci-4alkyl or halogen.

[0083] In any aspect defining LK1as optionally substituted with one or more identical or different substituent(s), unless stated otherwise in that aspect, it is preferred that said optional substituent(s) is / are halogen(s), in particular fluorine.

[0084] In another aspect, LK1is selected from the group consisting of

[0085] In another aspect, LK1is selected from the group consisting of

[0086] In another aspect, LK2is a bond or Ci-6alkylene, wherein the Ci-6alkylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0087] In another aspect, LK2is a bond or Ci-4alkylene, wherein the Ci-4alkylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0088] In another aspect, LK2is a bond or Ci-3alkylene, wherein the Ci-2alkylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0089] In another aspect, LK2is a bond or Ci-ealkylene.

[0090] In another aspect, LK2is a bond or Ci-4alkylene.

[0091] In another aspect, LK2is a bond or Ci-3alkylene.

[0092] In another aspect, LK2is a bond.

[0093] In another aspect, LK2is Ci-ealkylene, wherein the Ci-ealkylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

[0094] In another aspect, LK2is Ci-ealkylene.

[0095] In another aspect, LK2is Ci-4alkylene.

[0096] In another aspect, LK2is Ci-3alkylene.

[0097] In another aspect, LK2is methylene.

[0098] In another aspect, LK2is ethylene. In another aspect, LK2is n-propylene.

[0099] In another aspect, LK2is n-butylene.

[0100] In another aspect, LK is selected from the group consisting of stereoisomer thereof .

[0101] In another aspect, LK is selected from the group consisting of any stereoisomer thereof .

[0102] In all embodiments comprising LK1as disclosed herein above and below, wherein LK1is 3-7 membered heteroarylene, said 3-7 membered heteroarylene is preferably a 5-7 membered heteroarylene.

[0103] POI

[0104] In one aspect, R1aand R1bare both independently selected from the group consisting of hydrogen and Ci-4alkyl.

[0105] In another aspect, R2aand R2bare both independently selected from the group consisting of hydrogen and halogen.

[0106] In another aspect, R1aand R1bare both independently selected from the group consisting of hydrogen and methyl.

[0107] In another aspect, R2aand R2bare both independently selected from the group consisting of hydrogen and fluorine.

[0108] In another aspect, R1aand R1bare hydrogen.

[0109] In another aspect, R2aand R2bare hydrogen.

[0110] In another aspect, R1a, R1b, R2aand R2bare hydrogen.

[0111] In another aspect, R3aand R3bare hydrogen.

[0112] In another aspect, R1a, R1b, R2a, R2b, R3aand R3bare hydrogen.

[0113] In another aspect, n is 0.

[0114] In another aspect, n is 1.

[0115] In another aspect, n is 2.

[0116] In another aspect, Z is -CH2-.

[0117] In another aspect, R1a, R1b, R2aand R2bare hydrogen and Z is -CH2-.

[0118] In another aspect, Z is -S-.

[0119] In another aspect, the moiety of formula (IV) is of formula (IV*) , wherein

[0120] (LK), R1a, R1b, R2a, R2b, R4, R5, V, W, Z, m, p, q, and ring A are as defined herein above or below.

[0121] In another aspect, p is 0. In another aspect, the moiety of formula (IV) is of formula (IV-a) wherein

[0122] (LK), ring A, R5, V, W, m and q are as defined herein above or below.

[0123] In another aspect, the moiety of formula (IV) is of formula (IV-b) wherein ring A, R5, V, W, m and q are as defined herein above or below.

[0124] In another aspect, ring A is a ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole. In another aspect, ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole and triazole.

[0125] In another aspect, ring A is selected from the group consisting of

[0126] In another aspect, ring A is isoxazole or isothiazole.

[0127] In another aspect, ring A is selected from the group consisting of

[0128] In another aspect, ring A is isoxazole.

[0129] In another aspect, R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, ring A is isoxazole and p is 0.

[0130] In another aspect, ring A is

[0131] In another aspect, the moiety of formula (IV) is of formula (IV-c) or (IV-d)

[0132] R5, V, W, m and q are as defined herein above or below.

[0133] In another aspect, the moiety of formula (IV) is of formula (IV-c) as defined herein above or below.

[0134] In another aspect, the moiety of formula (IV) is of formula (IV-d) as defined herein above or below.

[0135] In another aspect, the moiety of formula (IV) is of formula (IV-e) or (IV-f)

[0136] R5, V, W, m and q are as defined herein above or below.

[0137] In another aspect, the moiety of formula (IV) is of formula (IV-e) as defined herein above or below.

[0138] In another aspect, the moiety of formula (IV) is of formula (IV-f) as defined herein above or below.

[0139] In another aspect, at least one of V and / or W is nitrogen (-N=).

[0140] In another aspect, V and W are nitrogen (-N=).

[0141] In another aspect, V is -CH= and W is nitrogen (-N=).

[0142] In another aspect, V is nitrogen (-N=) and W is -CH=.

[0143] In another aspect, V and W are -CH=.

[0144] In another aspect, R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, ring A is isoxazole, p is 0 and V and W are nitrogen (-N=).

[0145] In another aspect, the moiety of formula (IV) is of formula (IV-g) or (IV-h)

[0146] (IV-g) (IV-h)

[0147] (LK), R5, m and q are as defined herein above or below.

[0148] In another aspect, the moiety of formula (IV) is of formula (IV-g) as defined herein above or below.

[0149] In another aspect, the moiety of formula (IV) is of formula (IV-h) as defined herein above or below.

[0150] In another aspect, the moiety of formula (IV) is of formula (IV-i) or (IV-j)

[0151] (LK), R5, m and q are as defined herein above or below.

[0152] In another aspect, the moiety of formula (IV) is of formula (IV-i) as defined herein above or below.

[0153] In another aspect, the moiety of formula (IV) is of formula (IV-j) as defined herein above or below.

[0154] In another aspect, R5is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different substituent(s) independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy and 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl. In another aspect, R5is a 5-8 membered heterocyclyl optionally substituted with one or more identical or different substituent(s) selected from the group consisting of Ci-ealkyl, Ci-ealkoxy and 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl.

[0155] In another aspect, R5is a 5-8 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl.

[0156] In another aspect, R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6, and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0157] In another aspect, R5is -O-Ci-ealkyl substituted with a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with one or more, identical or different R6, and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0158] In another aspect, R5is selected from the group consisting of

[0159]

[0160] In another aspect, R5is selected from the group consisting of

[0161]

[0162] In another aspect, R5is selected from the group consisting of

[0163] In another aspect, R5is selected from the group consisting of

[0164] In another aspect, R5is

[0165] In another aspect, R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, ring A is isoxazole, p is

[0166] 0, V and W are nitrogen (-N=) and R5is selected from the group consisting of Preferably, in this aspect, the moiety of formula (IV) is of formula (IV*).

[0167] In another aspect, m is 1 and q is 1.

[0168] In another aspect, m is 1 and q is 2.

[0169] In another aspect, m is 2 and q is 1.

[0170] In another aspect, m is 2 and q is 2.

[0171] In another aspect,

[0172] R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, m is 1 and q is 1 , ring A is isoxazole, p is 0, V and W are nitrogen (-N=) and

[0173] R5is Preferably, in this aspect, the moiety of formula (IV) is of formula (IV*). In another aspect, the moiety of formula (IV) is of formula (IV**)

[0174] (LK), R1a, R1b, R2a, R2b, R4, R5, Z, ring A, p, V and W are as defined in any aspect herein.

[0175] In another aspect, the moiety of formula (IV) is of formula (IV-k)

[0176] (LK), ring A, R5, V and W are as defined herein.

[0177] In another aspect, the moiety of formula (IV) is of formula (IV-m)

[0178] (LK), ring A, R5, V and W are as defined herein.

[0179] In another aspect, the moiety of formula (IV) is of formula (IV-n) or (IV-o) , wherein (IV-n) (IV-o)

[0180] (LK), R5, V and W are as defined herein.

[0181] In another aspect, the moiety of formula (IV) is of formula (IV-n) as defined herein.

[0182] In another aspect, the moiety of formula (IV) is of formula (IV-o) as defined herein.

[0183] In another aspect, the moiety of formula (IV) is of formula (IV-p) or (IV-q)

[0184] (LK), R5, V and W are as defined herein.

[0185] In another aspect, the moiety of formula (IV) is of formula (IV-p) as defined herein.

[0186] In another aspect, the moiety of formula (IV) is of formula (IV-q) as defined herein.

[0187] In another aspect, the moiety of formula (IV) is of formula (IV-r) or (IV-s)

[0188] (LK) and R5are as defined herein. Preferably, in formulas (IV-r) and (IV-s), R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0189] In another aspect, the moiety of formula (IV) is of formula (IV-r) as defined herein.

[0190] In another aspect, the moiety of formula (IV) is of formula (IV-s) as defined herein.

[0191] In another aspect, the moiety of formula (IV) is of formula (IV-t) or (IV-u)

[0192]

[0193] (LK) and R5are as defined herein. Preferably, in formulas (IV-t) and (IV-u), R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0194] In another aspect, the moiety of formula (IV) is of formula (IV-t) as defined herein.

[0195] In another aspect, the moiety of formula (IV) is of formula (IV-u) as defined herein.

[0196] In another aspect, the moiety of formula (IV) is selected from the group consisting of

[0197]

[0198] In another aspect, the moiety of formula (IV) is selected from the group consisting of In another aspect, the moiety of formula (IV) is

[0199] In another aspect, the moiety of formula (IV) is

[0200] In another aspect, the moiety of formula (IV) is

[0201]

[0202] In another aspect, the moiety of formula (IV) is

[0203] In another aspect, the moiety of formula (IV) is

[0204] In an aspect, the invention refers to a compound selected from the group consisting of compounds 1-1, 1-3 to I-5, 1-7 to I-25, as defined hereinbelow, or a stereoisomer thereof.

[0205] In an aspect, the invention refers to a pharmaceutically acceptable salt of a compound selected from the group consisting of compounds 1-1, I-3 to I-5, I-7 to I-25, as defined hereinbelow, or a stereoisomer thereof.

[0206] In another aspect, the compound of the invention has a Dmax for KRAS G12D of at least 40 %, preferably of at least 50 %, preferably of at least 60 %, preferably of at least 70 %, preferably of at least 80 %, preferably of at least 90 %, preferably of at least 95 %. Said Dmax can be measured with any method known to the skilled person, in particular with the method described in the examples below.

[0207] In another aspect, the compound of the invention has a DCso for KRAS lower than 50 nM, preferably lower than 40 nM, preferably lower than 30 nM, 20 nM, preferably lower than 15 nM, preferably lower than 10 nM, preferably lower than 5 nM,. Said DCso can be measured with any method known to the skilled person, in particular with the method described in the examples below.

[0208] Intermediates

[0209] A further object of the present invention is represented by a compound of formula (V) wherein

[0210] R1aand R1bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl;

[0211] R2aand R2bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; and / or, optionally, one of R1aor R1band one of R2aor R2btogether with the carbon atoms they are attached to form a cyclopropane ring;

[0212] Z is -(CR3aR3b)n-; each R3aand R3bis independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; or R3aand R3btogether with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; or

[0213] Z is sulphur (-S-); ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, cyano-Ci-ealkyl, halogen, -OH, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, -CN, Cs-scycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1 , 2 and 3;

[0214] W is nitrogen (-N=) or -CH=;

[0215] V is nitrogen (-N=) or -CH=;

[0216] R5is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different substituent(s) selected from the group consisting of Ci-ealkyl, Ci-ealkoxy and 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl; or

[0217] R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl; m and q are each independently selected from the group consisting of 0, 1 and 2; or a salt thereof.

[0218] In formula (V), R1a, R1b, R2a, R2b, R4, R5, Z, W, V, m, p, q and ring A can be as defined above in any aspect or embodiment referring to formula (I) and / or (IV).

[0219] In an aspect of formula (V), R1a, R1b, R2aand R2bare hydrogen.

[0220] In an aspect of formula (V), Z is -CH2-.

[0221] In an aspect of formula (V), R1a, R1b, R2aand R2bare hydrogen and Z is -CH2-.

[0222] In an aspect, the compound of formula (V) is of formula (V*) wherein

[0223] R1a, R1b, R2a, R2b, R4, R5, Z, W, V, m, p, q and ring A are as defined herein above or below.

[0224] In another aspect, the compound of formula (V) is of formula (V-a)

[0225] wherein ring A, R5, m, q, V and W are as defined herein above or below.

[0226] In an aspect of formula (V), ring In an aspect of formula (V), V and W are nitrogen (-N=).

[0227] In another aspect of formula (V), R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, ring A is isoxazole, p is 0 and V and W are nitrogen (-N=).

[0228] In another aspect, the compound of formula (V) is of formula (V-b) or (V-c) m, q and R5is as defined herein above or below. In another aspect, the compound of formula (V) is of formula (V-b) as defined herein above or below.

[0229] In another aspect, the compound of formula (V) is of formula (V-c) as defined herein above or below.

[0230] In an aspect of formula (V), R5is selected from the group consisting of

[0231] I are hydrogen, Z is -CH2-, ring A is isoxazole, p is 0, V and W are nitrogen (-N=) and R5is selected from the group consisting Preferably, in this aspect, the compound of formula (V) is of formula (V*).

[0232] In an aspect of formula (V), m is 1 and q is 1.

[0233] In an aspect of formula (V), m is 1 and q is 2.

[0234] In an aspect of formula (V), m is 2 and q is 1.

[0235] In an aspect of formula (V), m is 2 and q is 2.

[0236] In an aspect of formula (V), R1a, R1b, R2aand R2bare hydrogen, Z is -CH2-, m is 1 , q is 1 , ring A is isoxazole, p is 0, V and W are nitrogen (-N=) and

[0237] R5is selected from the group consisting of Preferably, in this aspect, the compound of formula (V) is of formula (V*).

[0238] In another aspect, the compound of formula (V) is of formula (V**) wherein

[0239] R1a, R1b, R2a, R2b, R4, R5, Z, ring A, p, V and W are as defined in any aspect herein.

[0240] In another aspect, the compound of formula (V) is of formula (V-d) ring A, R5, V and W are as defined herein.

[0241] In another aspect, the compound of formula (V) is of formula (V-e) or (V-f)

[0242] R5, V and W are as defined herein.

[0243] In another aspect, the compound of formula (V) is of formula (V-e) as defined herein.

[0244] In another aspect, the compound of formula (V) is of formula (V-f) as defined herein.

[0245] In another aspect, the compound of formula (V) is of formula (V-g) or (V-h)

[0246] R5is as defined herein. Preferably, in formulas (V-g) and (V-h), R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0247] In another aspect, the compound of formula (V) is of formula (V-g) as defined herein.

[0248] In another aspect, the compound of formula (V) is of formula (V-h) as defined herein.

[0249] In another aspect, the compound of formula (V) is of formula (V-i) or (V-j)

[0250]

[0251] R5is as defined herein. Preferably, in formulas (V-i) and (V-j), R5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl.

[0252] In another aspect, the compound of formula (V) is of formula (V-i) as defined herein.

[0253] In another aspect, the compound of formula (V) is of formula (V-j) as defined herein.

[0254] In another aspect, the compound of formula (V) is selected from the group consisting of

[0255] It is to be understood that any two or more aspects and / or preferred embodiments may be combined in any way leading to a chemically stable structure to obtain further aspects and / or preferred embodiments of formula (I), (II), (III), (IV) or (V). Any further aspects and / or preferred embodiments thus combinable shall be regarded as disclosed herein, in particular any combination of preferred embodiments of E, LK and POI as disclosed herein.

[0256] Compounds of formula (V), as well as all their embodiments described herein, can serve as intermediates in the synthesis of compounds of formula (I) and their respective embodiments. Furthermore, compounds of formula (V) and their embodiments may also be used for medical purposes and in methods of treatment as described below, owing to their inhibitory activity on KRAS and its mutants, based on their function as KRAS ligands, and are thus also compounds of the invention.

[0257] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of a compound of the invention.

[0258] Compounds of the invention which e.g. bear ester groups are potential prodrugs the ester being cleaved under physiological conditions and are also part of the invention.

[0259] The present invention further relates to a pharmaceutically acceptable salt of a compound of the invention.

[0260] The present invention further relates to a pharmaceutically acceptable salt of a compound of the invention with anorganic or organic acids or bases.

[0261] Medical Uses - Methods of Treatment

[0262] Indications - patient populations

[0263] The present invention is directed to compounds as defined herein inhibiting or degrading KRAS (i.e. compounds of formula (I) and their embodiments and compounds of formula (V) and their embodiments), preferably KRAS mutated at residue 12, such as KRAS G12A, KRAS G12C, KRAS G12D and / or KRAS G12V, preferably degraders of KRAS G12V and / or KRAS G12D, or degraders selective for KRAS G12V, KRAS mutated at residue 13, such as KRAS G13D, or KRAS mutated at residue 61 , such as KRAS Q61 H, and / or wildtype KRAS gene and / or protein, especially wildtype amplified KRAS or KRAS, or wildtype overexpressed KRAS. In particular, compounds of the invention can be useful in the treatment and / or prevention of diseases and / or conditions dependent on or mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12V, or by an amplification of KRAS (especially an amplification of KRAS wildtype), or by KRAS mutated at residue 13, e.g. KRAS G13D, or by KRAS mutated at residue 61 , such as KRAS Q61 H.

[0264] Thus, in a further aspect the invention relates to a compound of the invention for use as a medicament.

[0265] In a further aspect the invention relates to a compound of the invention for use in a method of treatment of the human or animal body.

[0266] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of a disease and / or condition mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12V, or by an amplification of KRAS (especially an amplification of KRAS wildtype), or by KRAS mutated at residue 13, e.g. KRAS G13D, or by KRAS mutated at residue 61 , such as KRAS Q61 H.

[0267] In a further aspect the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of a disease and / or condition mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12V, or by an amplification of KRAS (especially an amplification of KRAS wildtype), or by KRAS mutated at residue 13, e.g. KRAS G13D, or by KRAS mutated at residue 61 , e.g. KRAS Q61 H.

[0268] In a further aspect the invention relates to a method for the treatment and / or prevention of a disease and / or condition mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12V, or by an amplification of KRAS (especially an amplification of KRAS wildtype), or by KRAS mutated at residue 13, e.g. KRAS G13D, or by KRAS mutated at residue 61 , e.g. KRAS Q61 H, comprising administering a therapeutically effective amount of a compound of the invention to a human being.

[0269] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer.

[0270] In a further aspect the invention relates to a compound of the invention for use in a method of treatment and / or prevention of cancer in the human or animal body. In a further aspect the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0271] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being.

[0272] Preferably, the cancer as defined herein (above or below) comprises a KRAS aberration. In particular, KRAS aberrations include e.g. aberrations of the KRAS gene and / or of the KRAS protein, such as overexpressed KRAS, amplified KRAS or KRAS, KRAS mutated at residue 12, KRAS mutated at residue 13, KRAS mutated at residue 61 , KRAS mutated at residue 146, in particular KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13C, KRAS G13D, KRAS G13V, KRAS Q61H, KRAS Q61 E, KRAS Q61 P, KRAS A146P, KRAS A146T, KRAS A146V. KRAS may present one or more of these mutations / alterations. The KRAS gene (wildtype or carrying one of the above listed mutations) can also be amplified, i.e. present in more than two copies per cell.

[0273] Preferably, the cancer as defined herein (above or below) comprises a BRAF aberration in addition to the KRAS mutation. Said BRAF aberration is in particular a class III BRAF mutation, e.g. as defined in Z. Yao, Nature, 2017, 548, 234-238.

[0274] Preferably, the cancer as defined herein (above or below) comprises an aberration in a receptor tyrosine kinase (RTK), including EGFR, MET and ERBB2 mutations, in addition to the KRAS aberration.

[0275] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS aberration, said KRAS aberration being preferably selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

[0276] In a further aspect the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS aberration, said KRAS aberration being preferably selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

[0277] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer comprises a KRAS aberration, said KRAS aberration being preferably selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

[0278] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12A mutation.

[0279] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12C mutation.

[0280] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12D mutation.

[0281] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12V mutation.

[0282] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G13D mutation.

[0283] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS Q61 H mutation.

[0284] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises wildtype amplified KRAS.

[0285] In a further aspect the invention relates to a compound of the invention for use in a method of inhibiting or degrading KRAS, wherein KRAS can be aberrant, wild-type, mutated, amplified or overexpressed as defined herein.

[0286] In a further aspect the invention relates to the use of a compound of the invention in the manufacture of a medicament for use in a method of inhibiting or degrading KRAS, wherein KRAS can be aberrant, wild-type, amplified, mutated or overexpressed as herein defined.

[0287] In a further aspect the invention relates to a method for inhibiting or degrading KRAS, wherein KRAS can be aberrant, wild-type, amplified, mutated or overexpressed as herein defined, comprising administering a therapeutically effective amount of a compound of the invention to a human being. In a further aspect the invention relates to a compound of the invention for use in a method of degrading or inducing degradation of KRAS, wherein KRAS can be aberrant, wild-type, amplified, mutated or overexpressed as herein defined above.

[0288] In a further aspect the invention relates to the use of a compound of the invention in the manufacture of a medicament for use in a method of degrading or inducing degradation of KRAS, wherein KRAS can be aberrant, wild-type, amplified, mutated or overexpressed as herein defined.

[0289] In a further aspect the invention relates to a method for degrading or inducing degradation of KRAS, wherein KRAS can be aberrant, wild-type, amplified, mutated or aberrant as herein defined, comprising administering a therapeutically effective amount of a compound of the invention to a human being.

[0290] Another aspect is based on identifying a link between the KRAS status of a patient and potential susceptibility to treatment with a compound of the invention. A KRAS inhibitor or degrader, such as a compound of the invention - or a pharmaceutically acceptable salt thereof - may then advantageously be used to treat patients with a disease dependent on KRAS, who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of the invention, particularly cancer patients. The selection is based on whether the tumor cells to be treated possess wild-type, preferably amplified, or KRAS mutated at residue 12, preferably G12A, G12C, G12D or G12V encoding gene, or KRAS mutated at residue 13, preferably G13D encoding gene, or KRAS mutated at residue 61 , preferably Q61 H encoding gene. The KRAS gene status could therefore be used as a biomarker to indicate that selecting treatment with a compound of the invention may be advantageous.

[0291] According to one aspect, there is provided a method for selecting a patient for treatment with a compound of the invention , the method comprising

[0292] • providing a tumor cell-containing sample from a patient;

[0293] • determining whether the KRAS gene in the patient's tumor cell-containing sample encodes for wild-type (e.g. glycine at position 12 and 13, glutamine at position 61) or aberrant (e.g. cysteine, aspartic acid, valine, alanine or aginine at position 12, aspartic acid at position 13, histidine at position 61 , amplification and / or overexpression) KRAS protein; and

[0294] • selecting a patient for treatment with said compound based thereon. The method may include or exclude the actual patient sample isolation step.

[0295] In one aspect, the patient is selected for treatment with a compound of the invention if the tumor cell DNA has or encodes an aberrant KRAS gene and / or protein.

[0296] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a KRAS mutation or an amplification of KRAS wildtype.

[0297] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G12A mutant, G12C mutant, G12D mutant, G12V mutant, G13D mutant or Q61 H mutant KRAS gene or an amplification of KRAS wildtype.

[0298] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G12A mutant KRAS gene.

[0299] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G12C mutant KRAS gene.

[0300] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G12D mutant KRAS gene.

[0301] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G12V mutant KRAS gene.

[0302] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a G13D mutant KRAS gene.

[0303] According to another aspect, there is provided a compound of the invention for use in treating a cancer with tumor cells harbouring a Q61 H mutant KRAS gene.

[0304] According to another aspect, there is provided a compound of the invention- for use in treating a cancer with tumor cells harbouring wildtype amplified KRAS or overexpressed KRAS.

[0305] According to another aspect, there is provided a method of treating a cancer with tumor cells harbouring a G12A mutant, G12C mutant, G12D mutant, G12V mutant, G13D mutant or Q61 H mutant KRAS gene or an amplification of KRAS wildtype gene comprising administering an effective amount of a compound of the invention- to a human being.

[0306] Determining whether a tumor or cancer comprises a KRAS aberration can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS mutant protein. The sequence of wild-type human KRAS is known in the art. Methods for detecting a mutation in a KRAS nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for KRAS mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS mutation can be used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is identified using a direct sequencing method of specific regions (e.g. exon 2 and / or exon 3) in the KRAS gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in a KRAS, protein are known by those of skill in the art and may not only be applied to identify presence of mutated / altered KRAS at baseline but also to monitor response to treatment in particular treatment related depletion of WT or mutated KRAS from tumor samples. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g. an antibody) which may also be specific for the mutant protein, protein electrophoresis, Western blotting, direct peptide sequencing and detection of wild type or mutated KRAS by mass spectrometry-based approaches. Methods for detecting an amplification of the wildtype or mutated KRAS nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to in-situ-hybridization (ISH), determination of protein expression levels by immunohistochemistry using an antibody specific for wildtype or mutated KRAS protein (IHC) or detecting copy number variations by analysis of nucleotide sequences.

[0307] Methods for determining whether a tumor or cancer comprises a KRAS aberration can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In some embodiments the sample is a liquid biopsy and the test is done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.

[0308] In another aspect, the disease / condition / cancer / tumors / cancer cells to be treated / prevented with a compound of the invention according to the methods and uses as herein (above and below) defined and disclosed is selected from the group consisting of pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC), especially non-small-cell lung adenocarcinoma), colorectal cancer (CRC, preferably colorectal adenocarcinoma), biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma and ampulla of Vater cancer), uterine cancer, endometrial cancer, urothelial cancer, gastric cancer (GC; preferably gastric adenocarcinoma, GAC), esophageal cancer (EC; preferably esophageal adenocarcinoma, EAC), gastroesophageal junction cancer (GEJC), cervical cancer, breast cancer and ovarian cancer.

[0309] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0310] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0311] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is pancreatic cancer, preferably wherein the pancreatic cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0312] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is pancreatic cancer, preferably wherein the pancreatic cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0313] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is non-small cell lung cancer, preferably wherein the non-small-cell lung cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0314] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is non-small cell lung cancer, preferably wherein the non-small cell lung cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0315] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer and gastroesophageal junction cancer, preferably wherein the gastric cancer, esophageal cancer and gastroesophageal junction cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0316] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer and gastroesophageal junction cancer, preferably wherein the gastric cancer, esophageal cancer and gastroesophageal junction cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype.

[0317] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS aberration, said KRAS aberration being preferably selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS and wherein the cancer is selected from the group consisting of pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC), especially non-small cell lung adenocarcinoma), colorectal cancer (CRC, preferably colorectal adenocarcinoma), biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma, ampulla of Vater cancer), uterine cancer, endometrial cancer, urothelial cancer, gastric cancer (GC; preferably gastric adenocarcinoma, GAC), esophageal cancer (EC; preferably esophageal adenocarcinoma, EAC), gastroesophageal junction cancer (GEJC), cervical cancer, breast cancer and ovarian cancer.

[0318] Preferably, said pancreatic cancer, lung cancer, biliary tract cancer, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma, ampulla of Vater cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), non-small cell lung adenocarcinoma (NSCLC) or colorectal adenocarcinoma comprises a KRAS mutation, in particular a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61 H mutation, or a KRAS wild-type amplification. Preferably (in alternative or in combination with the previous preferred embodiment), said non-small cell lung cancer (NSCLC) or non-small cell adenocarcinoma comprises a mutation (in particular a loss-of-function mutation) in the NF1 gene.

[0319] Preferably, said gastric cancer, biliary tract cancer, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma, ampulla of Vater cancer, ovarian cancer, esophageal cancer, gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) or gastroesophageal junction cancer (GEJC) comprises a KRAS mutation or wildtype amplified KRAS.

[0320] Particularly preferred, the cancer to be treated / prevented with a compound of the invention according to the methods and uses as herein (above and below) defined and disclosed is selected from the group consisting of:

[0321] • lung adenocarcinoma (preferably non-small cell lung cancer, NSCLC) harboring at least one KRAS aberration, in particular KRAS wildtype amplification and / or overexpression;

[0322] • lung adenocarcinoma (preferably non-small cell lung cancer, NSCLC) harboring at least one KRAS aberration, in particular KRAS G12A, G12C, G12D, G12V, G13D or Q61 H mutation;

[0323] • colorectal adenocarcinoma harboring at least one KRAS aberration, in particular KRAS wildtype amplification and / or overexpression;

[0324] • colorectal cancer (preferably colorectal adenocarcinoma) harboring at least one KRAS aberration, in particular KRAS G12A, G12C, G12D, G12V, G13D or Q61 H mutation;

[0325] • pancreatic cancer (preferably pancreatic ductal adenocarcinoma, PDAC) harboring at least one KRAS aberration, in particular KRAS G12A, G12C, G12D, G12V, G13D or Q61 H mutation;

[0326] • gastric cancer (preferably gastric adenocarcinoma, GAC) harboring at least one KRAS aberration, in particular KRAS wildtype amplification and / or overexpression;

[0327] • esophageal cancer (preferably esophageal adenocarcinoma, EAC) harboring at least one KRAS aberration, in particular KRAS wildtype amplification and / or overexpression;

[0328] • gastroesophageal junction cancer (GEJC) harboring at least one KRAS aberration, in particular KRAS wildtype amplification and / or overexpression.

[0329] Preferably, “cancer” as used herein (above or below) includes drug-resistant cancer and cancer that has failed one, two or more lines of mono- or combination therapy with one or more anti-cancer agents. In particular, “cancer” (and any embodiment thereof) refers to any cancer (especially the cancer species defined hereinabove and hereinbelow) that is resistant to treatment with a KRAS inhibitor or degrader, such as a KRAS G12C inhibitor.

[0330] Different resistance mechanisms have already been reported. For example, the following articles describe resistance in patients following treatment with a KRAS G12C inhibitor: (i) Awad MM, Liu S, Rybkin, II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med 2021 ;384:2382-93 and (ii) Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-ll pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 2021 ;11 :1913-22.

[0331] In another aspect the disease / condition / cancer / tumors / cancer cells to be treated / prevented with a compound of the invention according to the methods and uses as herein (above and below) defined and disclosed is a RASopathy, preferably selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML) (also referred to as LEOPARD syndrome), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome (also known as NF1-like Syndrome) and Hereditary gingival fibromatosis.

[0332] Additionally, the following cancers, tumors and other proliferative diseases may be treated with compounds of the invention without being restricted thereto: cancers / tumors / carcinomas of the head and neck: e.g. tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); cancers / tumors / carcinomas of the lung: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer); neoplasms of the mediastinum: e.g. neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma); cancers / tumors / carcinomas of the gastrointestinal (Gl) tract: e.g. tumors / carcinomas / cancers of the esophagus (e.g. esophageal cancer, gastroesophageal junction cancer), stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis); cancers / tumors / carcinomas of the testis: e.g. seminomas, non-seminomas, gynecologic cancers / tumors / carcinomas: e.g. tumors / carcinomas / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); cancers / tumors / carcinomas of the breast: e.g. mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; cancers / tumors / carcinomas of the endocrine system: e.g. tumors / carcinomas / cancers of the endocrine glands, thyroid gland (thyroid carcinomas / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; sarcomas of the soft tissues: e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of the bone: e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma; cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; neoplasms of the central nervous system and brain: e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axis tumors; lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T- cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL) B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous / myeloid leukemia (AML), acute lymphatic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML); cancers of unknown primary site (CUP);

[0333] All cancers / tumors / carcinomas mentioned above which are characterized by their specific location / origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.

[0334] All cancers / tumors / carcinomas mentioned above may be further differentiated by their histopathological classification:

[0335] Epithelial cancers, e.g. squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma;

[0336] Nonepithilial cancers, e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0337] The compounds of the invention may be used in therapeutic regimens in the context of first line, second line, or any further line treatments.

[0338] The compounds of the invention may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases / conditions / cancers / tumors, optionally also in combination with radiotherapy and / or surgery.

[0339] The methods of treatment, methods, uses and compounds for use as disclosed herein (above and below) can be performed with any compound or salt of the invention as disclosed or defined herein and with any pharmaceutical composition or kit comprising a compound or salt of the invention.

[0340] Combination treatment

[0341] The compounds of the invention and the pharmaceutical compositions comprising such compounds may also be co-administered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds (e.g. chemotherapy), or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. Preferably, the pharmacologically active substance(s) for coadministration is / are (an) anti-neoplastic compound(s).

[0342] Thus, in a further aspect, the invention relates to a compound of the invention for use as hereinbefore defined wherein said compound is administered before, after or together with one or more other pharmacologically active substance(s).

[0343] In a further aspect, the invention relates to a compound of the invention for use as hereinbefore defined, wherein said compound is administered in combination with one or more other pharmacologically active substance(s).

[0344] In a further aspect, the invention relates to a compound of the invention for use as hereinbefore defined, wherein said compound is administered in combination with cetuximab.

[0345] In a further aspect, the invention relates to the use of a compound of the invention as hereinbefore defined wherein said compound is administered before, after or together with one or more other pharmacologically active substance(s).

[0346] In a further aspect, the invention relates to a method {e.g. a method for the treatment and / or prevention) as hereinbefore defined wherein the compound of the invention is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substance(s).

[0347] In a further aspect, the invention relates to a method {e.g. a method for the treatment and / or prevention) as hereinbefore defined wherein the compound of the invention is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substance(s).

[0348] In a further aspect, the invention relates to a method e.g. a method for the treatment and / or prevention) as hereinbefore defined wherein the compound of the invention is administered in combination with a therapeutically effective amount of cetuximab.

[0349] In a further aspect, the invention relates to a method for the treatment and / or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of one or more other pharmacologically active substance(s), wherein the compound of the invention is administered simultaneously, concurrently, sequentially, successively, alternately or separately with one or more other pharmacologically active substance(s).

[0350] In a further aspect, the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the compound of the invention is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more other pharmacologically active substance(s).

[0351] In a further aspect, the invention relates to a kit comprising

[0352] • a first pharmaceutical composition or dosage form comprising a compound of the invention and, optionally, one or more pharmaceutically acceptable excipient(s), and

[0353] • a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s), for use in the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second and / or additional pharmaceutical composition or dosage form.

[0354] In one aspect such kit for said use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s).

[0355] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered simultaneously.

[0356] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered concurrently.

[0357] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered sequentially.

[0358] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered successively.

[0359] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered alternately.

[0360] In a further aspect, the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments and aspects) are administered separately.

[0361] The pharmacologically active substance(s) to be used together / in combination with the compound of the invention or in the medical uses, uses, methods of treatment and / or prevention, pharmaceutical compositions, kits as herein (above and below) defined can be selected from any one or more of the following (preferably there is one or two additional pharmacologically active substance used in all these embodiments):

[0362] 1. an inhibitor of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or of any mutants thereof a. irreversible inhibitors: e.g. afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib, zongertinib; b. reversible inhibitors: e.g. erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340; c. ant / -EGFR antibodies: e.g. necitumumab, panitumumab, cetuximab, amivantamab; d. ant / -HER2 antibodies: e.g. pertuzumab, trastuzumab; e. ant / -HER2 antibody drurg conjugates (ADCs): e.g. trastuzumab emtansine, trastuzumab deruxtecan; f. inhibitors of mutant EGFR; g. an inhibitor of HER2 with exon 20 mutations: e.g. zongertinib; h. preferred irreversible inhibitor is afatinib; i. preferred ant / -EGFR antibody is cetuximab.

[0363] 2. an inhibitor of MEK and / or of mutants thereof a. e.g. trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. preferred is trametinib c. a MEK inhibitor as disclosed in WO 2013 / 136249; d. a MEK inhibitor as disclosed in WO 2013 / 136254

[0364] 3. an inhibitor of SOS1 and / or of any mutants thereof ( / .e. a compound that modulates / inhibits the GEF functionality of SOS1 , e.g. by binding to SOS1 and preventing protein-protein interaction between SOS1 and a (mutant) Ras protein, e.g. KRAS) a. e.g. BAY-293; b. a SOS1 inhibitor as disclosed in WO 2018 / 115380; c. a SOS1 inhibitor as disclosed in WO 2019 / 122129; d. a SOS1 inhibitor as disclosed in WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250, WO 2019 / 201848, WO 2022 / 146698 and WO 2023 / 118250.

[0365] 4. an inhibitor of YAP1, WWTR1, TEAD1, TEAD2, TEAD3 and / or TEAD4 a. reversible inhibitors of TEAD transcription factors (e.g. disclosed in WO 2018 / 204532); b. irreversible inhibitors of TEAD transcription factors (e.g. disclosed in WO 2020 / 243423); c. protein-protein interaction inhibitors of the YAP / T AZ: :TEAD interaction (e.g. disclosed in WO 2021 / 186324); d. inhibitors of TEAD palmitoylation.

[0366] 5. an oncolytic virus

[0367] 6. a RAS vaccine a. e.g. Targovax. 7. a cell cycle inhibitor a. e.g. inhibitors of CDK4 / 6 and / or of any mutants therof i. e.g. palbociclib, ribociclib, abemaciclib, trilaciclib, ebvaciclib; ii. preferred are palbociclib and abemaciclib; iii. most preferred is abemaciclib. b. e.g. vinca alkaloids i. e.g. vinorelbine. c. e.g. inhibitors of Aurora kinase and / or of any mutants therof i. e.g. alisertib, barasertib.

[0368] 8. an inhibitor of PTK2 (= FAK) and / or of any mutants thereof a. e.g. TAE226, Bl 853520.

[0369] 9. an inhibitor of SHP2 and / or of any mutants thereof a. e.g. SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0370] 10. an inhibitor of PI3 kinase (= PI3K) and / or of any mutants thereof a. e.g. inhibitors of PI3Ka and / or of any mutants therof i. e.g. alpelisib, serabelisib, inavolisib, HH-CYH33, AMG 511 , buparlisib, dactolisib, pictilisib, taselisib.

[0371] 11. an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or of any mutants thereof a. e.g. ponatinib, infigratinib, nintedanib.

[0372] 12. an inhibitor of AXL and / or of any mutants thereof

[0373] 13. a taxane a. e.g. paclitaxel, nab-paclitaxel, docetaxel; b. preferred is paclitaxel.

[0374] 14. a platinum-containing compound a. e.g. cisplatin, carboplatin, oxaliplatin b. preferred is oxaliplatin.

[0375] 15. an antf-metabolite a. e.g. 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, combination of trifluridine and tipiracil (= TAS102); b. preferred is 5-fluorouracil.

[0376] 16. an immunotherapeutic agent a. e.g. an immune checkpoint inhibitor i. e.g. an ant / -CTLA4 mAb, ant / -PD1 mAb, ant / -PD-L1 mAb, ant / -PD-L2 mAb, ant / -LAG3 mAb, ant / -TIM3 mAb; ii. preferred is an ant / -PD1 mAb; iii. e.g. ipilimumab, nivolumab, pembrolizumab, tislelizumab atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. preferred are nivolumab, pembrolizumab, ezabenlimab and PDR-001 (= spartalizumab); v. most preferred is ezabenlimab, pembrolizumab and nivolumab. b. e.g.T cell engagers (TcEs) a. FAP TcE c. e.g. STING agonists (preferred a STING agonist as disclosed in WO 2022 / 229341)

[0377] 17. a topoisomerase inhibitor a. e.g. irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide; b. most preferred is irinotecan and liposomal irinotecan (nal-IRI).

[0378] 18. an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or of any mutants thereof a. e.g. encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= example 131 in WO 2014 / 151616), naporafenib, sorafenib, LY-3009120 (= example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, avutometinib, RAF265.

[0379] 19. an inhibitor of mTOR a. e.g. rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1 , dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055.

[0380] 20. an epigenetic regulator a. e.g. a BET inhibitor i. e.g. JQ-1, molibresib, OTX-015, pelabresib, TEN-010, OTX-015, PLX51107, mivebresib, ABBV-744, BMS986158, TGI-1601, trotabresib, AZD5153, I-BET151 , amredobresib.

[0381] 21. an inhibitor of IGF1 / 2 and / or of IGF1-R and / or of any mutants thereof a. e.g. xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (= dusigitumab), linsitinib.

[0382] 22. an inhibitor of a Src family kinase and / or of any mutants thereof a. e.g. an inhibitor of a kinase of the SrcA subfamily and / or of any mutants thereof, i.e. an inhibitor of Src, Yes, Fyn, Fgr and / or of any mutants thereof; b. e.g. an inhibitor of a kinase of the SrcB subfamily and / or of any mutants thereof, i.e. an inhibitor of Lek, Hek, Blk, Lyn and / or of any mutants thereof; c. e.g. an inhibitor of a kinase of the Frk subfamily and / or of any mutants thereof, i.e. an inhibitor of Frk and / or of any mutants thereof; d. e.g. dasatinib, ponatinib, bosutinib, vandetanib, KX-01 , saracatinib, KX2-391, SU 6656, WH-4-023. an apoptosis regulator a. e.g. an MDM2 inhibitor, e.g. an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 and / or of any mutants thereof; i. e.g. Siremadlin, NVP-CGM097, RG-7112, MK-8242, idasanutlin, SAR405838, AMG-232, milademetan, RG-7775, alrizomadlin, brigimadlin; ii. preferred are HDM-201, RG-7388 and AMG-232; iii. an MDM2 inhibitor as disclosed in WO 2015 / 155332; iv. an MDM2 inhibitor as disclosed in WO 2016 / 001376; v. an MDM2 inhibitor as disclosed in WO 2016 / 026937; vi. an MDM2 inhibitor as disclosed in WO 2017 / 060431; b. e.g. a PARP inhibitor; c. e.g. an MCL-1 inhibitor; i. e.g. AZD-5991 , AMG-176, murizatoclax, S64315, S63845, A-1210477; an inhibitor of c-MET and / or of any mutants thereof a. e.g. savolitinib, cabozantinib, foretinib; b. MET antibodies, e.g. emibetuzumab, amivantamab; an inhibitor of ERK and / or of any mutants thereof a. e.g. ulixertinib, LTT462; an inhibitor of farnesyl transferase and / or of any mutants thereof a. e.g. tipifarnib; an inhibitor of VEGF and / or of any mutants thereof a. e.g. ramucirumab; an inhibitor of Ras protein and / or of any mutants thereof a. e.g. a RAS inhibitor, preferred RMC-6236; b. e.g. a KRAS inhibitor, preferred a KRAS G12C or G12D inhibitor. a bi- or trispecific antibody a. e.g. bispecific antibodies: EGFR x LGR5 (e.g. petosemtamab), EGFR x MET (e.g. amivantanab), EGFR x HER3, PD1 x VEGF The compounds of the invention can also be used / administered together / in combination with multi-agent combination chemotherapy regimens known in the art according to their known dosing regimens, e.g. FOLFOX (folinic acid / leucovorin + fluorouracil / 5-FU + oxaliplatin), FOLFIRINOX (folinic acid / leucovorin + fluorouracil / 5-FU + irinotecan + oxaliplatin), FOLFOXIRI (folinic acid / leucovorin + fluorouracil / 5-FU + irinotecan + oxaliplatin), FOLFIRI (folinic acid / leucovorin + fluorouracil / 5-FU + irinotecan) and NALIRIFOX (liposomal irinotecan / nal-IRI + folinic acid / leucovorin + fluorouracil / 5-FU + oxaliplatin).

[0383] In a further embodiment of the (combined) use and method {e.g. method for the treatment and / or prevention) as hereinbefore described one other pharmacologically active substance is to be administered before, after or together with the compound of the invention, wherein said one other pharmacologically active substance is

[0384] • a SOS1 inhibitor; or

[0385] • a M EK inhibitor; or

[0386] • trametinib, or

[0387] • an anti-PD-1 antibody; or

[0388] • ezabenlimab; or

[0389] • cetuximab; or

[0390] • afatinib; or

[0391] • standard of care (SoC) in a given indication; or

[0392] • a PI3 kinase inhibitor; or

[0393] • an inhibitor of TEAD palmitoylation; or

[0394] • a YAP / TAZ::TEAD inhibitor.

[0395] In a further embodiment of the (combined) use and method e.g. method for the treatment and / or prevention) as hereinbefore described one other pharmacologically active substance is to be administered in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - wherein said one other pharmacologically active substance is

[0396] • a SOS1 inhibitor; or

[0397] • a M EK inhibitor; or

[0398] • trametinib; or

[0399] • an anti-PD-1 antibody; or

[0400] • ezabenlimab; or • cetuximab; or

[0401] • afatinib; or

[0402] • standard of care (SoC) in a given indication; or

[0403] • a PI3 kinase inhibitor; or

[0404] • an inhibitor of TEAD palmitoylation; or

[0405] • a YAP / TAZ::TEAD inhibitor.

[0406] In a further aspect of the (combined) use and method (e.g. method for the treatment and / or prevention) as hereinbefore described two other pharmacologically active substances are to be administered before, after or together with the compound of the invention, wherein said two other pharmacologically active substances are

[0407] • a MEK inhibitor and a SOS1 inhibitor; or

[0408] • trametinib and a SOS1 inhibitor; or

[0409] • an ant / -PD-1 antibody (preferably ezabenlimab) and an ant / - LAG-3 antibody; or

[0410] • an ant / -PD-1 antibody (preferably ezabenlimab) and a SOS1 inhibitor; or

[0411] • a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or ErbB2 (HER2) inhibitor and / or inhibitor of any mutants thereof; or

[0412] • a SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or ErbB2 (HER2) inhibitor and / or inhibitor of any mutants thereof; or

[0413] • a MEK inhibitor and afatinib; or

[0414] • a MEK inhibitor and cetuximab; or

[0415] • trametinib and afatinib; or

[0416] • trametinib and cetuximab; or

[0417] • a SOS1 inhibitor and afatinib; or

[0418] • a SOS1 inhibitor and cetuximab; or

[0419] • a SOS1 inhibitor and an inhibitor of TEAD palmitoylation; or

[0420] • a SOS1 inhibitor and a YAP / TAZ::TEAD inhibitor.

[0421] In a further aspect of the (combined) use and method (e.g. method for the treatment and / or prevention) as hereinbefore described two other pharmacologically active substances are to be administered in combination with the compound of the invention wherein said two other pharmacologically active substances are

[0422] • a MEK inhibitor and a SOS1 inhibitor; or

[0423] • trametinib and a SOS1 inhibitor; or

[0424] • an ant / -PD-1 antibody (preferably ezabenlimab) and an ant / -l_AG-3 antibody; or • an ant / -PD-1 antibody (preferably ezabenlimab) and a SOS1 inhibitor; or

[0425] • a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or ErbB2 (HER2) inhibitor and / or inhibitor of any mutants thereof; or

[0426] • a SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or ErbB2 (HER2) inhibitor and / or inhibitor of any mutants thereof; or

[0427] • a MEK inhibitor and afatinib; or

[0428] • a MEK inhibitor and cetuximab; or

[0429] • trametinib and afatinib; or

[0430] • trametinib and cetuximab; or

[0431] • a SOS1 inhibitor and afatinib; or

[0432] • a SOS1 inhibitor and cetuximab; or

[0433] • a SOS1 inhibitor and an inhibitor of TEAD palmitoylation; or

[0434] • a SOS1 inhibitor and a YAP / TAZ::TEAD inhibitor.

[0435] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype, and wherein the compound is administered in combination with cetuximab or panitumumab, preferably cetuximab.

[0436] In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype, and wherein the compound is administered in combination with cetuximab or panitumumab, preferably cetuximab.

[0437] In a further aspect the invention relates to a compound of the invention for use in the treatment and / or prevention of cancer, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype, and wherein the compound is administered in combination with cetuximab or panitumumab, preferably cetuximab, and with FOLFOX. In a further aspect the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention to a human being, wherein the cancer is colorectal cancer, preferably wherein the colorectal cancer comprises tumor cells harbouring a KRAS aberration selected from the group consisting of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; KRAS Q61 H and an amplification of KRAS wildtype, and wherein the compound is administered in combination with cetuximab or panitumumab, preferably cetuximab, and with FOLFOX.

[0438] Additional pharmacologically active substance(s) which can also be used together / in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - or in the medical uses, uses, methods of treatment and / or prevention, pharmaceutical compositions, kits as herein (above and below) defined include, without being restricted thereto, hormones, hormone analogues and antihormones {e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors {e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists e.g. goserelin acetate, luprolide), inhibitors of growth factors and / or of their corresponding receptors (growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors are for example (ant / -)growth factor antibodies, {anti- )growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab); antimetabolites {e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-Fll), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics {e.g. anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives {e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents {e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents {e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors {e.g. tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors {e.g. PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B- Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors {e.g. PTK2 / FAK inhibitors), protein protein interaction inhibitors {e.g. IAP inhibitors / SMAC mimetics, Mcl-1 , MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1 R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors {e.g. venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs {e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors {e.g. carfilzomib), immunotherapeutic agents such as immune checkpoint inhibitors {e.g. CTLA4, PD1 , PD-L1 , PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as e.g. ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers {e.g. anti-CD33 antibodies, anti- CD37 antibodies, anti-CD20 antibodies), t-cell engagers {e.g. bi-specific T-cell engagers (BiTEs®) like e.g. CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3), tumor vaccines, immunomodulator, e.g. STING agonist, and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.

[0439] It is to be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions or compounds for use according to this invention may envisage the simultaneous, concurrent, sequential, successive, alternate or separate administration of the active ingredients or components. It will be appreciated that the compound of the invention and the one or more other pharmacologically active substance(s) can be administered formulated either dependently or independently, such as e.g. the compound of the invention and the one or more other pharmacologically active substance(s) may be administered either as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0440] In this context, “combination” or “combined” within the meaning of this invention includes, without being limited, a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed {e.g. free) combinations (including kits) and uses, such as e.g. the simultaneous, concurrent, sequential, successive, alternate or separate use of the components or ingredients. The term “fixed combination” means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the patient.

[0441] The administration of the compound of the invention and the one or more other pharmacologically active substance(s) may take place by co-administering the active components or ingredients, such as e.g. by administering them simultaneously or concurrently in one single or in two or more separate formulations or dosage forms. Alternatively, the administration of the compound of the invention and the one or more other pharmacologically active substance(s) may take place by administering the active components or ingredients sequentially or in alternation, such as e.g. in two or more separate formulations or dosage forms.

[0442] For example, simultaneous administration includes administration at substantially the same time. This form of administration may also be referred to as “concomitant” administration. Concurrent administration includes administering the active agents within the same general time period, for example on the same day(s) but not necessarily at the same time. Alternate administration includes administration of one agent during a time period, for example over the course of a few days or a week, followed by administration of the other agent(s) during a subsequent period of time, for example over the course of a few days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administration of one agent during a first time period (for example over the course of a few days or a week) using one or more doses, followed by administration of the other agent(s) during a second and / or additional time period (for example over the course of a few days or a week) using one or more doses. An overlapping schedule may also be employed, which includes administration of the active agents on different days over the treatment period, not necessarily according to a regular sequence. Variations on these general guidelines may also be employed, e.g. according to the agents used and the condition of the subject.

[0443] Pharmaceutical Compositions - Kits

[0444] It is a further object of the invention a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipient(s).

[0445] In one aspect, said pharmaceutical composition optionally comprises one or more other pharmacologically active substance(s). Said one or more other pharmacologically active substance(s) may be the pharmacologically active substances or combination partners herein defined.

[0446] Suitable pharmaceutical compositions for administering the compounds according to the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, suspensions - particularly solutions, suspensions or other mixtures for parenteral administration (s.c., i.v., i.m., etc...) and infusion (injectables) - elixirs, syrups, sachets, emulsions, inhalatives or dispersible powders. The content of the compounds of the invention should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

[0447] Suitable tablets may be obtained, for example, by mixing the compounds of the invention with known pharmaceutically acceptable excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablets may also comprise several layers.

[0448] Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with excipients normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

[0449] Syrups or elixirs containing one or more compounds of the invention or combinations with one or more other pharmaceutically active substance(s) may additionally contain excipients like a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain excipients like suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[0450] Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of excipients like isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and / or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

[0451] Capsules containing one or more compounds of the invention or combinations with one or more other pharmaceutically active substance(s) may for example be prepared by mixing the compounds / active substance(s) with inert excipients such as lactose or sorbitol and packing them into gelatine capsules.

[0452] Suitable suppositories may be made for example by mixing with excipients provided for this purpose such as neutral fats or polyethyleneglycol or the derivatives thereof.

[0453] Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0454] The pharmaceutical compositions are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may of course contain, apart from the above-mentioned excipients, additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various excipients such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

[0455] For parenteral use, solutions of the active substances with suitable liquid excipients may be used.

[0456] The dosage range of the compounds of the invention applicable per day is usually from 1 mg to 2000 mg, preferably from 100 to 1500 mg. However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, age, the route of administration, severity of the disease, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered (continuous or intermittent treatment with one or multiple doses per day). Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

[0457] Thus, in a further aspect the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of the invention and one or more pharmaceutically acceptable excipient(s).

[0458] The compounds of the invention and the pharmaceutical compositions comprising such compound and salts may also be co-administered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used in combination (see combination treatment further above).

[0459] The elements of such combinations may be administered (whether dependently or independently) by methods customary to the skilled person and as they are used in monotherapy, e.g. by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant), nasal, vaginal, rectal, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.

[0460] In a further aspect the invention also relates to a pharmaceutical preparation comprising a compound of the invention and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

[0461] Thus, in a further aspect the invention also relates to a pharmaceutical composition comprising a compound of the invention and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

[0462] Pharmaceutical compositions to be co-administered or used in combination can also be provided in the form of a kit.

[0463] Thus, in a further aspect the invention also relates to a kit comprising

[0464] • a first pharmaceutical composition or dosage form comprising a compound of the invention and, optionally, one or more pharmaceutically acceptable excipient(s), and

[0465] • a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).

[0466] In one aspect such kit comprises a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).

[0467] Definitions

[0468] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to:

[0469] The use of the prefix Cx-y, wherein x and y each represent a positive integer (x < y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.

[0470] The indication of the number of members in groups that contain one or more heteroatom(s) (e.g. heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.

[0471] The indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members.

[0472] In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, the substituent aryl-Ci-ealkyl means an aryl group which is bound to a Ci-ealkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.

[0473] In groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself.

[0474] The expression “compound of the invention” and grammatical variants thereof comprises compounds of formula (l) / (l*), (V), (V*), (V**), (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), (V-h), (V-i) or (V-j), including all salts, aspects and preferred embodiments thereof as herein defined. Any reference to a compound of the invention or to a compound of formula (l) / (l*), (V), (V*), (V**), (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), (V-h), (V-i) or (V-j) is intended to include a reference to the respective (sub)aspects and embodiments.

[0475] Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.

[0476] The term ”Ci-5alkyl“ includes for example H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0477] Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl ( / -Pr; / so-propyl; -CH(CH3)2), 1 -butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1 -propyl ( / so-butyl; / -Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; f-Bu; -C(CH3)3), 1 -pentyl (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1 -butyl ( / so-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2, 2-dimethyl-1 -propyl (neo-pentyl; -CH2C(CH3)3), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (n-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2),

[0478] 2.3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3),

[0479] 2.3-dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1 -pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1 -pentyl (-CH2CH2CH(CH3)CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1 -hexyl, 3-methyl-1 -hexyl, 2, 2-dimethyl-1 -pentyl,

[0480] 2.3-dimethyl-1 -pentyl, 2, 4-dimethyl-1 -pentyl, 3, 3-dimethyl-1 -pentyl, 2,2,3-trimethyl-1 -butyl, 3-ethyl-1 -pentyl, 1 -octyl (n-octyl), 1 -nonyl (n-nonyl); 1 -decyl (n-decyl) etc.

[0481] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

[0482] The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example Cx-yalkylamino or Cx-yalkyloxy. “Alkyloxy” and “alkoxy” are used as synonyms.

[0483] The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH3 and -CH2-, -CH2CH3 and -CH2CH2- or >CHCH3etc.

[0484] The term “Ci-4alkylene” includes for example -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)- and -C(CH3)(CH2CH3)-.

[0485] Other examples of alkylene are methylene, ethylene, propylene, 1 -methylethylene, butylene, 1 -methylpropylene, 1,1 -dimethylethylene, 1,2-dimethylethylene, pentylene, 1 , 1 -dimethylpropylene, 2,2-dimethylpropylene, 1 ,2-dimethylpropylene,

[0486] 1.3-dimethylpropylene, hexylene etc.

[0487] By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1 -methylethylene and butylene includes 1 -methylpropylene, 2-methylpropylene, 1,1 -dimethylethylene and 1,2-dimethylethylene. The above definition for alkylene also applies if alkylene is part of another (combined) group such as for example in HO-Cx-yalkyleneamino or H2N-Cx-yalkyleneoxy.

[0488] Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

[0489] Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1 -methylidenepropyl, pent-1 -enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl,

[0490] 2.3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl,

[0491] 2.3-dimethyl-but-1-enyl, hexa-1, 3-dienyl, hexa-1, 4-dienyl, penta-1, 4-dienyl, penta-1 , 3-dienyl, buta-1 , 3-dienyl, 2,3-dimethylbuta-1 ,3-diene etc.

[0492] By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1 -enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

[0493] Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

[0494] The above definition for alkenyl also applies when alkenyl is part of another (combined) group such as for example in Cx-yalkenylamino or Cx-yalkenyloxy.

[0495] Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.

[0496] Examples of alkenylene are ethenylene, propenylene, 1 -methylethenylene, butenylene, 1 -methylpropenylene, 1 ,1 -dimethylethenylene, 1 ,2-dimethylethenylene, pentenylene, 1 , 1 -dimethylpropenylene, 2,2-dimethylpropenylene, 1 ,2-dimethylpropenylene, 1 ,3-dimethylpropenylene, hexenylene etc.

[0497] By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1 -methylethenylene and butenylene includes 1 -methylpropenylene, 2-methylpropenylene, 1 ,1 -dimethylethenylene and 1 ,2-dimethylethenylene.

[0498] Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

[0499] The above definition for alkenylene also applies when alkenylene is a part of another (combined) group as for example in HO-Cx.yalkenyleneamino or H2N-Cx.yalkenyleneoxy.

[0500] Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed. Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc. By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1 -ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1 -methyl-prop-1 -ynyl, 1 -methyl-prop-2-ynyl, etc.

[0501] If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.

[0502] The above definition for alkynyl also applies if alkynyl is part of another (combined) group, as for example in Cx-yalkynylamino or Cx-yalkynyloxy.

[0503] Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

[0504] Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1 ,1-dimethylethynylene, 1 ,2-dimethylethynylene, pentynylene, 1 , 1 -dimethylpropynylene, 2,2-dimethylpropynylene, 1 ,2-dimethylpropynylene, 1 ,3-dimethylpropynylene, hexynylene etc.

[0505] By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1 ,1-dimethylethynylene and 1 ,2-dimethylethynylene.

[0506] The above definition for alkynylene also applies if alkynylene is part of another (combined) group, as for example in HO-Cx.yalkynyleneamino or H2N-Cx.yalkynyleneoxy.

[0507] By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

[0508] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

[0509] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F,

[0510] -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -C C-CF3, -CHFCH2CH3, -CHFCH2CF3 etc.

[0511] From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).

[0512] Corresponding groups are for example -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F etc.

[0513] The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.

[0514] Halogen denotes fluorine, chlorine, bromine and / or iodine atoms.

[0515] Cycloalkyl is made up of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spiro-cycloalkyl. The ring systems are saturated and formed by linked carbon atoms. In bicyclic cycloalkyl two rings are joined together so that they have at least two carbon atoms in common. In spiro-cycloalkyl one carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

[0516] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1 .1 ]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

[0517] The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in Cx ycycloalkylamino, Cx ycycloalkyloxy or Cx.ycycloalkylalkyl.

[0518] If the free valency of a cycloalkyl is saturated, then an alicycle is obtained.

[0519] The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example: cyclohexyl and (cyclohexylene).

[0520] The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO-Cx.ycycloalkyleneamino or H2N-Cx.ycycloalkyleneoxy.

[0521] Cycloalkenyl is made up of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl and spiro-cycloalkenyl. However, the systems are unsaturated, i.e. there is at least one C-C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained.

[0522] If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

[0523] Examples of cycloalkenyl are cycloprop- 1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent- 1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex- 1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept- 1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1 , 3-dienyl, cyclopenta-1 , 4-dienyl, cyclopenta-1 , 3-dienyl, cyclopenta-2, 4-dienyl, cyclohexa-1 , 3-dienyl, cyclohexa-1 , 5-dienyl, cyclohexa-2, 4-dienyl, cyclohexa-1 , 4-dienyl, cyclohexa-2, 5-dienyl, bicyclo[2.2.1]hepta-2, 5-dienyl (norborna-2, 5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl etc.

[0524] The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group as for example in Cx-ycycloalkenylamino, Cx-ycycloalkenyloxy or Cx-ycycloalkenylalkyl.

[0525] If the free valency of a cycloalkenyl is saturated, then an unsaturated alicycle is obtained. The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example: cyclopentenyl and (cyclopentenylene) etc. The above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group as for example in HO-Cx-ycycloalkenyleneamino or H2N-Cx-ycycloalkenyleneoxy.

[0526] Aryl denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be partially saturated.

[0527] If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

[0528] Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1 ,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1 ,2- dihydronaphthyl), fluorenyl etc. Most preferred is phenyl.

[0529] The above definition of aryl also applies if aryl is part of another (combined) group as for example in arylamino, aryloxy or arylalkyl.

[0530] If the free valency of an aryl is saturated, then an arene is obtained.

[0531] The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are for example:

[0532] The above definition for arylene also applies if arylene is part of another (combined) group as for example in HO-aryleneamino or F^N-aryleneoxy.

[0533] Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups -CH2- independently of one another in the hydrocarbon rings by the groups -O-, -S- or -NH- or by replacing one or more of the groups =CH- by the group =N-, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulphur atoms or between an oxygen and a sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur sulfoxide -SO-, sulphone -SO2-; nitrogen N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system.

[0534] A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiro-heterocyclyl, which may be present in saturated or unsaturated form.

[0535] By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterocyclyl two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterocyclyl one carbon atom (spiroatom) belongs to two rings together.

[0536] If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and / or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Substituents on heterocyclyl do not count for the number of members of a heterocyclyl.

[0537] Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1 ,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1 ,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1 ,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2 / 7-pyrrolyl, 4 / 7-pyranyl, 1 ,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1 ,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2.8-diaza- spiro[4,5]decyl etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

[0538]

[0539] Preferred monocyclic heterocyclyl is 4 to 7 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0540] Preferred monocyclic heterocyclyls are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl. Preferred bicyclic heterocyclyl is 6 to 10 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0541] Preferred tricyclic heterocyclyl is 9 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0542] Preferred spiro-heterocyclyl is 7 to 11 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0543] The above definition of heterocyclyl also applies if heterocyclyl is part of another (combined) group as for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.

[0544] If the free valency of a heterocyclyl is saturated, then a heterocycle is obtained. The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example: piperidinyl

[0545] The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group as for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy.

[0546] Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system.

[0547] If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and / or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Substituents on heteroaryl do not count for the number of members of a heteroaryl. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl- / V-oxide, pyrrolyl- / V-oxide, pyrimidinyl-A / - oxide, pyridazinyl- / V-oxide, pyrazinyl- / V-oxide, imidazolyl-ZV-oxide, isoxazolyl- / V-oxide, oxazolyl- / V-oxide, thiazolyl- / V-oxide, oxadiazolyl- / V-oxide, thiadiazolyl- / V-oxide, triazolyl-A / - oxide, tetrazolyl- / V-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl- / V-oxide, indolyl- / V-oxide, isoquinolyl- / V-oxide, quinazolinyl- / V-oxide, quinoxalinyl- / V-oxide, phthalazinyl- / V-oxide, indolizinyl- Z-oxide, indazolyl- / V-oxide, benzothiazolyl- / V- oxide, benzimidazolyl-ZV-oxide etc.

[0548] Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

[0549] Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 membered bicyclic, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0550] The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0551] If the free valency of a heteroaryl is saturated, a heteroarene is obtained.

[0552] The term heteroarylene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example: pyrrolyl etc.

[0553] The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group as for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy. By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound ( / .e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination).

[0554] Bivalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2 or the like, may only be substituents on carbon atoms, whereas the bivalent substituents =0 and =NR may also be a substituent on sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement of two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH2- or sulphur atoms (=0 group or =NR group only, one or two =0 groups possible or, e.g., one =0 group and one =NR group, each group replacing a free electron pair) of a ring system. Isotopes: It is to be understood that all disclosures of an atom or compound of the invention include all suitable isotopic variations. In particular, a reference to hydrogen also includes deuterium.

[0555] Stereochemistry / solvates / hydrates: Unless specifically indicated, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, EIZ isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.

[0556] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and / or by using chiral reagents.

[0557] Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and / or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0558] Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases, or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt, or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group, or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0559] Salts: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0560] As used herein “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0561] For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl- benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.

[0562] Further pharmaceutically acceptable salts can be formed with cations from ammonia, L- arginine, calcium, 2,2’-iminobisethanol, L-lysine, magnesium, / V-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0563] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0564] Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts), also comprise a part of the invention.

[0565] As used herein, the expression “protecting group” refers to a derivative of a functional group that can be cleaved by means of a chemical reaction to release the functional group. Examples of protecting groups are well known to the skilled chemist. In particular, preferred protecting groups include esters that can release alcohols.

[0566] As used herein, the expression “prodrug group” refers to a derivative of a functional group that can be metabolised to release the functional group. Examples of prodrug groups are well known to the skilled chemist. In particular, preferred prodrug groups include phosphates that can release alcohols.

[0567] In a representation such as for example x3x( l 0 0 x’orNorthe letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.

[0568] A dotted line ( / or / ) or a squiggly line ( —-) may be used in sub-formulas to indicate the atom or bond which is connected to the core molecule as defined. In certain cases, the substituent(s) of the core molecule to which the sub-formula is connected to may be specified, in particular on the side of the dotted line or squiggly line opposite to the side of the sub-formula.

[0569] For groups, especially bivalent groups, in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets where necessary for clarification purposes, as in the following representations:

[0570] If such a clarification is missing then the bivalent group can bind in both directions, i.e., e.g., -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0571] Groups or substituents are frequently selected from among a number of alternative groups / substituents with a corresponding group designation (e.g. Ra, Rbetc). If such a group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is pointed out that the various uses are to be regarded as totally independent of one another.

[0572] By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient. Examples

[0573] Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention. List of abbreviations

[0574]

[0575] Chemical Examples

[0576] The compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used.

[0577] The general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.

[0578] If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist). Consequently, any chemical structure of a compound of the invention of formula (I) depicted hereinbelow, e.g. in Tables 28, which represents more than one enantiomer or diastereomer due to undefined stereocenters shall be understood and deemed to individually disclose each and every specific compound with fully defined stereocenters that falls within the scope of said chemical structure.

[0579] Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and / or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).

[0580] If a compound is represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive.

[0581] Chromatography

[0582] The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck.

[0583] The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 pm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 pm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 pm, 50 x 150 mm or XBridge™ Prep C18, OBD™ 5 pm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 pm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 pm, 30 x 50 mm).

[0584] Different gradients of H2O / acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H2O / acetonitrile (1 / 1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH.

[0585] For the chromatography under basic conditions for Agilent systems H2O / acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH4HCO3 + 50 mL NH3 (25 % in H2O) to 1 L with H2O). For Gilson systems the water is made alkaline as follows: 5mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28 % in H2O) are replenished to 1 L with H2O.

[0586] The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a Agilent 1260 SFC-system or JASCO SFC-system or Sepiatec SFC-system or Waters Thar SFC-System or Waters UPC2-MS SFC-System with the following colums: Chiralcel OJ (250 x 20 mm, 5 pm), Chiralpak AD-H (21 x 250 mm), 5 pm, Chiralpak AD (250 x 20 mm, 5 pm), Chiralpak AS (250 x 20 mm, 5 pm), Chiralpak IC (250 x 20 mm, 5 pm), Chiralpak IA (250 x 20 mm, 5 pm), Chiralcel OJ (250 x 20 mm, 5 pm), Chiralcel OD (250 x 20 mm, 5 pm), Chiralcel OX-3 (150 x 4.6 mm, 3 pm), Phenomenex Lux C2 (250 x 20 mm, 5 pm), Lux Cellulose-4 column (250 x 30 mm, 5pm).

[0587] Analytical SFC / UV-spectrometry Methods and SFC-mass spectroscopy / UV-spectrometry

[0588] Method SFC-A

[0589] SFC: Agilent 1260 (binary pump) SFC

[0590] Column: Chiralpak AD-H (250 x 4.6 mm), 5 pm Flow: 2 ml / min

[0591] Mobile Phase: A: CO2+ B: MeOH

[0592] ABPR: 120 Bar

[0593] Temp: 37.5 °C

[0594] UV: 220 nm

[0595] Gradient 80 % A + 20 % B (isocratic)

[0596] Stop time 10 min

[0597] Method SFC-B

[0598] Make Waters UPC2-MS

[0599] Soft Empowers

[0600] MS QDa

[0601] Column CHIRALCEL OX-3 (4.6 x 150 mm) 3pm

[0602] A-Solvent CO2

[0603] B-solvent AON

[0604] Total Flow 3g / min

[0605] % of Co-Solvent 15

[0606] ABPR 1500psi

[0607] Colum temp 30 °C

[0608] PDA range 200 nm to 400 nm

[0609] Resolution 1.2 nm

[0610] MS Parameters

[0611] QDa MS scan range 100 Da to 1000 Da

[0612] Cone voltage

[0613] Positive scan 20 V

[0614] Negative Scan 15 V

[0615] The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridge™ C18, 2.5 pm, 2.1 x 20 mm or XBridge™ C18, 2.5 pm, 2.1 x 30 mm orAquity LIPLC BEH C18, 1.7 pm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 pm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case.

[0616] HPLC-mass spectroscopy / UV-spectrometry

[0617] The retention times / MS-ESI+for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time tRet. = 0.00.

[0618] Method A

[0619] HPLC Agilent 1100 system

[0620] MS 1200Series LC / MSD(API-ES+ / -3000V, Quadrupol, G6140)

[0621] MSD signal settings Scan pos / neg 120 - 1500 m / z Detection signal 315 nm (bandwidth 170nm, reference off) Spectrum range 230 - 400 nm Peak width <0.01 min

[0622] Column Waters, Xbridge C18, 2.5 pm, 2.1 x 20 mm column

[0623] Column temperature 60 °C

[0624] Solvent A: 20 mM aq. NH4HCO3 / NH3 pH 9

[0625] B: ACN HPLC grade

[0626] Flow 1.00 mL / min

[0627] Gradient 0.00 - 1.50 min 10 % to 95 % B

[0628] 1.50 - 2.00 min 95 % B

[0629] 2.00 - 2.10 min 95 % to 10 % B

[0630] Method B

[0631] HPLC Agilent 1260 Series

[0632] MS Agilent LC / MSD Quadrupole

[0633] Detection MS: positive and negative mode

[0634] Mass range 100 - 1200 m / z

[0635] Column Waters X-Bridge BEH C18, 2.5 pm, 2.1 x 30 mm XP

[0636] Column temperature 45 °C

[0637] Solvent A: 20 mM NH4HCO3 / 30 mM NH3in H2O; B: AON (HPLC grade)

[0638] Flow 1.40 mL / min

[0639] Gradient 0.00 - 1.00 min: 15% B to 95% B

[0640] 1.00 - 1.30 min: 95 % B Method C

[0641] HPLC Agilent 1100 / 1200 system

[0642] MS 1200 Series LC / MSD (MM-ES + APCI + / - 3000 V, Quadrupol,

[0643] G6130B)

[0644] MSD signal settings Scan pos / neg 150 - 750

[0645] Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off)

[0646] Spectrum range: 190 - 400 nm; slit: 4 nm

[0647] Peak width > 0.0031 min (0.063 s response time, 80Hz)

[0648] Column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 pm, 2.1 x 30 mm) column

[0649] Column temperature 45 °C

[0650] Solvent A: 5 mM NH4HCO3 / 18 mM NH3 in H2O (pH = 9.2)

[0651] B: ACN (HPLC grade)

[0652] Flow 1.4 mL / min

[0653] Gradient 0.0 - 1.0 min 15 % to 95 % B

[0654] 1.0 - 1.1 min 95 % B

[0655] Stop time: 1.3 min

[0656] Method D

[0657] HPLC Agilent 1100 / 1200 system

[0658] MS 1200 Series LC / MSD (API-ES + / - 3000 / 3500 V, Quadrupol,

[0659] G6140A)

[0660] MSD signal settings Scan pos / neg 150 - 750

[0661] Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 10, reference off)

[0662] Spectrum range: 190 - 400 nm; slit: 4 nm

[0663] Peak width > 0.0031 min (0.063 s response time, 80Hz)

[0664] Column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 pm, 12 nm;

[0665] 30 x 2.0 mm column

[0666] Column temperature 45 °C

[0667] Solvent A: H2O + 0.11% formic acid

[0668] B: ACN + 0.1% formic acid (HPLC grade)

[0669] Flow 1.4 mL / min

[0670] Gradient 0.0 - 1.0 min 15 % to 95 % B

[0671] 1.0 - 1.1 min 95 % B Stop time: 1.23 min

[0672] Method E

[0673] UPLC-MS Waters Acquity-UPLC-SQ Detector-2

[0674] MSD signal settings Scan pos & Neg 100 - 1500,

[0675] Source Voltage: Capillary Vol(kV)- 3.50, Cone(V): 50

[0676] Source Temp: Desolvation Temp(°C): 350

[0677] Source Gas Flow: Desolvation(L / Hr): 750, Cone(L / Hr): 50

[0678] Detection signal Diode Array

[0679] Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

[0680] Sampling rate 10 point / sec

[0681] Column AQUITY UPLC BEH C18 1.7pm, 2.1X50mm

[0682] Column temperature 35 °C

[0683] Solvent A: 0.07% formic acid in ACN

[0684] B: 0.07% formic acid in water

[0685] Flow 0.6 mL / min

[0686] Gradient 0.0 - 0.30 min 97% B

[0687] 0.30 - 2.20 min 97 % to 2 % B

[0688] 2.20 - 3.30 min 2 % B

[0689] 3.30 - 4.50 min 2 % to 97 % B

[0690] 4.50 - 4.51 min 97 % B

[0691] Method F

[0692] UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-

[0693] 2

[0694] MSD signal settings Scan pos & Neg 100 - 1500,

[0695] Source Voltage: Capillary Vol(kV)- 3.50, Cone(V): 50

[0696] Source Temp: Desolvation Temp(°C): 350

[0697] Source Gas Flow: Desolvation(L / Hr): 750, Cone(L / Hr): 50

[0698] Detection signal Diode Array

[0699] Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

[0700] Sampling rate 10 point / sec

[0701] Column AQUITY UPLC BEH C18 1.7pm, 2.1X50mm

[0702] Column temperature 35 °C Solvent A: 0.07% formic acid in ACN

[0703] B: 0.07% formic acid in water

[0704] Flow 0.6 mL / min

[0705] Gradient 0.0 - 0.40 min 97% B

[0706] 0.40 - 2.50 min 97 % to 2 % B

[0707] 2.50 - 3.40 min 2 % B

[0708] 3.40 - 3.50 min 2 % to 97 % B

[0709] 3.50 - 4.0 min 97 % B

[0710] Method G

[0711] UPLC-MS Shimadzu series LC-MS 2020 system with photodiode array detector

[0712] MSD signal settings APCI and ESI positive / negative 100-1000 m / z

[0713] Detection signal Photodiode Array

[0714] Spectrum Range 200-400 nm; detection wavelength at 254 nm

[0715] Sampling rate 40 Hz

[0716] Column Hypersil Gold column 1.9 pm particle size, 2.1 x 50 mm;

[0717] Column temperature 40 °C

[0718] Solvent A: 0.1% FA in H2O;B: 0.1% FA in MeCN

[0719] B: 0.07% formic acid in water

[0720] Flow 0.8 mL / min

[0721] Gradient 0.0 - 3.0 min: 5 % - 95 % B for the D-4 (Weinreb amid formation followed

[0722] Grignard addition, CBZ reduction and LAH reduction)

[0723] D-1a

[0724] To a stirred solution of (2S)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (25 g,

[0725] 116.15 mmol, 1.0 eq) and N,O-dimethylhydroxylamine hydrochloride (20.39 g, 209.06 mmol, 1.8 eq) in DMF (400 ml) is added EDCI hydrochloride (33.4 g, 174.2 mmol, 1.5 eq), HOBT (26.68 g, 174.2 mmol, 1.5 eq) and TEA (35.25 mg, 348.44 mmol, 3.0 eq). The reaction mixture is stirred at 100 °C for 3 h. After complete conversion the reaction mixture is concentrated under reduced pressure, diluted with water (250 ml) and a saturated sodium bicarbonate solution (250 ml) is added. The mixture is extracted EtOAc and the separated organic phase is washed with a saturated sodium bicarbonate solution (3 x 500 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure to get the crude product D-1a.

[0726] The following intermediates D-1 (Table 1) are available in analogue manner using different carboxylic acids as starting materials. The intermediates D-1 are purified by chromatography if necessary.

[0727] Table 1

[0728] To the crude product D-1a (26.83 g, 103.9 mmol, 1.0 eq) dissolved in THF (400 ml) is added at O °C methylmagnesium bromide (3.4 M in THF, 109.2 g, 332.37 mmol, 3.2 eq) and stirred for 2 h. After complete conversion the reaction mixture is quenched by addition of a saturated sodium chloride solution (500 ml) and extracted with EtOAc (3 x 500 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product D-2a. The following intermediates D-2 (Table 2) are available in analogue manner using different intermediates D-1 as starting materials. The intermediates D-2 are purified by chromatography if necessary.

[0729] Table 2

[0730] To a solution of (R)-Methyl oxazaborolidine (5.427 g, 19.58 mmol, 0.2 eq) in THF (200 ml) is added borane-dimethyl sulfide complex (2 M in THF, 54.41 g, 127.27 mmol, 1.3 eq) and stirred at rt for 1 h. To the reaction mixture a solution of D-2a (20.88 g, 97.9 mmol, 1.0 eq) dissolved in THF (100 ml) is added slowly and the reaction mixture is stirred at rt for 1 h. After complete conversion the reaction mixture is carefully quenched with MeOH and concentrated under reduced pressure. The crude is purified by NP column chromatography using Cyclohexane / EtOAC as eluent (15-45 %). The product containing fractions are combined and concentrated under reduced pressure to yield D-3a.

[0731] The following intermediates D-3 (Table 3) are available in analogue manner using different intermediates D-2 as starting materials. The intermediates D-3 are purified by chromatography if necessary. Table 3

[0732] D-3a D-4a

[0733] D-3a (15.36 g, 71.35 mmol, 1.0 eq) is treated with a lithium aluminium hydride solution (2 M in THF, 97.4 g, 214 mmol, 3.0 eq) and stirred at 80 °C for 1 h. After complete conversion the reaction mixture is quenched under cooling in an ice bath by addition of water (4 ml).

[0734] The precipitated Li-salts are removed, the organic phase is dried over sodium sulfate, filtered and carefully concentrated at 100 mbar pressure at 45 °C bath temperature to yield the product D-4a.

[0735] The following intermediates D-4 (Table 4) are available in analogue manner using different intermediates D-3 as starting materials. The intermediates D-4 are purified by chromatography if necessary.

[0736] Table 4 followed by Boc

[0737] To a stirred solution of (2S)-2-methyl-1 ,4-diazepane-1 -carboxylate (5 g, 23.33 mmol, 1.0 eq) and potassium carbonate (9.673 g, 70.0 mmol, 3.0 eq) in dry ACN is added 2-iodo- propane (10.12 g, 58.33 mmol, 2.5 eq). The reaction mixture is stirred at 45°C overnight, concentrated under reduced pressure, diluted with DCM and washed with water. The water phase is extracted twice with DCM and the combined organic phases are dried over MgSCU, filtered and concentrated under reduced pressure. The crude product is purified by chromatography over silica gel. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure to get the crude product which is purified by chromatography to yield tert-butyl (2S)-2-methyl-4-(propan-2-yl)-1 ,4-diazepane-1- carboxylate (HPLC method A: tret = 1.38 min; [M+H]+= 257).

[0738] To a stirred solution of tert-butyl (2S)-2-methyl-4-(propan-2-yl)-1 ,4-diazepane-1 -carboxylate (5.65 g, 21.38 mmol, 1.0 eq) in MeOH is added a 4M HCI solution (10.69 ml, 42.75 mmol, 2.0 eq) and the reaction mixture is stirred at 60°C for 4 h. The reaction mixture is concentrated under reduced pressure and the crude product D-5 (HPLC method A: tret = 0.47 min; [M+H]+= 157) is used without any further purification. Experimental procedure for the synthesis of K-5a (cyanation)

[0739] K-5a

[0740] To a solution of K-4a (15 g, 51.7 mmol, 1.0 eq.) and TEA (13.08 g, 129.25 mmol, 2.5 eq) in dry ACN (80 mL) is added D-4a (85.5 % content, 8.589 g, 129.2 mmol, 1.1 eq.). The reaction mixture is heated to 40 °C for 24 hours before tetraethyl ammonium cyanide (12.118 g, 77.547 mmol, 1.5 eq) and 1 ,4-diazabicyclo[2.2.2]octane (11.6 g, 103.4 mmol, 2.0 eq.) are added. The reaction mixture is stirred at 40 °C for additional 3 h, concentrated under reduced pressure, diluted with DCM and washed with water. The water phase is extracted twice with DCM and the combined organic phases are dried over MgSC filtered and concentrated under reduced pressure. The crude product is purified by chromatography to obtain K-5a.

[0741] The following intermediates K-5 (Table 5) are available in an analogous manner. The crude product K-5 is purified by chromatography if necessary.

[0742] Table 5 Experimental procedure for the synthesis of K-5c (SNAr)

[0743] K-4a

[0744] To a solution of K-4a (3.8 g, 12.7 mmol, 0.9 eq.) and D-5 (2.3 g, 14.13 mmol, 1.0 eq) in iPrOH is added TEA (7.15 g, 70.65 mmol, 5.0 eq) and stirred at room temperature for 1 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with water. The water phase is extracted twice with DCM and the combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by chromatography tert-butyl 2-chloro-4-[(2S)-2-methyl-4-(propan-2-yl)- 1 ,4-diazepan-1-yl]-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (HPLC method A: tret = 1.62 min; [M+H]+= 410).

[0745] K-5c

[0746] To a solution of tert-butyl 2-chloro-4-[(2S)-2-methyl-4-(propan-2-yl)-1 ,4-diazepan-1-yl]- 5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (8.4 g, 20.49 mmol, 1.0 eq.) and 1 ,4- diazabicyclo[2.2.2]octane (5.746 g, 51.225 mmol, 2.5 eq) in dry ACN is added tetraethyl ammonium cyanide (7.044 g, 45.08 mmol, 2.2 eq). The reaction mixture is stirred at 50°C for additional 3 days. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with water. The water phase is extracted twice with DCM and the combined organic phases are dried over MgSCU, filtered and concentrated under reduced pressure. The crude product is purified by chromatography over silica gel (using a gradient cycloHexane / EtOAc with EtOAc from 0-60 % under basic conditions) and the product containing fractions are combined, concentrated under reduced pressure, and freeze dried to obtain K-5c (Table 6).

[0747] Table 6

[0748] Experimental procedure for the synthesis of B-2a

[0749] B-1a B-2a

[0750] To a suspension of 5-chloropentanenitrile (22.9 g, 194.8 mmol, 1.0 eq.) in dry EtOH (136 mL) is added acetyl chloride (111.3 mL, 1.558 mol, 8.0 eq.) dropwise at 0°C. The reaction mixture is allowed to reach rt and stirred for 12 h. The mixture is concentrated under reduced pressure and washed with Et20 and the crude product B-2a is used as the HCI salt directly in the next step without further purification.

[0751] Experimental procedure for the synthesis of B-3a

[0752] B-2a B-3a

[0753] Crude B-2a (HCI salt) (28 g, 139.9 mmol, 1.0 eq.) and ethylene glycol (7.382 g, 118.94 mmol, 0.9 eq.) are dissolved in DCM (300 mL) and stirred at rt for 6 d. The resulting suspension is concentrated under reduced pressure, diluted with Et20 (200 mL) and filtered. The filtrate is concentrated under reduced pressure, taken up in DCM (200 mL) and treated with a 2N KOH solution (150 mL). The mixture is stirred at rt overnight keeping the phases intact. The phases are separated, the water phase is extracted twice with DCM and the combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude orthoester B-3a is used for the next step without further purification.

[0754] Experimental procedure for the synthesis of B-4a

[0755] B-3a B-4a

[0756] Crude B-3a (22.3 g, 106.9 mmol, 1.0 eq.), 1-cyclohexenyloxytrimethylsilane (16.42 mL, 82.3 mmol, 0.8 eq.) and zinc chloride (10.195 g, 74.8 mmol, 0.7 eq.) are dissolved in DCM (120 mL) and stirred at rt for 5 h. The reaction mixture is treated by addition of saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSCL, filtered and concentrated under reduced pressure. The crude product is purified by NP- chromatography (gradient elution: 0 % to 50 % EtOAc in cyclohexane) to give the desired compound B-4a (HPLC method A: tret = 1 .23 min; [M+Na]+= 283).

[0757] Experimental procedure for the synthesis of B-5a

[0758] B-4a B-5a

[0759] B-4a (14.9 g, 57.14 mmol, 1.0 eq.) and sodium iodide (25.954 g, 171.4 mmol, 3.0 eq.) are dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium thiosulfate solution. The organic phase is separated, dried over MgSCL, filtered and concentrated under reduced pressure. The crude product B-5a is used for the next step without further purification. Experimental procedure for the synthesis of B-6b

[0760] B-5a (30 g, 85.0 mmol, 1.0 eq.) is dissolved in THF. The mixture is treated with potassium tert.-butoxide (28.67 g, 256.0 mmol, 3.0 eq.) at 0°C and stirred at rt overnight. The reaction mixture is quenched by addition of water (2 mL), diluted by addition of Et20 and a saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by NP- chromatography (gradient elution: 0 % to 50 % EtOAc in cHexane) to give (racemic) compound B-6a (HPLC method A: tret = 1.18 min; [M+H]+= 225; synthesis based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., European Journal of Organic Chemistry 2004, 79:3962-3967). Enantiomer B-6b can then be obtained after chiral separation via SFC (using a Lux Cellulose-4 column (250 x 30 mm, 5 pm), 30°C column temperature, 90 % CO2, 10% ACN as cosolvent) with enantiomer B-6b (HPLC method: A; tret = 1.17 min; [M+H]+ = 225, SFC method: SFC-B; tret = 2.99 min) eluting as the 2nd peak after the other enantiomer.

[0761] K-5a K-10a

[0762] K-5a (4.646 g, 9.953 mmol, 1.0 eq.) is dissolved in ACN and a 2N aqueous LiOH solution (7.464 mL, 14.929 mmol, 1.5 eq.) is added. The reaction mixture is heated to 50°C and stirred overnight. The reaction mixture is cooled down to rt, neutralized with formic acid, concentrated under reduced pressure and filtered. The crude product is purified by RP- chromatography over silica gel to obtain K-10a. The following intermediates K-10 (Table 7) are available in analogue manner using different intermediates K-5. The intermediates K-10 are purified by chromatography if necessary.

[0763] Table 7 Experimental procedure for the synthesis of K-11a:

[0764] To a stirred solution of D-4a (2.12 g, 14.4 mmol, 1.00 equiv.) in THF (50 mL) at 0°C is added NaH (60 % in mineral oil, 723 mg, 18.1 mmol, 1.1 equiv.) followed by K-4b (5.00 g, 16.4 mmol, 1.00 equiv.). The mixture is allowed to reach rt and stirred for 5 h. After complete conversion, the reaction mixture is diluted with EtOAc, washed with water and brine and the organic phase is dried, filtered and concentrated. The crude product is purified via NP chromatography yielding tert-butyl 2-chloro-4-[(1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]- 5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carboxylate (HPLC method: F, tret = 1 46 min; [M+H]+= 397).

[0765] K-11a

[0766] To a solution of tert-butyl 2-chloro-4-[(1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]- 5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carboxylate (3.00 g, 7.56 mmol, 1.00 equiv.) in MeOH (60 mL) is added sodium acetate (1.86 g, 22.7 mmol, 3.00 equiv.) and the mixture is purged with Argon for 15 min. 1,1-bis(diphenylphosphino)ferrocene (126 mg, 0.23 mmol, 0.03 equiv.) and palladium(ll)acetate (17mg, 0.08 mmol, 0.01 equiv.) is added and the mixture is stirred for 16 h at 90 °C under CO pressure (150 psi) in a pressure reactor. After complete conversion, the reaction mixture is filtered and concentrated under reduced pressure. The crude product is purified via NP chromatography yielding K-11a (HPLC method: E, tret = 1 62 min; [M+H]+= 421).

[0767] Experimental procedure for the synthesis of K-12a

[0768] CDI (6.628 g, 39.648 mmol, 4.0 eq.) is dissolved in dry THF, activated molsieve is added and the mixture is heated to 50 °C. In a second flask K-10a (3.89 g, 9.912 mmol, 1.0 eq.) and activated molsieve in dry THF are stirred for 15 min at rt before being added to the GDI solution. The reaction mixture is stirred at 50 °C for 15 min. In a third flask B-6b (5.293 g, 19.824 mmol, 2.0 eq.) is dissolved in a 1 M LiHMDS solution in THF (41.631 mL, 41.631 mmol, 4.2 eq.) and stirred at rt for 20 min before being added to the reaction mixture. The reaction mixture is stirred at 50°C overnight. After cooling down to rt the reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium hydrogencarbonate solution. The water phase is extracted with DCM (three times). The combined organic phases are dried over MgSCU, filtered and concentrated under reduced pressure. The crude product is purified by NP-chromatography to yield K-12a.

[0769] The following intermediates K-12 (Table 8) are available in an analogous manner starting from different intermediates K-10. The crude product K-12 is purified by chromatography if necessary. Multiple HPLC retention times are reported because different tautomers of K-12 are present.

[0770] Table 8

[0771] Experimental procedure for the synthesis of K-12d

[0772] K-11b

[0773] K-12d

[0774] B-6b (293 mg, 1.31 mmol, 1.10 equiv.) is dissolved in THF (5 mL), activated molecular sieve 3 A is added and stirred at 0 °C for 20 min under an argon atomsphere. Then LiHMDS (1 M in THF, 2.94 mL, 2.94 mmol, 2.50 equiv.) is added and stirred for 15 min at rt. K-11b (500 mg, 1.19 mmol, 1.00 equiv.) is added and the mixture is stirred at 50 °C for 2 h. After complete conversion, the mixture is quenched with water, concentrated under reduced pressure, brought to pH 7-8 with 1 N aq. HCI and extracted with DCM. The combined organic phases are dried, filtered, concentrated under reduced pressure and purified by NP chromatography to give K-12d (Table 9).

[0775] Table 9 Experimental procedure for the synthesis of K-13a

[0776] To a solution of K-12a (0.5 g, 0.835 mmol, 1.0 eq.) in pyridine is added hydroxylamine hydrochloride (50 % content in water, 118.433 mg, 1.67 mmol, 2.0 eq.) and the reaction mixture is heated to 80 °C for 60 min. The reaction mixture is diluted with DCM and water. The water phase is extracted with DCM (three times), the combined organic phases are concentrated under reduced pressure, taken up in MeOH and treated with cone. HCI at 60 °C for 1 h. The reaction mixture is concentrated under reduced pressure, dissolved in DCM and neutralized by careful addition of a saturated solution of sodium carbonate. The water phase is extracted with DCM (three times), the combined organic phases are dried over MgSCU, filtered and concentrated under reduced pressure. The crude product is purified via RP-chromatography (basic conditions). The product containing fractions were combined, concentrated under reduced pressure and lyophilized to yield K-13a.

[0777] The following intermediates K-13 (Table 10) are available in an analogous manner starting from different intermediates K-12. The crude products are purified by chromatography if necessary. Table 10 Experimental procedure for the synthesis of K-13e

[0778] To a solution of K12a (3.30 g, 0.006 mol) in methanol (16.50 mL) is added hydroxylamine (50 % solution in water, 0.910 g, 0.844 mL, 0.014 mol, 2.5 eq.). The reaction mixture is stirred for 1.5 h at 50 °C and all volatiles are removed under reduced pressure afterwards. Methanol (36.4 mL) and cone. HCI (36.4 mL) are added and the reaction mixture is stirred at 60 °C for 1 h. All volatiles are removed under reduced pressure and the residue was diluted with saturated NaHCCh solution and EtOAc. The aqueous phase is extracted with EtOAc (3 x). The combined organic layers are dried over MgSCL, filtered and all volatiles are removed under reduced pressure to obtain K-13e (Table 11). The crude product is used directly in the next step.

[0779] Table 11 Experimental procedure for the synthesis of K-14a

[0780] To a solution of K-13a (2.50 g, 451 mmol, 1.0 eq.) in THF and TEA (1.12 g, 11.073 mmol, 2.0 eq.) is added Boc-anhydride (1.328 g, 6.090 mmol, 1.1 eq.). The reaction mixture is stirred at rt for 2 h. Reaction mixture is diluted with DCM and treated with water. The water phase is extracted twice with DCM. The combined organic phases are dried over MgSCU, filtered and concentrated under reduced pressure. The crude product K-14a is directly used in the next reaction step without further purification.

[0781] The following intermediates K-14 (Table 12) are available in an analogous manner starting from different intermediates K-13. The crude products are purified by chromatography if necessary.

[0782] Table 12 Experimental procedure for the synthesis of K-15a

[0783] To a solution of K-14a (1.0 g, 1.816 mmol, 1.0 eq.) in EtOH (10 mL) is added under nitrogen gas malononitrile (95 % purity, 631.5 mg, 9.08 mmol, 5.0 eq.), beta-alanine (95 % purity, 511 mg, 5.45 mmol, 3.0 eq.) and activated molecular sieve (from Roth, 1 g) at rt. The reaction mixture is heated to 80°C for 5 h. Upon complete condensation reaction monitored by HPLC-MS sulfur (174.723 mg, 5.45 mmol, 3.0 eq.) is added and the reaction mixture is stirred at 80°C for 60 min. The reaction mixture is cooled down to rt, dissolved with water and EtOAc and filtered. The layers are separated. To the water phase is added a 4N NaOH solution (10 mL) and extracted 3 x with EtOAc. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by RP-chromatography to yield K-15a.

[0784] The following intermediates K-15 (Table 13) are available in an analogous manner starting from different intermediates K-14. The crude products are purified by chromatography if necessary.

[0785] Table 13

[0786] Experimental procedure for the synthesis of K-16a

[0787] To a solution of K-15a (400 mg, 0.633 mmol, 1.0 eq.) in MeOH (10 mL) is added cone. HCI (2 mL) and the reaction mixture is heated to 50 °C for 2 h. The reaction mixture is concentrated under reduced pressure and purified via SCX-ion-exchange-chromatography to yield K-16a.

[0788] The following intermediates K-16 (Table 14) are available in an analogous manner starting from different intermediates K-15. The crude products are purified by chromatography if necessary.

[0789] Table 14

[0790]

[0791] Experimental procedure for the synthesis of K-16e

[0792] K-13d (95.0 mg, 0.171 mmol, 1.00 equiv.), malonitrile (34.2 mg, 0.513 mmol, 3.00 eq.) ammonium acetate (26.3 mg, 0.513 mmol, 3.00 eq.) and sulfur (16.6 mg, 0.513 mmol, 3.00 equiv.) is suspended in EtOH (1.2 mL) and stirred at 65 °C for 1 h. After full conversion the mixture is diluted with water and extracted with DCM. The organic layer is dried, filtered, concentrated, and purified with RP chromatography to afford K-16e (Table 15). Table 15 Experimental procedure for the synthesis of 4-bromo-3-fluoro-phthalic acid (carboxylation)

[0793] To a solution of LDA (prepared by stirring diisoproylamine (0.32 mL, 2.30 mmol, 2.3 eq.) and n-BuLi (2.5 M, 0.88 mL, 2.20 mmol, 2.2 eq.) in THF (2.50 mL) at 0 °C for 15 min) is added 4-bromo-3-fluoro-benzoic acid (219.00 mg, 1.00 mmol) in THF (2.50 mL). The resulting suspension is stirred at 0 °C for 30 min. Dry ice CO2 (132.00 mg, 3.00 mmol, 3.0 eq.) is added and the resulting solution is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is quenched with HCI (1 M) and the aqueous layer is extracted with EtOAc (3x). The combined organic layers are dried over MgSCL and concentrated under reduced pressure to give 4-bromo-3-fluoro-phthalic acid (Table 16), which is used without further purification.

[0794] Table 16

[0795] Experimental procedure for the synthesis of 5-bromo-2-(2,6-dioxo-3-piperidyl)-4-fluoro- isoindoline-1 , 3-dione (Imide formation)

[0796] To a suspension of 4-bromo-3-fluoro-phthalic acid (235.00 mg, 0.893 mmol, 1.0 eq.) and 3-aminopiperidine-2, 6-dione hydrochloride (162.00 mg, 0.983 mmol, 1.1 eq.) in acetic acid (4.00 mL) is added sodium acetate (257.00 mg, 3.13 mmol, 3.5 eq.). The resulting suspension is stirred and heated for 16 h. The reaction mixture is quenched with water and stirred at 0 °C for 30 min. The suspension is filtered, washed with water and then Et20 to give 5-bromo-2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1 , 3-dione (Table 17), which is used without further purification.

[0797] Table 17

[0798] Experimental procedure for the synthesis of E-1a (Suzuki Coupling):

[0799] A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (3.02 g, 8.611 mmol, 1.0 eq), N-Boc-1 ,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.363 g, 10.333 mmol, 1.2 eq), sodium bicarbonate (3.36 g, 40.0 mmol, 4.6 eq) and XPhos PD G3 (0.537 g, 0.603 mmol, 0.1 eq) in 3:1 DMSO / water (60 ml) is degassed with argon and stirred at 80°C for 2 h. The reaction mixture is cooled down, treated with water (75 ml) and filtered.

[0800] The solid is purified by chromatography to yield E-1a.

[0801] The following intermediates E-1 (Table 18) are available in an analogous manner using other bromides and boronic acids analogs. The reaction products are purified by chromatography if necessary. Table 18

[0802]

[0803] Experimental procedure for the synthesis of E-1 h (Buchwald):

[0804] 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (50.00 mg, 0.14 mmol), 1-boc- piperazine (39.04 mg, 0.20 mmol, 1.5 eq.) and milled cesium carbonate (264.31 mg, 0.81 mmol, 6.0 eq.) are dissolved in DMA (1.00 mL). The reaction mixture is degassed with Argon for 10 min and dichloro[1 ,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) (21.52 mg, 0.03 mmol, 20 mol%) is added. The reaction mixture is stirred at 110 °C for 30 min. The reaction mixture is allowed to cool to room temperature and is diluted with DCM. The organic layer is washed with AcOH (5%) and brine. The combined organic layer is concentrated under reduced pressure. The residue is taken up in acetonitrile and purified by chromatography to obtain E-1 h (Table 19). Table 19

[0805] Experimental procedure for the synthesis of E-1 i : To a stirred solution of 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1 , 3-dione (100.00 mg, 0.36 mmol) in DMSO (1.00 mL) is added piperazine-1 -carboxylic acid tert-butyl ester (80.91 mg, 0.43 mmol, 1.2 eq.) and DIPEA (0.01 mL, 0.04 mmol, 0.1 eq.). The reaction mixture is stirred at 110 °C for 18 h. The reaction mixture is allowed to cool to room temperature and is diluted with water. The reaction mixture is filtered and washed with water. The filtered solid is dried in vacuo at 45 °C overnight and E-1 i is obtained without further purification.

[0806] The following intermediates E-1 (Table 20) are available in analogue manner using different amines. Reaction products were additionally purified by chromatography if necessary. Table 20

[0807] Experimental procedure for the synthesis of E-1k (hydrogenation):

[0808] Method A in Table 21 :

[0809] E-1 b (55 mg, 1.0 eq) and palladium on carbon (10 wt. % loading, 16 mg) are taken up in DMF (1.1 mL) and THF (1.1 mL). The reaction mixture is stirred under 8 bar of a hydrogen atmosphere for 20 h at room temperature. The hydrogen atmosphere is removed, and the reaction mixture is filtered over celite. The solvent is removed under reduced pressure and the crude product E-1k is used in the next step without further purification.

[0810] The following intermediates E-1 marked with method A in Table 21 are available in analogue manner using different intermediates E-1. Reaction products were additionally purified by chromatography if necessary. Experimental procedure for the synthesis of E-11 (hydrogenation):

[0811] Method B in Table 21 :

[0812] To a solution of E-1f (287.0 mg, 0.653 mmol, 1.0 eq.) in THF (5.0 mL) and DMF (5.0 mL) is added platinum(IV) oxide (96.4 mg, 0.424 mmol, 0.65 eq.) at room temperature. The reaction mixture is stirred under 6 bar of a hydrogen atmosphere for 21 hours. The hydrogen atmosphere is removed and the reaction mixture is diluted with THF (5 mL) and filtered over celite. The solvent is removed under reduced pressure and the crude product is purified by column chromatography to obtain E-11. The following intermediates E-1 marked with method B in Table 21 are available in analogue manner using different intermediates E-1. Reaction products were additionally purified by chromatography if necessary.

[0813] Experimental procedure for the synthesis of E-2a (Boc deprotection):

[0814] To a stirred suspension of E-1a (10.6 g, 24.913 mmol, 1.0 eq) in DCE (110 ml) is added a 4M HCI in 1 ,4-dioxane solution (31.141 ml, 124.566 mmol, 5.0 eq) and the reaction mixture is stirred at 65°C for 2 h. The reaction mixture is diluted with diethyl ether, filtered and concentrated under reduced pressure to yield the crude product E-2a as the HCI salt, which is used without further purifications.

[0815] The following intermediates E-2 (Table 22) are available as salts in analogue manner using different intermediates E-1 as starting material. The crude intermediates E-2 are purified by chromatography if necessary to obtain the intermediates E-2 as the free base.

[0816] Table 22

[0817] Experimental procedure for the synthesis of E-2m (Hydrogenation):

[0818] To a solution of benzyl E-1c (122.00 mg, 0.248 mmol) in ethanol (10.00 mL) is added 10 % Pd / C (26.00 mg, 0.025 mmol, 0.10 eq.). The resulting suspension is evacuated and backfilled with N2 (3x). Then the suspension is evacuated again, and back filled with hydrogen. The resulting suspension is stirred at rt for 16 h. LCMS shows 80% conversion of desired product and Ethanol (5.0 mL) is added and the reaction is resubjected to hydrogen gas and stirred for another 16 h. The suspension is filtered through celite, washed with 10% MeOH / DCM and concentrated under reduced pressure. The residue is redissolved in MeOH / DCM (10:1) and resubjected to hydrogenation conditions. LCMS shows full conversion so the suspension is filtered through celite, washed with 10% MeOH / DCM and concentrated under reduced pressure to give E-2m (Table 23) without further purification.

[0819] Table 23

[0820] Experimental procedure for the synthesis of E-2n (SNAr):

[0821] E-2n

[0822] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1 , 3-dione (100.0 mg, 0.362 mmol, 1 eq.) and 6,6-dimethyl-1 ,4-diazepane (57.4 mg, 0.434 mmol, 1.2 eq.) are suspended in DMSO (1.0 mL) and DIPEA (0.189 mL, 1.08 mmol, 3.0 eq.) are added at room temperature. The reaction mixture is stirred at 110 °C for 18 h. After cooling to room temperature a few drops of formic acid are added, the reaction mixture is diluted with MeCN and water and directly purified by chromatography to obtain E-2n.

[0823] The following intermediates E-2 (Table 24) are available in analogues manner using different amines.

[0824] Table 24

[0825] Experimental procedure for the synthesis of E-3a (Alkylation): -

[0826] To a suspension of E-2b (34.00 mg, 0.09 mmol) in anhydrous acetontrile (1.00 mL) tertbutyl bromoacetate (0.08 mL, 0.53 mmol, 6.0 eq.) and triethylamine (0.186 mL, 1.34 mmol, 6.0 eq.) are added. The reaction mixture is stirred at 60 °C overnight. The reaction mixture is allowed to cool to room temperature and is diluted with acetonitrile / water (1 :1) and directly purified by chromatography to give E-3a.

[0827] The following intermediates E-3 (Table 25) are available in analogue manner using different amines E-2 as free base or as a salt thereof. For some examples tert-butyl 3- bromopropanoate was used instead of tert-butyl bromoacetate in analogue manner. Table 25

[0828]

[0829] Experimental procedure for the synthesis of E-3p (hydrogenation):

[0830] E-3d (61 mg, 0.139 mmol, 1.0 eq) and palladium on carbon (10 wt. % loading, 18 mg) are taken up in DMF (1 mL) and THF (1 mL). The reaction mixture is stirred under 7 bar of a hydrogen atmosphere for 3 h. The hydrogen atmosphere is removed, and the reaction mixture is filtered over celite. The solvent is removed under reduced pressure and the crude product E-3p (Table 26) is used in the next step without further purification.

[0831] Table 26

[0832]

[0833] Experimental procedure for the synthesis of E-4a (t-butyl ester cleavage):

[0834] To a stirred solution of E-3p (43 mg. 0.126 mmol, 1 eq.) in DCM (1 mL) is added HCI in dioxane (4 M, 1 mL) at 0 °C. The reaction mixture is allowed to warm to rt and is stirred for

[0835] 16 h at rt. The solvents are removed under reduced pressure and the crude product is purified by RP chromatography to obtain E-4a.

[0836] The following compounds E-4 (Table 27) are available in an analogous manner using other intermediates E-3. The crude products E-4 are purified by chromatography if necessary. Table 27

[0837]

[0838] Experimental procedure for the synthesis of 1-1 (amide coupling):

[0839] To a solution of E-4a (457 mg, 1.08 mmol, 1.2 eq), 1-hydroxy-7-azabenzotriazole (122.9 mg, 0.903 mmol, 1.0 eq) and TBTLI (434.7 mg, 1.354 mmol, 1.5 eq) in DMSO (0.5 ml) is added a solution of K-16a (480 mg, 0.903 mmol, 1.0 eq) in a mixture of

[0840] DMSO / ACN (1.5 mL and 2.0 mL) and the reaction mixture is treated with TEA (0.629 ml, 4.514 mmol, 5.0 eq). After 10 min at room temperature the reaction mixture is concentrated under reduced pressure and treated with water. The precipitate is filtered and the water phase is extracted with DCM. The organic phase and the precipitate are combined, concentrated under reduced pressure and purified by chromatography to obtain 1-1.

[0841] The following compounds I (Table 28) are available in an analogous manner using other intermediates K-4 and one of K-16 or K-9. The crude products I are purified by chromatography if necessary.

[0842] Table 28

[0843]

[0844]

[0845]

[0846] The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples. Biological Examples

[0847] KRAS::SOS1 AlphaScreen Binding Assay

[0848] This assay measures the inhibitory effect of compounds on KRAS mutant protein-protein interactions using the Alpha Screen technology by Perkin Elmer. This assay can be used to examine the potency with which compounds according to the invention binding to a mutated KRAS inhibit the protein-protein interaction between SOS1 and the mutated KRAS e.g., KRAS G12C, KRAS G12D or KRAS G12V. This inhibits the GEF functionality of SOS1 and locks the corresponding mutated KRAS protein in its inactive, GDP-bound state. Low IC50 values in this assay setting are indicative of strong inhibition of protein-protein interaction between SOS1 and KRAS. The following mutant enzyme forms of KRAS and interacting proteins have been used in these assays at the given concentrations: KRAS (G12D) 1-169, N-terminal 6His-tag, C-terminal avi-tag (Xtal BioStructures, Inc.); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 5 nM

[0849] KRAS (G12C) 1-169, C-terminal avi-tag, biotinylated, mutations: C51S, C80L, C118S (in house); final assay concentration 7.5 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 5 nM

[0850] KRAS (G12V) 1-169, N-terminal 6His-tag, C-terminal avi-tag, TEV cleavage site, mutation: C118S (in house); final assay concentration 10nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM

[0851] Test compounds dissolved in DMSO are dispensed onto assay plates (Proxiplate 384 PLUS, white, PerkinElmer; 6008289) using an Access Labcyte Workstation with the Labcyte Echo 55x. For the chosen highest assay concentration of 100 pM, 150 nL of compound solution is transferred from a 10 mM DMSO compound stock solution. A series of eleven fivefold dilutions per compound is transferred to the assay plate, compound dilutions are tested in duplicates. DMSO is added as backfill to a total volume of 150 nL.

[0852] The assays run on a fully automated robotic system in a darkened room below 100 Lux. To 150nl of compound dilution 10 pl of a mix including KRAS mutant protein, SOS1 (final assay concentrations see above) and GDP nucleotide (Sigma G7127; final assay concentration 10pM) in assay buffer (1 x PBS, 0.1% BSA, 0.05% Tween 20) are added into columns 1- 24.

[0853] After 30 minutes incubation time 5 pl of Alpha Screen bead mix in assay buffer are added into columns 1-23. Bead mix consists of AlphaLISA Glutathione Acceptor Beads (PerkinElmer, Cat No AL109) and AlphaScreen Streptavidin Donor Beads (PerkinElmer Cat No 6760002) in assay buffer at a final assay concentration of 10 pg / ml each.

[0854] Plates are kept at room temperature in a darkened incubator. After an additional 60 minutes incubation time the signal is measured in a PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen specs from PerkinElmer.

[0855] Each plate contains up to 16 wells of a negative control depending on the dilution procedure (platewise or serial) (diluted DMSO instead of test compound; w KRAS mutant::SOS1 GDP mix and bead mix; column 23) and 16 wells of a positive control (diluted DMSO instead of test compound; w KRAS mutant::SOS1 GDP mix w / o bead mix; column 24).

[0856] As internal control known inhibitors of KRAS mutant: :SOS1 interaction can be measured on each compound plate.

[0857] IC50 values are calculated and analyzed with Boehringer Ingelheim’s MEGALAB IC50 application using a 4 parametric logistic model.

[0858] Tables of example compounds disclosed herein contain IC50 values determined using the above assay (see Table 29).

[0859] Table 29

[0860] Hi Bit Degradation assay

[0861] A HiBit protein detection tag (amino acid sequence VSGWRLFKKIS, Seq ID No 1) is introduced immediately downstream of the initiating Methionine codon of the endogenous KRAS locus (Ensembl gene ID ENSG00000133703.7) of GP5d cells (ECACC Cat. No. 95090715) by CRISPR-based genome engineering using a KRAS(G12D) mutant donor construct encoding the HiBit tag. This results in the heterozygous introduction of an N- terminal HiBit tagged version of KRAS(G12D) into the KRAS(WT) allele. Correct modification of the KRAS locus is assessed by PCR-based genotyping and Sanger sequencing of the isolated PCR products. The resulting cell line is referred to as GP5d- HiBit-KRAS(G12D).

[0862] To assess PROTAC-mediated degradation of KRAS(G12D), GP5d-HiBit-KRAS(G12D) cells are seeded at 25000 cells per well in 100 pL Dulbecco’s Modified Eagle medium (Sigma cat. no. D6429) supplemented with 10 % fetal calf serum into white bottom opaque 96 well plates (Perkin Elmer cat no. 5680). Plates are incubated at 37 °C, 5 % CO2 in a humidified incubator over night to allow the cells to adhere.

[0863] Test compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan), normalizing for added DMSO. Plates are further incubated at 37°C for 18 hours. Following incubation, 100 pL per well Promega Nano-Gio HiBit lytic detection reagent mix (Promega Nano-Gio HiBit Lytic Detection System #N3050), prepared according to the manufacturer's instructions in the kit, are added. To allow for adequate cell lysis, plates are incubated on an orbital shaker for 15 min and further incubated 30 min at room temperature. Upon completion of cell lysis, luminescence is measured using an Envision plate reader using the Ultrasensitive Luminescence Protocol for 96 well plates. Luminescence levels are normalized by the values obtained with DMSO- treated samples and plotted as percent of DMSO control. DC50 values are computed using a four parametric logistic model. Dmax values represent the maximal extent of degradation observed and is stated as percent of control treatments. D50 and Dmax are reported in Table 30 for representative compounds of the invention. Table 30

[0864] A corresponding degradation experiment can also be performed for G12V:

[0865] GP5d cells are modified by introduction of a HiBit-KRAS G12V plasmid through stable transfection, the resulting cell line is referred to as GP5d-HiBit-KRAS(G12V). To assess PROTAC-mediated degradation of KRAS(G12V), GP5d-HiBit-KRAS(G12V) cells are seeded at 5000 cells per well in 40 pL Dulbecco’s Modified Eagle medium (Sigma cat. no. D6429) supplemented with 10 % fetal calf serum (HyClone SH30084.03) and 1x Non-Essential Amino Acid Solution (Gibco 11140-035) into white flat-bottom tissue-culture treated 384 well plates (Greiner 781080). Plates are incubated at 37 °C, 5 % CO2 in a humidified incubator overnight to allow the cells to adhere.

[0866] Test compounds (10 mM stock in DMSO) are added at logarithmic dose series using an Echo® 555 Liquid Handler (Beckman Coulter Life Sciences), normalizing for added DMSO and including DMSO controls (final concentration 0.5%). All compound treatments are performed in technical duplicates. Plates are further incubated at 37 °C for 18 hours. Following incubation, 20 pL per well Promega Nano-Gio HiBit lytic detection reagent mix (Promega Nano-Gio HiBit Lytic Detection System #N3050), prepared according to the manufacturer's instructions in the kit, are added. To allow for adequate cell lysis, plates are incubated on an orbital shaker for 15 min. Upon completion of cell lysis, luminescence is measured using an Envision plate reader using the Ultrasensitive Luminescence Protocol for 384 well plates. In brief, luminescence levels are normalized by the values obtained with DMSO-treated samples and plotted as percent of DMSO control. DC50 values are computed using a four parametric logistic model. Dmax values represent the maximal extent of degradation observed and are stated as percent of control (%Ctrl.) treatments, below. DC50 and Dmax are reported in Table 31 for representative compounds of the invention.

[0867] Table 31

[0868] Proliferation assays with mutant cancer cell lines

[0869] GP2d CTG proliferation assay (120 h) (colorectal adenocarcinoma, G12D)

[0870] GP2d cells (ECACC No. 95090714) are dispensed into white 384-well Culturplates, flat bottom (Revvity PNr 6007680) at a density of 500 cells per well in 40 pL DMEM (Sigma D6429) + 10 % FCS (fetal calf serum, HyClone, SH30084.03) + 1X GlutaMAX (Gibco PNr 35050038).

[0871] Cells are incubated for 24 h at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using a HP D300 Digital Dispenser (Tecan), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the To time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four- parameter model and reported in Table 32.

[0872] NCI-H727 CTG proliferation assay (120 h) (lung cancer, G12V)

[0873] NCI-H727 cells (ATCC No. CRL-5815) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pl RPMI ATCC- Formulation (PAN P04-18047) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the To time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 33.

[0874] A-375 CTG proliferation assay (120 h) (melanoma, wt, B-Raf mutant, negative control) A-375 cells (ATCC No. CRL-1619) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 100 or 300 cells per well in 60 pL RPMI 1640 (ATCC Gibco, PNr.: A1049-01) or DMEM (Sigma D6429) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. Alternatively, compound dilutions are prepared using a HP D300 (Tecan) dispenser. All compound treatments are performed in technical duplicates. For the To time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls.

[0875] IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 32.

[0876] GP5d CTG proliferation assay (120 h) (colorectal cancer, G12D)

[0877] GP5d cells (ECACC No. 95090715; Solic N. et al., Int J Cancer 1995, 62(1):48-57) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pL DMEM (Sigma D6429) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 33.

[0878] SW620 CTG proliferation assay (120 h) (colorectal cancer, G12V)

[0879] SW620 cells (ECACC No. 87051203; Abaan OD et al., Cancer Res. 2013, 73(14):4372-82) are dispensed into white 384-well plates, white bottom and tissue-culture treated (Perkin Elmer / Revvity cat no. 6007680) at a density of 500 cells per well in 40 pL DMEM (Sigma #D6429-500ml) + 10 % FCS (fetal calf serum, PAN-Biotech (PNr.: P04-18047)). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan), including DMSO controls. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four- parameter model and reported in Table 32. SK-CO-1 CTG proliferation assay (120 h) (colorectal cancer, G12V)

[0880] SK-CO-1 cells (ATCC HTB-39) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pL EMEM (Sigma M5650) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 32.

[0881] LOVO CTG proliferation assay (120 h) (colorectal cancer, G13D)

[0882] LOVO cells (ATCC No. CCL-229) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 1000 cells per well in 60 pL DMEM (Sigma D6429) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 32.

[0883] AsPC-1 CTG proliferation assay (120 h) (pancreatic cancer, G12D)

[0884] AsPC-1 cells (ATCC CRL-1682) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pL RPMI ATCC- Formulation (PAN P04-18047) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 32.

[0885] SW1990 CTG proliferation assay (120 h) (pancreatic cancer, G12D)

[0886] SW1990 cells (ATCC CRL-2172) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pl DMEM (Sigma D6429) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four- parameter model and reported in Table 33.

[0887] LS513 CTG proliferation assay (120 h) (colorectal cancer, G12D)

[0888] LS513 cells (ATCC CRL-2134) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pL RPMI-1640 ATCC- Formulation (Gibco # A10491) + 10 % FCS (fetal calf serum, HyClone, SH30084.03). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo® 2.0 Cell Viability Reagent (Promega G9243). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 33.

[0889] H358 CTG proliferation assay (120 h) (NSCLC, G12C)

[0890] NCI-H358 cells (ATCC No. CRL-5807) are dispensed into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 200 cells per well in 60 pL RPMI-1640 ATCC-Formulation (Gibco # A10491) + 10 % FCS (fetal calf serum). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the ECHO acoustic liquid handler system (Beckman Coulter), normalizing for added DMSO and including DMSO controls. All compound treatments are performed in technical duplicates. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model and reported in Table 32.

[0891] Table 32

[0892] Table 33

[0893] Ex. 156 = example 156 disclosed in WO 2024 / 233838 (page 97) comprising a partially saturated, annulated 2-amino-3-cyano thiophene.

[0894] Example 156 is the only degrader in the application with that motif amongst many example compounds with completely different scaffolds and is reported to have anti-proliferative activity below 100 nM on AGS, LLI65A and NCI-H727 cell lines (page 107). This, however, could not be confirmed after resynthesis and measurement, i.e. Example 156 did not show substantial degradation or anti-proliferative activity (see Tables 30 to 33). Furthermore, the compounds of the invention differ structurally, particularly in the KRAS ligand moiety. Specifically, the CRBN ligand-linker unit (E-LK-) is connected to the KRAS ligand (POI) via an annulated, nitrogen-containing ring. No such KRAS ligands have been described so far. In addition, the exit vector employed in these degraders is oriented in a different direction compared to previously described degrader structures.

[0895] Formulation

[0896] The formulation examples which follow illustrate the present invention without restricting its scope:

[0897] Examples of pharmaceutical formulations

[0898] A) Tablets per tablet active substance according to formula (I) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

[0899] >

[0900] 500 mg

[0901] The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

[0902] B) Tablets per tablet active substance according to formula (I) 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodiumcarboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

[0903] The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

[0904] C) Tablets per tablet active substance according to formula (I) 25 mg lactose 50 mg microcrystalline cellulose 24 mg magnesium stearate 1 mg

[0905] 100 mg

[0906] The active substance, lactose and cellulose are mixed together. The mixture is screened, then either moistened with water, kneaded, wet-granulated and dried or dry-granulated or directly final blend with the magnesium stearate and compressed to tablets of suitable shape and size. When wet-granulated, additional lactose or cellulose and magnesium stearate is added and the mixture is compressed to produce tablets of suitable shape and size.

[0907] D) Ampoule solution active substance according to formula (I) 50 mg sodium chloride 50 mg water for inj. 5 mL

[0908] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

1. Claims1. A compound of formula (I):whereinE is a moiety of formula (II)denotes a single or double bond;R7is -H or =0; r is selected from the group consisting of 0, 1 and 2; each R8, if present, is independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, -S-Ci-4alkyl, halogen, hydroxy and -CN;LK is a moiety of formula (III)O(E)- / LK1')-LK2(POI) f111) , whereinLK1is selected from the group consisting of Cs-ycycloalkylene, Cs-ycycloalkenylene, arylene, 3-12 membered heterocyclylene, 3-7 membered heteroarylene and C2- ealkynylene, wherein the Cs-ycycloalkylene, Cs-ycycloalkenylene, arylene, 3-12 membered heterocyclylene, 3-7 membered heteroarylene or C2-6alkynylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl, wherein any one or more carbon atom(s) of the C2-6alkynylene is optionally replaced by a hetereoatom selected from the group consisting of oxygen, nitrogen and sulfur;LK2is selected from the group consisting of a bond, Ci-ealkylene, Ci-ealkoxylene and C2- ealkynylene, wherein the Ci-ealkylene, Ci-ealkoxylene or C2-ealkynylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl;POI is a moiety of formula (IV), whereinR1aand R1bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl;R2aand R2bare both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; and / or, optionally, one of R1aor R1band one of R2aor R2btogether with the carbon atoms they are attached to form a cyclopropane ring;Z is -(CR3aR3b)n-; each R3aand R3bis independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; or R3aand R3btogether with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; orZ is sulphur (-S-); ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R4, if present, is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, cyano-Ci-ealkyl, halogen, -OH, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, -CN, Cs-scycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1 , 2 and 3;W is nitrogen (-N=) or -CH=;V is nitrogen (-N=) or -CH=;R5is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different substituent(s) selected from the group consisting of Ci-ealkyl, Ci-ealkoxy and 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl; orR5is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R6and wherein the -O-Ci-ealkyl is optionally substituted on one carbon by replacing two hydrogens to form a Cs-ealicycle; each R6is independently selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen, Cs- cycloalkyl and 3-11 membered heterocyclyl; m and q are each independently selected from the group consisting of 0, 1 and 2; or a salt thereof.

2. The compound or salt according to claim 1 , wherein r is 0 or 1.

3. The compound or salt according to claim 1 or 2, wherein R8, if present, is halogen.

4. The compound or salt according to any one of claims 1 to 3, wherein E is selected from the group consisting of5. The compound or salt according to any one of claims 1 to 4, whereinLK1is a 3-12 membered heterocyclylene, wherein the 3-12 membered heterocyclylene is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl;LK2is Ci-6alkylene.

6. The compound or salt according to any one of claims 1 to 5, wherein LK1is a ring selected from the group consisting ofany hydrogen atom is replaced by a bond to E; any other hydrogen atom is replaced by a bond to LK2or, in case LK2is a bond, to C(O); the ring is optionally substituted with one or more identical or different substituent(s), each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, halogen, hydroxy, -N(Ci-4haloalkyl)2, -N(Ci-4alkoxy)2, -CN, Cs-ycycloalkyl and 3-4 membered heterocyclyl.

7. The compound or salt according to any one of claims 1 to 6, wherein LK1is selected from the group consisting of8. The compound or salt according to any one of claims 1 to 7, wherein LK2is Ci-3alkylene.

9. The compound or salt according to any one of claims 1 to 8, wherein R1a, R1b, R2aand R2bare hydrogen and Z is -CH2-.

10. The compound or salt according to any one of claims 1 to 9, wherein the moiety of formula (IV) is of formula (IV-c) or (IV-d)(IV-c) (IV-d) wherein R5, V, W, m and q are as defined in claim 1.

11. The compound or salt according to any one of claims 1 to 10, wherein the moiety of formula (IV) is of formula (IV-e) or (IV-f)(IV-e) (IV-f) wherein R5, V, W, m and q are as defined in claim 1.

12. The compound or salt according to any one of claims 1 to 11 , wherein the moiety of formula (IV) is of formula (IV-p) or (IV-q)wherein R5, V and W are as defined in claim 1.

13. The compound or salt according to any one of claims 1 to 12, wherein V and W are nitrogen (-N=).

14. The compound or salt according to any one of claims 1 to 13, wherein R5is selected from the group consisting of15. The compound or salt according to any one of claims 1 to 14, wherein R5is selected from the group consisting of16. The compound or salt according to claim 1, wherein the compound is selected from theor a stereoisomer therof, and wherein, optionally, the salt is a pharmaceutically acceptable salt.

17. The compound according to any one of claims 1 to 16 - or a pharmaceutically acceptable salt thereof - for use as a medicament.

18. The compound according to any one of claims 1 to 16 - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of cancer.

19. The compound - or pharmaceutically acceptable salt thereof - for use according to claim 18, wherein said compound or salt is administered in combination with one or more other pharmacologically active substance(s).

20. The compound - or pharmaceutically acceptable salt thereof - for use according to any one of claim 18 or 19, wherein the cancer is selected from the group consisting of pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC), especially non-small-cell lung adenocarcinoma), colorectal cancer (CRC, preferably colorectal adenocarcinoma), cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, gastric cancer (GC), esophageal cancer (EC; preferably esophageal adenocarcinoma, EAC), gastroesophageal junction cancer (GEJC), cervical cancer, breast cancer and ovarian cancer.

21. The compound - or pharmaceutically acceptable salt thereof - for use according to any one of claims 18 to 20, wherein the cancer comprises tumor cells harbouring a KRAS mutation or an amplification of KRAS wildtype.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipient(s).

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